Iron is an essential nutrient for sustaining life-forms as diverse as plankton and humans. But too much iron, or too little, can spell trouble. Mammalian cells maintain the proper balance partly with the help of a specialized cell surface protein called the transferrin receptor (TfR). TfRs bind to the iron-carrying transferrin protein (Fe-Tf) and escort their cargo to the cell's interior. (To learn more about iron metabolism, see the primer by Tracey A. Rouault in this issue [DOI:  10.3171/journal.pbio.0000079 ].) This receptor also binds the hereditary hemochromatosis protein (HFE), which is mutated in individuals who have the common iron-overload disorder hereditary hemochromatosis. While the molecular pathway that mediates cellular intake of iron through the TfR is known, it was not clear just how TfR assists in iron release to the cell and how it binds HFE and transferrin. By introducing multiple mutations in human TfRs, Pamela Bjorkman and colleagues identified functional binding sites for transferrin in both its iron-loaded and iron-free (apo-Tf) forms and for HFE. From these data, the researchers mapped out a scenario of the dynamic interactions between receptor and ligands (the bound molecule) and worked out a structure-based model for the mechanism of TfR-assisted iron release from Fe-Tf.Bjorkman's lab, which had previously solved the structures of both HFE and HFE bound to the TfR, used their structural information to investigate how the proteins interact, which amino acid residues are required for binding, whether the two ligands bind differently to the receptor, and how HFE binding affects transferrin binding. They found that Fe-Tf and HFE occupy the same or an overlapping site on the receptor, but since transferrin is much larger than the HFE protein, it appeared that transferrin could also interact with other parts of TfR. And it remained to be seen whether TfR discriminated between the iron-loaded and iron-free states of transferrin.In this study, Bjorkman and colleagues expanded their library of TfR mutants to clarify the transferrin binding signature on TfR and to see how the TfR mutations affect the way apo-Tf and Fe-Tf interact with the receptor. They characterized the binding affinities of 30 TfR mutants to HFE and Fe-Tf and to apo-Tf, and they report that mutations in 11 of the TfR residues interfere with either one or both forms of transferrin. Four of these residues are essential for transferrin binding and are conserved in all known TfR DNA sequences. Since residues that didn't have much impact are not conserved, the scientists say the results are likely to describe transferrin–TfR interactions for other species as well.As expected, the most critical residues required for transferrin binding fall within the receptor's helical domain and have significant physical overlap with residues required for HFE binding; though some residues that are required for apo-Tf binding do not affect Fe-Tf binding. Bjorkman et al. also identify additional residues in another domain on TfR (called the protease-like domain) that support Fe-Tf but not apo-Tf binding, confirming that the receptor binding footprints of the two metal-binding states of transferrin are indeed different. With a structural model showing  where  Fe-Tf and apo-Tf bind to the receptor, they could evaluate  how  they bind and thus explain how the receptor mediates iron release.wherehowBy suggesting a mechanism through which TfR binding regulates iron release, this structural model of the transferrin–TfR complex will bolster efforts to elucidate the molecular details of this process. Confirmation that transferrin and HFE do indeed compete for docking privileges reveals a possible role for HFE in maintaining iron homeostasis and will provide valuable insights into the dysregulation that leads to the warehousing of iron and resulting tissue and organ damage associated with hemochromatosis.


Background Recent studies relating to the association between DNA repair-gene polymorphisms and colorectal cancer risk would, to the best of our knowledge, appear to be very limited. This study was designed to examine the polymorphisms associated with three DNA repair genes, namely:  XRCC1  Arg399Gln,  XRCC3  Thr241Met and  XPD  Lys751Gln, and investigate their role as susceptibility markers for colorectal cancer.
Background
Recent studies relating to the association between DNA repair-gene polymorphisms and colorectal cancer risk would, to the best of our knowledge, appear to be very limited. This study was designed to examine the polymorphisms associated with three DNA repair genes, namely:  XRCC1  Arg399Gln,  XRCC3  Thr241Met and  XPD  Lys751Gln, and investigate their role as susceptibility markers for colorectal cancer.XRCC1XRCC3XPDMethods We conducted a case-control study including 727 cases of cancer and 736 hospital-based age- and sex-matched healthy controls to examine the role of genetic polymorphisms of three DNA-repair genes ( XRCC1 ,  XRCC3  and  XPD ) in the context of colorectal cancer risk for the Taiwanese population. Genomic DNA isolated from 10 ml whole blood was used to genotype  XRCC1  Arg399Gln,  XRCC3  Thr241Met and  XPD  Lys751Gln by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis.
Methods
We conducted a case-control study including 727 cases of cancer and 736 hospital-based age- and sex-matched healthy controls to examine the role of genetic polymorphisms of three DNA-repair genes ( XRCC1 ,  XRCC3  and  XPD ) in the context of colorectal cancer risk for the Taiwanese population. Genomic DNA isolated from 10 ml whole blood was used to genotype  XRCC1  Arg399Gln,  XRCC3  Thr241Met and  XPD  Lys751Gln by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis.XRCC1XRCC3XPDXRCC1XRCC3XPDResults The risk for colorectal cancer did not appear to differ significantly amongst individuals featuring the  XRCC1  399Arg/Arg genotype (OR = 1.18; 95% CI, 0.96–1.45), the  XRCC3  241Thr/Thr genotype (OR = 1.25; 95% CI, 0.88–1.79) or the  XPD  751Gln allele (OR = 1.20; 95% CI, 0.90–1.61), although individuals featuring a greater number of risk genotypes (genotype with OR greater than 1) did experience a higher risk for colorectal cancer when compared to those who didn't feature any risk genotypes (Trend test  P  = 0.03). Compared with those individuals who didn't express any putative risk genotypes, individuals featuring all of the putative risk genotypes did experience a significantly greater cancer risk (OR = 2.43, 95% CI = 1.21–4.90), particularly for individuals suffering tumors located in the rectum (OR = 3.18, 95% CI = 1.29–7.82) and diagnosed prior to the age of 60 years (OR = 4.90, 95% CI = 1.72–14.0).
Results
The risk for colorectal cancer did not appear to differ significantly amongst individuals featuring the  XRCC1  399Arg/Arg genotype (OR = 1.18; 95% CI, 0.96–1.45), the  XRCC3  241Thr/Thr genotype (OR = 1.25; 95% CI, 0.88–1.79) or the  XPD  751Gln allele (OR = 1.20; 95% CI, 0.90–1.61), although individuals featuring a greater number of risk genotypes (genotype with OR greater than 1) did experience a higher risk for colorectal cancer when compared to those who didn't feature any risk genotypes (Trend test  P  = 0.03). Compared with those individuals who didn't express any putative risk genotypes, individuals featuring all of the putative risk genotypes did experience a significantly greater cancer risk (OR = 2.43, 95% CI = 1.21–4.90), particularly for individuals suffering tumors located in the rectum (OR = 3.18, 95% CI = 1.29–7.82) and diagnosed prior to the age of 60 years (OR = 4.90, 95% CI = 1.72–14.0).XRCC1XRCC3XPDPConclusions Our results suggest that DNA-repair pathways may simultaneously modulate the risk of colorectal cancer for the Taiwanese population, and, particularly for rectal cancer and younger patients.
Conclusions
Our results suggest that DNA-repair pathways may simultaneously modulate the risk of colorectal cancer for the Taiwanese population, and, particularly for rectal cancer and younger patients.

Background Humans are routinely exposed to mutagenic and carcinogenic aromatic amines via smoking, well-cooked food and other sources [ 1 ]. These chemicals can form DNA adducts  in vivo  and thus lead to DNA damage [ 2 ]. The integrity of most of the so-damaged DNAs is typically restored as a consequence of the action of certain DNA-repairing enzymes, the normal function of which is important for maintaining genomic integrity and preventing cellular neoplastic transformation [ 3 ]. Since the genetic polymorphisms of DNA-repair enzymes might be able to influence DNA adduct levels [ 4 - 6 ], the particular degree of DNA-repair capacity has often been associated with the risk of human cancers [ 7 - 11 ]. Amongst the known genetic polymorphisms of the DNA-repair genes [ 12 ], the xeroderma pigmentosum group D (XPD, also known as ERCC2) and x-ray repair cross-complementing groups 1 and 3 (XRCC1 and XRCC3) have been studied most commonly [ 13 ]. The  XPD  gene encodes a helicase that is a component of the transcription factor TFIIH [ 14 ], this factor being an essential member of the nucleotide-excision repair (NER) pathway that is responsible for effecting repairs to bulky adducts and UV-induced DNA damage [ 15 ]. In 2002, Qiao et al. [ 16 ] reported that individuals featuring  XPD  751Gln/Gln did demonstrate suboptimal DNA-repair capacity (DRC) in regard to its ability to remove UV photoproducts when compared to the  XPD  751Lys/Lys and Lys/Gln genotypes. The XRCC1 protein is a scaffolding protein directly associated with polymerase beta, DNA ligase III and poly (ADP-ribose) polymerase (PARP) and functions in a complex to facilitate the base-excision repair (BER) and single-strand break-repair processes [ 17 - 19 ]. In 1999, Lunn et al. noted that individuals harboring the  XRCC1  399Gln allele were associated, more significantly, with higher levels of both aflatoxin B1-DNA adducts and glycophorin A variants when compared to individuals who exhibited the Arg/Arg genotype [ 4 ]. XRCC3 participates in DNA double-strand break repair and is a member of an emerging family of Rad-51-related proteins that likely participate in homologous recombinational repair (HRR) in order to maintain chromosome stability [ 20 ]. To the best of our knowledge, studies pertaining to these DNA-repair genes focusing on colorectal cancer risk would appear to be limited and controversial. In 2000, Abdel-Rahman et al. [ 21 ] observed that the  XRCC1  399Gln allele, compared to the  XRCC1  399Arg/Arg genotype, was associated with an increased risk for developing colorectal cancer, especially amongst young urban residents, although in 2003, Mort et al. [ 22 ] failed to reveal any significant associations between colorectal cancer risk and any polymorphisms of four of the NER genes ( XPD ,  XPF ,  XPG ,  ERCC1 ) or  XRCC1 . In the present paper, we conducted a hospital-based case-controlled study to examine the role of genetic polymorphisms of three DNA-repair genes ( XRCC1 ,  XRCC3  and  XPD ) in the context of colorectal cancer risk for the Taiwanese population.
Background
Humans are routinely exposed to mutagenic and carcinogenic aromatic amines via smoking, well-cooked food and other sources [ 1 ]. These chemicals can form DNA adducts  in vivo  and thus lead to DNA damage [ 2 ]. The integrity of most of the so-damaged DNAs is typically restored as a consequence of the action of certain DNA-repairing enzymes, the normal function of which is important for maintaining genomic integrity and preventing cellular neoplastic transformation [ 3 ]. Since the genetic polymorphisms of DNA-repair enzymes might be able to influence DNA adduct levels [ 4 - 6 ], the particular degree of DNA-repair capacity has often been associated with the risk of human cancers [ 7 - 11 ].in vivoAmongst the known genetic polymorphisms of the DNA-repair genes [ 12 ], the xeroderma pigmentosum group D (XPD, also known as ERCC2) and x-ray repair cross-complementing groups 1 and 3 (XRCC1 and XRCC3) have been studied most commonly [ 13 ]. The  XPD  gene encodes a helicase that is a component of the transcription factor TFIIH [ 14 ], this factor being an essential member of the nucleotide-excision repair (NER) pathway that is responsible for effecting repairs to bulky adducts and UV-induced DNA damage [ 15 ]. In 2002, Qiao et al. [ 16 ] reported that individuals featuring  XPD  751Gln/Gln did demonstrate suboptimal DNA-repair capacity (DRC) in regard to its ability to remove UV photoproducts when compared to the  XPD  751Lys/Lys and Lys/Gln genotypes. The XRCC1 protein is a scaffolding protein directly associated with polymerase beta, DNA ligase III and poly (ADP-ribose) polymerase (PARP) and functions in a complex to facilitate the base-excision repair (BER) and single-strand break-repair processes [ 17 - 19 ]. In 1999, Lunn et al. noted that individuals harboring the  XRCC1  399Gln allele were associated, more significantly, with higher levels of both aflatoxin B1-DNA adducts and glycophorin A variants when compared to individuals who exhibited the Arg/Arg genotype [ 4 ]. XRCC3 participates in DNA double-strand break repair and is a member of an emerging family of Rad-51-related proteins that likely participate in homologous recombinational repair (HRR) in order to maintain chromosome stability [ 20 ].XPDXPDXPDXRCC1To the best of our knowledge, studies pertaining to these DNA-repair genes focusing on colorectal cancer risk would appear to be limited and controversial. In 2000, Abdel-Rahman et al. [ 21 ] observed that the  XRCC1  399Gln allele, compared to the  XRCC1  399Arg/Arg genotype, was associated with an increased risk for developing colorectal cancer, especially amongst young urban residents, although in 2003, Mort et al. [ 22 ] failed to reveal any significant associations between colorectal cancer risk and any polymorphisms of four of the NER genes ( XPD ,  XPF ,  XPG ,  ERCC1 ) or  XRCC1 . In the present paper, we conducted a hospital-based case-controlled study to examine the role of genetic polymorphisms of three DNA-repair genes ( XRCC1 ,  XRCC3  and  XPD ) in the context of colorectal cancer risk for the Taiwanese population.XRCC1XRCC1XPDXPFXPGERCC1XRCC1XRCC1XRCC3XPDMethods Subjects Detailed descriptions of the specific characteristics of the study participants have been published previously [ 23 ]. In brief, participants were recruited from the Chang Gung Memorial Hospital between January 1995 and January 1999 inclusively. The colorectal adenocarcinoma cancer cases ( n  = 776) participating in this study were newly diagnosed and histologically confirmed. Patients suffering from familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, or inflammatory bowel disease and other related malignancies were excluded from study participation. Seven hundred and twenty-seven of the original 776 cases (94%) were finally included in this study. Seven hundred and forty-seven age (same age) and sex-matched controls were recruited from the Physical Check-Up Department during the same period. All the participating controls had received comprehensive health examinations including colonoscopies. After excluding individuals diagnosed with other colorectal diseases, a history of other cancers or the existence of a family history of colorectal cancer, 736 controls (98%, 736/747) were finally included in this study. With informed consent, the socio-demographic characteristics of study participants were ascertained by means of the application of a structured questionnaire, at which time 10 ml of venous blood was collected. Genotyping Genomic DNA isolated from 10 ml whole blood was used to genotype  XRCC1  Arg399Gln,  XRCC3  Thr241Met and  XPD  Lys751Gln by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. All of the PCR reactions were carried out by a Mastercycler gradient thermocycler (Eppendorf, Hamburg, Germany) in a final volume of 25 ul containing 200 ng of each primer, 50 ng genomic DNA, 1.5 mM MgCl 2 , 200 ul dNTPs and 1.0 unit of Taq DNA Polymerase in the buffer provided by the manufacturer. In addition, all laboratory genotyping personnel were blind to the case-control status of the samples. The 615 bp  XRCC1  PCR products were amplified with the primers 5'-TTGTGCTTTCTCTGTGTCCA-3' (sense) and 5'-TCCTCCAGCCTTTTCTGATA-3' (antisense) and digested with  Msp I (New England BioLabs, Beverly, MA, USA). The Arg allele revealed 374 and 221 bp fragments following digestion and polyacrylamide gel electrophoresis, whilst the Gln allele was not digested by  Msp I [ 4 ]. The 136 bp  XRCC3  PCR products were amplified with the primers 5'-GCCTGGTGGTCATCGACTC-3' (sense) and 5'-ACAGGGCTCTGGAAGGCACTGCTCAGCTCACGCACC-3' (antisense) and digested with  Nco I (New England BioLabs). The Met allele revealed 97 and 39 bp fragments following digestion and polyacrylamide gel electrophoresis, while the Thr allele was not digested by  Nco I [ 24 ]. The 734 bp  XPD  PCR products were amplified with the primers 5'-CCTCTCCCTTTCCTCTGTTC-3' (sense) and 5'-CAGGTGAGGGGGACATCT-3' (antisense) and digested with  Pst I (Takara, Japan). The Gln allele revealed 646 and 88 bp fragments following digestion and polyacrylamide gel electrophoresis, whilst the Lys allele was not able to be digested by  Pst I [ 25 ]. Statistical analysis Tests for Hardy-Weinberg equilibrium amongst controls were conducted using observed genotype frequencies and a chi-square test featuring one degree of freedom. Baseline sociodemographic characteristics between cases and controls were analyzed using the chi-square test and two-sample Students'  t -test. Multivariate unconditional logistic regressions were used to examine the association between the  XRCC1 ,  XRCC3  and  XPD  genotypes and the risk for colorectal cancer. Since the differences in the estimated risks between conditional logistical regression and unconditional logistical regression were small, unconditional logistical regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) with the matching factors (age and gender) included in the model for estimation [ 26 ]. Other potential confounders (such as physical activity, cigarette smoking, alcohol use, coffee intake, and consumption of staple, meat, vegetable/fruit and fish/shrimp) would be also included if they have >10% effect on the gene main effects. However, none of these factors have met the inclusion criteria. Based on the multiplicative scale, the likelihood ratio test was further used to evaluate the interaction between  XRCC1 ,  XRCC3  and  XPD  genes on the risk for the colorectal cancer. Since the associations between polymorphisms of DNA-repair gene, cancer susceptibility and DNA repair capacity are inconsistent [ 13 ], we defined the risk allele as the allele with OR>1 observed in the present study. Stratified analyses were also conducted to evaluate the differences between specific tumor sites (colon and rectum) and age groups (< = 60 years old and > 60 years old). All analyses were performed using the SAS statistical package (version 8.1 for windows; SAS Institute, Inc., Cary, NC, USA) and all tests were two-sided.
Methods
Subjects Detailed descriptions of the specific characteristics of the study participants have been published previously [ 23 ]. In brief, participants were recruited from the Chang Gung Memorial Hospital between January 1995 and January 1999 inclusively. The colorectal adenocarcinoma cancer cases ( n  = 776) participating in this study were newly diagnosed and histologically confirmed. Patients suffering from familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, or inflammatory bowel disease and other related malignancies were excluded from study participation. Seven hundred and twenty-seven of the original 776 cases (94%) were finally included in this study. Seven hundred and forty-seven age (same age) and sex-matched controls were recruited from the Physical Check-Up Department during the same period. All the participating controls had received comprehensive health examinations including colonoscopies. After excluding individuals diagnosed with other colorectal diseases, a history of other cancers or the existence of a family history of colorectal cancer, 736 controls (98%, 736/747) were finally included in this study. With informed consent, the socio-demographic characteristics of study participants were ascertained by means of the application of a structured questionnaire, at which time 10 ml of venous blood was collected.
Subjects
Detailed descriptions of the specific characteristics of the study participants have been published previously [ 23 ]. In brief, participants were recruited from the Chang Gung Memorial Hospital between January 1995 and January 1999 inclusively. The colorectal adenocarcinoma cancer cases ( n  = 776) participating in this study were newly diagnosed and histologically confirmed. Patients suffering from familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, or inflammatory bowel disease and other related malignancies were excluded from study participation. Seven hundred and twenty-seven of the original 776 cases (94%) were finally included in this study. Seven hundred and forty-seven age (same age) and sex-matched controls were recruited from the Physical Check-Up Department during the same period. All the participating controls had received comprehensive health examinations including colonoscopies. After excluding individuals diagnosed with other colorectal diseases, a history of other cancers or the existence of a family history of colorectal cancer, 736 controls (98%, 736/747) were finally included in this study. With informed consent, the socio-demographic characteristics of study participants were ascertained by means of the application of a structured questionnaire, at which time 10 ml of venous blood was collected.nGenotyping Genomic DNA isolated from 10 ml whole blood was used to genotype  XRCC1  Arg399Gln,  XRCC3  Thr241Met and  XPD  Lys751Gln by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. All of the PCR reactions were carried out by a Mastercycler gradient thermocycler (Eppendorf, Hamburg, Germany) in a final volume of 25 ul containing 200 ng of each primer, 50 ng genomic DNA, 1.5 mM MgCl 2 , 200 ul dNTPs and 1.0 unit of Taq DNA Polymerase in the buffer provided by the manufacturer. In addition, all laboratory genotyping personnel were blind to the case-control status of the samples. The 615 bp  XRCC1  PCR products were amplified with the primers 5'-TTGTGCTTTCTCTGTGTCCA-3' (sense) and 5'-TCCTCCAGCCTTTTCTGATA-3' (antisense) and digested with  Msp I (New England BioLabs, Beverly, MA, USA). The Arg allele revealed 374 and 221 bp fragments following digestion and polyacrylamide gel electrophoresis, whilst the Gln allele was not digested by  Msp I [ 4 ]. The 136 bp  XRCC3  PCR products were amplified with the primers 5'-GCCTGGTGGTCATCGACTC-3' (sense) and 5'-ACAGGGCTCTGGAAGGCACTGCTCAGCTCACGCACC-3' (antisense) and digested with  Nco I (New England BioLabs). The Met allele revealed 97 and 39 bp fragments following digestion and polyacrylamide gel electrophoresis, while the Thr allele was not digested by  Nco I [ 24 ]. The 734 bp  XPD  PCR products were amplified with the primers 5'-CCTCTCCCTTTCCTCTGTTC-3' (sense) and 5'-CAGGTGAGGGGGACATCT-3' (antisense) and digested with  Pst I (Takara, Japan). The Gln allele revealed 646 and 88 bp fragments following digestion and polyacrylamide gel electrophoresis, whilst the Lys allele was not able to be digested by  Pst I [ 25 ].
Genotyping
Genomic DNA isolated from 10 ml whole blood was used to genotype  XRCC1  Arg399Gln,  XRCC3  Thr241Met and  XPD  Lys751Gln by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. All of the PCR reactions were carried out by a Mastercycler gradient thermocycler (Eppendorf, Hamburg, Germany) in a final volume of 25 ul containing 200 ng of each primer, 50 ng genomic DNA, 1.5 mM MgCl 2 , 200 ul dNTPs and 1.0 unit of Taq DNA Polymerase in the buffer provided by the manufacturer. In addition, all laboratory genotyping personnel were blind to the case-control status of the samples.XRCC1XRCC3XPDThe 615 bp  XRCC1  PCR products were amplified with the primers 5'-TTGTGCTTTCTCTGTGTCCA-3' (sense) and 5'-TCCTCCAGCCTTTTCTGATA-3' (antisense) and digested with  Msp I (New England BioLabs, Beverly, MA, USA). The Arg allele revealed 374 and 221 bp fragments following digestion and polyacrylamide gel electrophoresis, whilst the Gln allele was not digested by  Msp I [ 4 ]. The 136 bp  XRCC3  PCR products were amplified with the primers 5'-GCCTGGTGGTCATCGACTC-3' (sense) and 5'-ACAGGGCTCTGGAAGGCACTGCTCAGCTCACGCACC-3' (antisense) and digested with  Nco I (New England BioLabs). The Met allele revealed 97 and 39 bp fragments following digestion and polyacrylamide gel electrophoresis, while the Thr allele was not digested by  Nco I [ 24 ]. The 734 bp  XPD  PCR products were amplified with the primers 5'-CCTCTCCCTTTCCTCTGTTC-3' (sense) and 5'-CAGGTGAGGGGGACATCT-3' (antisense) and digested with  Pst I (Takara, Japan). The Gln allele revealed 646 and 88 bp fragments following digestion and polyacrylamide gel electrophoresis, whilst the Lys allele was not able to be digested by  Pst I [ 25 ].XRCC1MspMspXRCC3NcoNcoXPDPstPstStatistical analysis Tests for Hardy-Weinberg equilibrium amongst controls were conducted using observed genotype frequencies and a chi-square test featuring one degree of freedom. Baseline sociodemographic characteristics between cases and controls were analyzed using the chi-square test and two-sample Students'  t -test. Multivariate unconditional logistic regressions were used to examine the association between the  XRCC1 ,  XRCC3  and  XPD  genotypes and the risk for colorectal cancer. Since the differences in the estimated risks between conditional logistical regression and unconditional logistical regression were small, unconditional logistical regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) with the matching factors (age and gender) included in the model for estimation [ 26 ]. Other potential confounders (such as physical activity, cigarette smoking, alcohol use, coffee intake, and consumption of staple, meat, vegetable/fruit and fish/shrimp) would be also included if they have >10% effect on the gene main effects. However, none of these factors have met the inclusion criteria. Based on the multiplicative scale, the likelihood ratio test was further used to evaluate the interaction between  XRCC1 ,  XRCC3  and  XPD  genes on the risk for the colorectal cancer. Since the associations between polymorphisms of DNA-repair gene, cancer susceptibility and DNA repair capacity are inconsistent [ 13 ], we defined the risk allele as the allele with OR>1 observed in the present study. Stratified analyses were also conducted to evaluate the differences between specific tumor sites (colon and rectum) and age groups (< = 60 years old and > 60 years old). All analyses were performed using the SAS statistical package (version 8.1 for windows; SAS Institute, Inc., Cary, NC, USA) and all tests were two-sided.
Statistical analysis
Tests for Hardy-Weinberg equilibrium amongst controls were conducted using observed genotype frequencies and a chi-square test featuring one degree of freedom. Baseline sociodemographic characteristics between cases and controls were analyzed using the chi-square test and two-sample Students'  t -test. Multivariate unconditional logistic regressions were used to examine the association between the  XRCC1 ,  XRCC3  and  XPD  genotypes and the risk for colorectal cancer. Since the differences in the estimated risks between conditional logistical regression and unconditional logistical regression were small, unconditional logistical regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) with the matching factors (age and gender) included in the model for estimation [ 26 ]. Other potential confounders (such as physical activity, cigarette smoking, alcohol use, coffee intake, and consumption of staple, meat, vegetable/fruit and fish/shrimp) would be also included if they have >10% effect on the gene main effects. However, none of these factors have met the inclusion criteria.tXRCC1XRCC3XPDBased on the multiplicative scale, the likelihood ratio test was further used to evaluate the interaction between  XRCC1 ,  XRCC3  and  XPD  genes on the risk for the colorectal cancer. Since the associations between polymorphisms of DNA-repair gene, cancer susceptibility and DNA repair capacity are inconsistent [ 13 ], we defined the risk allele as the allele with OR>1 observed in the present study. Stratified analyses were also conducted to evaluate the differences between specific tumor sites (colon and rectum) and age groups (< = 60 years old and > 60 years old). All analyses were performed using the SAS statistical package (version 8.1 for windows; SAS Institute, Inc., Cary, NC, USA) and all tests were two-sided.XRCC1XRCC3XPDResults More men (56%) than women participated in this study (Table  1 ). The mean age for both groups was 60 years. From the cancer cases, 352 patients suffered from colon cancer (48%) and 375 patients from rectal cancer (52%), with most such cases being deemed to be at stage II or stage III (both were 33%). Detailed analyses of the sociodemographic characteristics and potential risk factors associated with colorectal cancer amongst the study population have been published previously [ 23 ]. The genotypic distributions of the three DNA-repair genes for both cancer cases and controls are shown in Table  2 . The frequencies for the  XRCC1  399Gln,  XRCC3  241Met and  XPD  751Gln allele amongst the controls were, respectively, 0.27, 0.05 and 0.07, these genotype frequencies being in Hardy-Weinberg equilibrium. Due to the relatively low frequencies of variant alleles for these genes in the present study, any genotype featuring one or more variant alleles was combined for further analyses. The risk for colorectal cancer was not significantly different for individuals featuring the  XRCC1  399Arg/Arg genotype (OR = 1.18; 95% CI, 0.96–1.45), the  XRCC3  241Thr/Thr genotype (OR = 1.25; 95% CI, 0.88–1.79) or the  XPD  751Gln allele (OR = 1.20; 95% CI, 0.90–1.61). As revealed in Table  3 , those individuals exhibiting a greater number of risk genotypes (genotype with OR greater than 1) faced a greater risk for colorectal cancer when compared to those individuals who did not display any risk genotypes (Trend test,  P  = 0.03). Subjects who demonstrated two or three of the putative risk genotypes did reveal a significantly greater risk for colorectal cancer (OR = 1.95; 95% CI, 1.08–3.52 and OR = 2.43; 95% CI, 1.21–4.90, respectively) as compared to those individuals who did not feature any putative risk genotypes, although it appears that no gene-gene interactions arose amongst these three genes (all  P  levels for interaction were >0.21). When stratified by tumor site and age at diagnosis, these combined gene effects upon cancer risk were observed for individuals who revealed that their tumor was located in the rectum (Trend test  P  = 0.03) and those individuals for whom their tumor was diagnosed prior to their being 60 years of age (Trend test  P  = 0.004; Table  4 ). The ORs for subjects with three putative risk genotypes were 3.18 (95% CI, 1.29–7.82) for rectal cancer and 4.90 (95% CI, 1.72–14.0) for those individuals diagnosed prior to 60 years of age, respectively.
Results
More men (56%) than women participated in this study (Table  1 ). The mean age for both groups was 60 years. From the cancer cases, 352 patients suffered from colon cancer (48%) and 375 patients from rectal cancer (52%), with most such cases being deemed to be at stage II or stage III (both were 33%). Detailed analyses of the sociodemographic characteristics and potential risk factors associated with colorectal cancer amongst the study population have been published previously [ 23 ].The genotypic distributions of the three DNA-repair genes for both cancer cases and controls are shown in Table  2 . The frequencies for the  XRCC1  399Gln,  XRCC3  241Met and  XPD  751Gln allele amongst the controls were, respectively, 0.27, 0.05 and 0.07, these genotype frequencies being in Hardy-Weinberg equilibrium. Due to the relatively low frequencies of variant alleles for these genes in the present study, any genotype featuring one or more variant alleles was combined for further analyses. The risk for colorectal cancer was not significantly different for individuals featuring the  XRCC1  399Arg/Arg genotype (OR = 1.18; 95% CI, 0.96–1.45), the  XRCC3  241Thr/Thr genotype (OR = 1.25; 95% CI, 0.88–1.79) or the  XPD  751Gln allele (OR = 1.20; 95% CI, 0.90–1.61).XRCC1XRCC3XPDXRCC1XRCC3XPDAs revealed in Table  3 , those individuals exhibiting a greater number of risk genotypes (genotype with OR greater than 1) faced a greater risk for colorectal cancer when compared to those individuals who did not display any risk genotypes (Trend test,  P  = 0.03). Subjects who demonstrated two or three of the putative risk genotypes did reveal a significantly greater risk for colorectal cancer (OR = 1.95; 95% CI, 1.08–3.52 and OR = 2.43; 95% CI, 1.21–4.90, respectively) as compared to those individuals who did not feature any putative risk genotypes, although it appears that no gene-gene interactions arose amongst these three genes (all  P  levels for interaction were >0.21). When stratified by tumor site and age at diagnosis, these combined gene effects upon cancer risk were observed for individuals who revealed that their tumor was located in the rectum (Trend test  P  = 0.03) and those individuals for whom their tumor was diagnosed prior to their being 60 years of age (Trend test  P  = 0.004; Table  4 ). The ORs for subjects with three putative risk genotypes were 3.18 (95% CI, 1.29–7.82) for rectal cancer and 4.90 (95% CI, 1.72–14.0) for those individuals diagnosed prior to 60 years of age, respectively.PPPPDiscussion To the best of our knowledge, few studies have investigated the role of polymorphisms in DNA-repair genes for patients suffering colorectal cancer [ 21 , 22 ]. In this hospital-based case-control study of colorectal cancer-suffering patients in Taiwan, we found polymorphisms in three DNA-repair genes associated with an elevated risk of colorectal cancer. In addition, a gene-dosage effect was found for rectal cancer and younger patients. These findings suggest that those genes involved in different DNA-repair pathways may act simultaneously in the process of carcinogenesis for colorectal cancer. Although we didn't find any significant independent associations between these DNA-repair genes and colorectal cancer risk, the risk appeared to be slightly increased for individuals who featured the  XRCC1  399Arg/Arg,  XRCC3  241Thr/Thr genotypes and the  XPD  751Gln allele. Our results do not appear to be entirely consistent with the results of some previous reports [ 21 , 22 ], the former group reporting that the  XRCC1  399Gln allele significantly increased the risk of colorectal cancer (OR = 3.98, 95% CI = 1.50–10.6). In 2003, Mort et al. [ 22 ] noted that the risk of suffering colorectal cancer was significantly heightened for individuals who featured the  XRCC3  241Thr allele (OR = 1.52, 95% CI = 1.04–2.22) and only slightly increased for those individuals who revealed the  XRCC1  399Gln and  XPD  751Gln alleles. In 2001, Park et al. [ 27 ] reported that advanced colorectal cancer-suffering patients who revealed the  XPD  751Gln/Gln genotype featured a poorer (positive) response rate to chemotherapy and also a shorter survival period compared with colorectal cancer-suffering individuals who belonged to either the 751Lys/Lys or the 751Lys/Gln group. The apparent divergence between these studies and ours might be due to one of two reasons. Firstly, it may simply be that ethnic differences in allele frequency for the polymorphism might explain the controversial findings. The frequencies for the  XRCC1  399Gln,  XRCC3  241Met and  XPD  751Gln alleles amongst the healthy controls in this study (0.27, 0.05 and 0.07, respectively) were similar to the results for other studies conducted in Taiwan [ 28 , 29 ] and China [ 30 , 31 ], but appeared to be much lower than those reported in 2003 by Mort et al. [ 22 ] (0.42 for  XRCC1  399Gln, 0.45 for  XRCC3  241Met and 0.36 for  XPD  751Gln) for a British population. On the other hand, the  XRCC1  399Gln allele frequency observed in the present study is greater than that observed by Abdel-Rahman et al. in 2000 (0.14 for  XRCC1  399Gln) [ 21 ]. Abdel-Rahman et al. also found that urban residents have 9.97-fold increased risk of early-onset colorectal carcinoma than rural residents with the  XRCC1  399Gln allele [ 21 ]. Therefore, it is possible that the divergence in results from different studies might be related to different levels of carcinogen exposure for different populations. Moreover, inadequate study design such as a too-small sample size and/or the inadequate controlling for certain confounders (such as age and gender) should also be considered as constituting the underpinning for such differing results. Combined effects of polymorphisms of the  XRCC1  Arg399Gln,  XRCC3  Thr241Met and  XPD  Lys751Gln genes in regard to colorectal cancer risk were observed in the present study. With the complexity of detail of environmental exposures to various carcinogens, it is plausible that the effective repair of DNA damaged by chemical mixtures necessitates multiple DNA-repair pathways (including BER, HRR and NER pathways). The failure of, or the presence of deficient DNA repair capacity for each specific DNA-repair pathway may contribute to an increase in cancer risk. Additive or multiplicative effects of combined genetic variants for different DNA-repair pathways have been previously reported for lung cancer [ 32 ], melanoma [ 33 ] and breast cancer [ 34 ]. In 2003, Zhou et al. [ 35 ] found that the risk of lung cancer amongst nonsmokers increased progressively with the increase in the number of high-risk alleles of  XRCC1  and  XPD  genes. Hu et al. [ 36 ] also observed that prolonged cell-cycle delay was significantly associated with the number of variant alleles of the  APE1  and  XRCC1  genes that were present. It would therefore appear reasonable to hypothesize that genetic polymorphism(s) for DNA-repair genes may simultaneously contribute to colorectal cancer susceptibility. In this study, we found that the combined effect of multiple DNA-repair genes upon colorectal cancer risk was significant for our younger age group, but not so for the older age group. This finding appears to be similar to the results of most of the previous studies pertaining to colorectal cancer [ 21 ], basal-cell carcinoma [ 37 ], head-and-neck cancer [ 38 ], hepatocellular carcinoma [ 39 ], and lung cancer [ 6 , 32 , 35 , 40 ] that we reviewed, although we did note that one study reported that such an elevated risk was also observed for old-aged head-and-neck cancer patients [ 41 ]. In addition, few studies that we reviewed failed to find a difference between age groups in regard to for cancer risk [ 31 , 42 - 46 ]. In 2000, Duell et al. [ 47 ] noted that old healthy subjects who featured the  XRCC1  399Gln allele appeared to be significantly associated with detectable DNA adducts in their blood mononuclear cells when compared to younger subjects who featured the 399Arg/Arg genotype. In 2001, Hemminki et al. [ 48 ] also found that old subjects who revealed the  XPD  751Gln/Gln genotype exhibited a decreased DNA-repair rate for, specifically, UV-specific cyclobutane pyrimidine dimers in the skin. Therefore, it is possible that individuals who demonstrate a less-efficient DNA-repair capacity might develop tumors at a younger age than individuals who reveal an efficient DNA-repair capacity. In our study, we also found that the combined genetic effect of these three DNA-repair genes in regard to cancer risk was more pronounced for the rectum than for the colon. This difference may reflect certain etiological differences between colon and rectal carcinogenesis. In fact, different epidemiological characteristics, etiology, pathogenesis and clinical behavior have been reported for different anatomical sites of colorectal cancer [ 49 , 50 ], this latter group suggesting that carcinogenesis within the distal colon was associated with bulky-adduct-forming (BAF) agents and that these DNA lesions were repaired through NER pathways. In 2001, Hong et al. [ 51 ] also found that much more DNA-repair and apoptosis activity occurred in the distal rather than the proximal colon for the rat azoxymethane carcinogenesis model. Taken together, these observations support the notion that insufficient DNA-repair capacity could contribute to the risk of cancer associated with exogenous carcinogen exposure. To the best of our knowledge, this study is the first to report on  XRCC1 ,  XRCC3  and  XPD  polymorphisms in relation to the risk of colorectal cancer for the Taiwanese population. Our results suggest that genetic polymorphisms of the  XRCC1 ,  XRCC3  and  XPD  genes, particularly in combination, may be associated with an individual's susceptibility to colorectal cancer. Acknowledging the relatively limited sample size in the subgroups for the low allelic frequencies, further studies incorporating a larger sample size and/or another ethnic population are needed to confirm the genetic role of DNA-repair mechanisms as regards colorectal cancer susceptibility.
Discussion
To the best of our knowledge, few studies have investigated the role of polymorphisms in DNA-repair genes for patients suffering colorectal cancer [ 21 , 22 ]. In this hospital-based case-control study of colorectal cancer-suffering patients in Taiwan, we found polymorphisms in three DNA-repair genes associated with an elevated risk of colorectal cancer. In addition, a gene-dosage effect was found for rectal cancer and younger patients. These findings suggest that those genes involved in different DNA-repair pathways may act simultaneously in the process of carcinogenesis for colorectal cancer.Although we didn't find any significant independent associations between these DNA-repair genes and colorectal cancer risk, the risk appeared to be slightly increased for individuals who featured the  XRCC1  399Arg/Arg,  XRCC3  241Thr/Thr genotypes and the  XPD  751Gln allele. Our results do not appear to be entirely consistent with the results of some previous reports [ 21 , 22 ], the former group reporting that the  XRCC1  399Gln allele significantly increased the risk of colorectal cancer (OR = 3.98, 95% CI = 1.50–10.6). In 2003, Mort et al. [ 22 ] noted that the risk of suffering colorectal cancer was significantly heightened for individuals who featured the  XRCC3  241Thr allele (OR = 1.52, 95% CI = 1.04–2.22) and only slightly increased for those individuals who revealed the  XRCC1  399Gln and  XPD  751Gln alleles. In 2001, Park et al. [ 27 ] reported that advanced colorectal cancer-suffering patients who revealed the  XPD  751Gln/Gln genotype featured a poorer (positive) response rate to chemotherapy and also a shorter survival period compared with colorectal cancer-suffering individuals who belonged to either the 751Lys/Lys or the 751Lys/Gln group.XRCC1XRCC3XPDXRCC1XRCC3XRCC1XPDXPDThe apparent divergence between these studies and ours might be due to one of two reasons. Firstly, it may simply be that ethnic differences in allele frequency for the polymorphism might explain the controversial findings. The frequencies for the  XRCC1  399Gln,  XRCC3  241Met and  XPD  751Gln alleles amongst the healthy controls in this study (0.27, 0.05 and 0.07, respectively) were similar to the results for other studies conducted in Taiwan [ 28 , 29 ] and China [ 30 , 31 ], but appeared to be much lower than those reported in 2003 by Mort et al. [ 22 ] (0.42 for  XRCC1  399Gln, 0.45 for  XRCC3  241Met and 0.36 for  XPD  751Gln) for a British population. On the other hand, the  XRCC1  399Gln allele frequency observed in the present study is greater than that observed by Abdel-Rahman et al. in 2000 (0.14 for  XRCC1  399Gln) [ 21 ]. Abdel-Rahman et al. also found that urban residents have 9.97-fold increased risk of early-onset colorectal carcinoma than rural residents with the  XRCC1  399Gln allele [ 21 ]. Therefore, it is possible that the divergence in results from different studies might be related to different levels of carcinogen exposure for different populations. Moreover, inadequate study design such as a too-small sample size and/or the inadequate controlling for certain confounders (such as age and gender) should also be considered as constituting the underpinning for such differing results.XRCC1XRCC3XPDXRCC1XRCC3XPDXRCC1XRCC1XRCC1Combined effects of polymorphisms of the  XRCC1  Arg399Gln,  XRCC3  Thr241Met and  XPD  Lys751Gln genes in regard to colorectal cancer risk were observed in the present study. With the complexity of detail of environmental exposures to various carcinogens, it is plausible that the effective repair of DNA damaged by chemical mixtures necessitates multiple DNA-repair pathways (including BER, HRR and NER pathways). The failure of, or the presence of deficient DNA repair capacity for each specific DNA-repair pathway may contribute to an increase in cancer risk. Additive or multiplicative effects of combined genetic variants for different DNA-repair pathways have been previously reported for lung cancer [ 32 ], melanoma [ 33 ] and breast cancer [ 34 ]. In 2003, Zhou et al. [ 35 ] found that the risk of lung cancer amongst nonsmokers increased progressively with the increase in the number of high-risk alleles of  XRCC1  and  XPD  genes. Hu et al. [ 36 ] also observed that prolonged cell-cycle delay was significantly associated with the number of variant alleles of the  APE1  and  XRCC1  genes that were present. It would therefore appear reasonable to hypothesize that genetic polymorphism(s) for DNA-repair genes may simultaneously contribute to colorectal cancer susceptibility.XRCC1XRCC3XPDXRCC1XPDAPE1XRCC1In this study, we found that the combined effect of multiple DNA-repair genes upon colorectal cancer risk was significant for our younger age group, but not so for the older age group. This finding appears to be similar to the results of most of the previous studies pertaining to colorectal cancer [ 21 ], basal-cell carcinoma [ 37 ], head-and-neck cancer [ 38 ], hepatocellular carcinoma [ 39 ], and lung cancer [ 6 , 32 , 35 , 40 ] that we reviewed, although we did note that one study reported that such an elevated risk was also observed for old-aged head-and-neck cancer patients [ 41 ]. In addition, few studies that we reviewed failed to find a difference between age groups in regard to for cancer risk [ 31 , 42 - 46 ]. In 2000, Duell et al. [ 47 ] noted that old healthy subjects who featured the  XRCC1  399Gln allele appeared to be significantly associated with detectable DNA adducts in their blood mononuclear cells when compared to younger subjects who featured the 399Arg/Arg genotype. In 2001, Hemminki et al. [ 48 ] also found that old subjects who revealed the  XPD  751Gln/Gln genotype exhibited a decreased DNA-repair rate for, specifically, UV-specific cyclobutane pyrimidine dimers in the skin. Therefore, it is possible that individuals who demonstrate a less-efficient DNA-repair capacity might develop tumors at a younger age than individuals who reveal an efficient DNA-repair capacity.XRCC1XPDIn our study, we also found that the combined genetic effect of these three DNA-repair genes in regard to cancer risk was more pronounced for the rectum than for the colon. This difference may reflect certain etiological differences between colon and rectal carcinogenesis. In fact, different epidemiological characteristics, etiology, pathogenesis and clinical behavior have been reported for different anatomical sites of colorectal cancer [ 49 , 50 ], this latter group suggesting that carcinogenesis within the distal colon was associated with bulky-adduct-forming (BAF) agents and that these DNA lesions were repaired through NER pathways. In 2001, Hong et al. [ 51 ] also found that much more DNA-repair and apoptosis activity occurred in the distal rather than the proximal colon for the rat azoxymethane carcinogenesis model. Taken together, these observations support the notion that insufficient DNA-repair capacity could contribute to the risk of cancer associated with exogenous carcinogen exposure.To the best of our knowledge, this study is the first to report on  XRCC1 ,  XRCC3  and  XPD  polymorphisms in relation to the risk of colorectal cancer for the Taiwanese population. Our results suggest that genetic polymorphisms of the  XRCC1 ,  XRCC3  and  XPD  genes, particularly in combination, may be associated with an individual's susceptibility to colorectal cancer. Acknowledging the relatively limited sample size in the subgroups for the low allelic frequencies, further studies incorporating a larger sample size and/or another ethnic population are needed to confirm the genetic role of DNA-repair mechanisms as regards colorectal cancer susceptibility.XRCC1XRCC3XPDXRCC1XRCC3XPDConclusions Our results suggest that DNA-repair pathways may simultaneously modulate the risk of colorectal cancer for the Taiwanese population, and, particularly for rectal cancer and younger patients.
Conclusions
Our results suggest that DNA-repair pathways may simultaneously modulate the risk of colorectal cancer for the Taiwanese population, and, particularly for rectal cancer and younger patients.Competing interests The author(s) declare that they have no competing interests.
Competing interests
The author(s) declare that they have no competing interests.Authors' contributions CCY carried out the genotyping analysis, performed the statistical analysis and drafted the manuscript. FCS participated in the design of the study. RT and CRCC participated in the design of the study and provided clinical biospecimens. LLH conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.
Authors' contributions
CCY carried out the genotyping analysis, performed the statistical analysis and drafted the manuscript. FCS participated in the design of the study. RT and CRCC participated in the design of the study and provided clinical biospecimens. LLH conceived of the study, and participated in its design and coordination. All authors read and approved the final manuscript.Pre-publication history The pre-publication history for this paper can be accessed here:
Pre-publication history
The pre-publication history for this paper can be accessed here:


Australia and New Zealand Health Policy  is a new journal which aims to promote debate and understanding about contemporary health policy developments in Australia and New Zealand. Although there are other international journals focussing on health policy, there are no Australian or New Zealand journals with this focus.Australia and New Zealand Health PolicyOne of the aims of  Australia and New Zealand Health Policy  is to focus on contemporary critiques and contemporary developments. Accordingly an e-journal format is particularly appropriate.  Australian and New Zealand Health Policy  is an open access journal which means that all articles will be freely and universally accessible online which, amongst other things, means that all articles will be freely and universally accessible online without any barriers to access, which increases their visibility.Australia and New Zealand Health PolicyAustralian and New Zealand Health Policy

Editorial Welcome to  Australia and New Zealand Health Policy  a new journal which aims to promote debate and understanding about contemporary health policy developments in Australia and New Zealand. Health policy is regularly in the media and is a high profile issue at election times. In Australia the health system has been characterised by conflicts over values and policy choices over the decades. So pervasive is this conflict that Sax entitled his 1984 book about health services, "A Strife of Interests" [ 1 ]. Health policy in New Zealand has also had a turbulent time over the past decade [ 2 , 3 ]. Health policy changes in Australia and New Zealand are thus ripe for analysis.  Australia and New Zealand Health Policy  aims to provide a prestigious venue for analysis and critique of health policy in the two countries.
Editorial
Welcome to  Australia and New Zealand Health Policy  a new journal which aims to promote debate and understanding about contemporary health policy developments in Australia and New Zealand. Health policy is regularly in the media and is a high profile issue at election times. In Australia the health system has been characterised by conflicts over values and policy choices over the decades. So pervasive is this conflict that Sax entitled his 1984 book about health services, "A Strife of Interests" [ 1 ]. Health policy in New Zealand has also had a turbulent time over the past decade [ 2 , 3 ]. Health policy changes in Australia and New Zealand are thus ripe for analysis.  Australia and New Zealand Health Policy  aims to provide a prestigious venue for analysis and critique of health policy in the two countries.Australia and New Zealand Health PolicyAustralia and New Zealand Health PolicyWhy a new journal? Although there are other international journals focussing on health policy, there are no Australian or New Zealand journals with this focus. Other related-area local journals are medical, public health or hospital-related. Although the local journals publish occasional policy articles, this area is not their principal interest, nor are they necessarily the journals which policy-oriented academics or policy practitioners scan to keep abreast of developments. The absence of a health policy journal serving Australia and New Zealand has long-term consequences for the development of systematic analysis of and research into health policy. One consequence is that there is no forum where health policy developments are documented and tracked, a lacuna which precludes cumulative analyses of trends.  Australia and New Zealand Health Policy  will address this by publishing annual reviews of policy developments. As one of the aims of  Australia and New Zealand Health Policy  is to focus on contemporary critiques and contemporary developments, an e-journal format is particularly appropriate. Debate will also be stimulated by providing for 'Comment' on published articles, in a way analogous to a letters column. Australia and New Zealand Health Policy  is a peer reviewed journal. In keeping with its policy-applied focus, articles will be refereed by two referees, preferably one with a strong practitioner background, such as currently or recently employed in a policy role in a health authority, and one from an academic background. At least one of the referees will have substantive content knowledge relating to the article. Articles published in  Australia and New Zealand Health Policy  will be listed in PubMed and permanently archived in PubMed Central as well as certain other national archives.
Why a new journal?
Although there are other international journals focussing on health policy, there are no Australian or New Zealand journals with this focus. Other related-area local journals are medical, public health or hospital-related. Although the local journals publish occasional policy articles, this area is not their principal interest, nor are they necessarily the journals which policy-oriented academics or policy practitioners scan to keep abreast of developments.The absence of a health policy journal serving Australia and New Zealand has long-term consequences for the development of systematic analysis of and research into health policy. One consequence is that there is no forum where health policy developments are documented and tracked, a lacuna which precludes cumulative analyses of trends.  Australia and New Zealand Health Policy  will address this by publishing annual reviews of policy developments.Australia and New Zealand Health PolicyAs one of the aims of  Australia and New Zealand Health Policy  is to focus on contemporary critiques and contemporary developments, an e-journal format is particularly appropriate. Debate will also be stimulated by providing for 'Comment' on published articles, in a way analogous to a letters column.Australia and New Zealand Health PolicyAustralia and New Zealand Health Policy  is a peer reviewed journal. In keeping with its policy-applied focus, articles will be refereed by two referees, preferably one with a strong practitioner background, such as currently or recently employed in a policy role in a health authority, and one from an academic background. At least one of the referees will have substantive content knowledge relating to the article. Articles published in  Australia and New Zealand Health Policy  will be listed in PubMed and permanently archived in PubMed Central as well as certain other national archives.Australia and New Zealand Health PolicyAustralia and New Zealand Health PolicyJournal scope Australia and New Zealand Health Policy  contributes to understanding of health policy development and practice with a particular focus on Australia and New Zealand. It welcomes submissions which: • Review and critique contemporary health policy issues; • Identify major trends in health policy and emerging policy issues, including new evidence about the effect of policy changes; • Identify impacts of health services research on new policies; • Identify major public policy and governance trends and their application to health policy; • Analyse contemporary health policy themes which cut across a range of policy areas; • Report on international policy developments and new international comparisons of health policy involving Australia and/or New Zealand; or • Critique contemporary health policy developments.
Journal scope
Australia and New Zealand Health Policy  contributes to understanding of health policy development and practice with a particular focus on Australia and New Zealand. It welcomes submissions which:Australia and New Zealand Health Policy• Review and critique contemporary health policy issues;• Identify major trends in health policy and emerging policy issues, including new evidence about the effect of policy changes;• Identify impacts of health services research on new policies;• Identify major public policy and governance trends and their application to health policy;• Analyse contemporary health policy themes which cut across a range of policy areas;• Report on international policy developments and new international comparisons of health policy involving Australia and/or New Zealand; or• Critique contemporary health policy developments.Open Access Australia and New Zealand Health Policy  is an Open Access journal, which means: • All articles will be freely and universally accessible online without any barriers to access, which increases their visibility. • You and your peers will be free to print out copies of your article, email it to colleagues, and post it on the web because of the  BioMed Central copyright and license agreement . Open access journals are funded by article processing charges rather than journal subscriptions. The costs are therefore borne by the authors, their institutions of from their grants. That is, all access to journals is free to readers via the web (BMC online-only journals). Authors from institutional supporters are exempt from authorship charges. The institutional supporters pay a sliding scale based on the number of staff and postgraduate students in biomedical sciences. Institutional subscription has a number of benefits. In addition to the direct benefits in terms of waived author fees, there are public policy benefits in supporting an open access journal regime such as Biomed Central. Open access journals are one mechanism for putting pressure on regular journal publishers to moderate their price increases. Unfortunately there are no New Zealand institutional subscribers to BioMed Central at present, which means that New Zealand authors will face article processing charges, although no article processing charges will be payable on manuscripts submitted in the first six months following the launch of the journal. Article processing charges are also usually regarded as a legitimate charge against research grants. In the medium term, alternative arrangements, such as institutional support, should be encouraged, although after this time the editor-in-chief will be able to grant a limited number of discretionary processing charge waivers.
Open Access
Australia and New Zealand Health Policy  is an Open Access journal, which means:Australia and New Zealand Health Policy• All articles will be freely and universally accessible online without any barriers to access, which increases their visibility.• You and your peers will be free to print out copies of your article, email it to colleagues, and post it on the web because of the  BioMed Central copyright and license agreement .Open access journals are funded by article processing charges rather than journal subscriptions. The costs are therefore borne by the authors, their institutions of from their grants. That is, all access to journals is free to readers via the web (BMC online-only journals). Authors from institutional supporters are exempt from authorship charges. The institutional supporters pay a sliding scale based on the number of staff and postgraduate students in biomedical sciences.Institutional subscription has a number of benefits. In addition to the direct benefits in terms of waived author fees, there are public policy benefits in supporting an open access journal regime such as Biomed Central. Open access journals are one mechanism for putting pressure on regular journal publishers to moderate their price increases.Unfortunately there are no New Zealand institutional subscribers to BioMed Central at present, which means that New Zealand authors will face article processing charges, although no article processing charges will be payable on manuscripts submitted in the first six months following the launch of the journal. Article processing charges are also usually regarded as a legitimate charge against research grants. In the medium term, alternative arrangements, such as institutional support, should be encouraged, although after this time the editor-in-chief will be able to grant a limited number of discretionary processing charge waivers.The first articles Australia and New Zealand Health Policy  commences its publication program with a series of articles which describe and evaluate health policy developments in Australia in 2003. Responses or commentaries on these articles would be welcome. It is the aim of the Editorial Board to encourage a cluster of articles at the start of each year about health policy developments in Australia and New Zealand in the previous calendar year. Authors who have an interest in reviewing contemporary developments are encouraged to submit manuscripts on these themes early in the New Year so that the articles can contribute in a timely way to health policy debate in the two countries. S.J.Duckett Editor-in-Chief
The first articles
Australia and New Zealand Health Policy  commences its publication program with a series of articles which describe and evaluate health policy developments in Australia in 2003. Responses or commentaries on these articles would be welcome. It is the aim of the Editorial Board to encourage a cluster of articles at the start of each year about health policy developments in Australia and New Zealand in the previous calendar year. Authors who have an interest in reviewing contemporary developments are encouraged to submit manuscripts on these themes early in the New Year so that the articles can contribute in a timely way to health policy debate in the two countries.Australia and New Zealand Health PolicyS.J.DuckettEditor-in-Chief