Genome-wide association study of sepsis in extremely premature infants.
OBJECTIVE
To identify genetic variants associated with sepsis (early-onset and late-onset) using a genome-wide association (GWA) analysis in a cohort of extremely premature infants.


STUDY DESIGN
Previously generated GWA data from the Neonatal Research Network's anonymised genomic database biorepository of extremely premature infants were used for this study. Sepsis was defined as culture-positive early-onset or late-onset sepsis or culture-proven meningitis. Genomic and whole-genome-amplified DNA was genotyped for 1.2 million single-nucleotide polymorphisms (SNPs); 91% of SNPs were successfully genotyped. We imputed 7.2 million additional SNPs. p Values and false discovery rates (FDRs) were calculated from multivariate logistic regression analysis adjusting for gender, gestational age and ancestry. Target statistical value was p<10-5. Secondary analyses assessed associations of SNPs with pathogen type. Pathway analyses were also run on primary and secondary end points.


RESULTS
Data from 757 extremely premature infants were included: 351 infants with sepsis and 406 infants without sepsis. No SNPs reached genome-wide significance levels (5×10-8); two SNPs in proximity to FOXC2 and FOXL1 genes achieved target levels of significance. In secondary analyses, SNPs for ELMO1, IRAK2 (Gram-positive sepsis), RALA, IMMP2L (Gram-negative sepsis) and PIEZO2 (fungal sepsis) met target significance levels. Pathways associated with sepsis and Gram-negative sepsis included gap junctions, fibroblast growth factor receptors, regulators of cell division and interleukin-1-associated receptor kinase 2 (p values<0.001 and FDR<20%).


CONCLUSIONS
No SNPs met genome-wide significance in this cohort of extremely low birthweight infants; however, areas of potential association and pathways meriting further study were identified.
['Srinivasan|Lakshmi|L|', 'Page|Grier|G|', 'Kirpalani|Haresh|H|', 'Murray|Jeffrey C|JC|', 'Das|Abhik|A|', 'Higgins|Rosemary D|RD|', 'Carlo|Waldemar A|WA|', 'Bell|Edward F|EF|', 'Goldberg|Ronald N|RN|', 'Schibler|Kurt|K|', 'Sood|Beena G|BG|', 'Stevenson|David K|DK|', 'Stoll|Barbara J|BJ|', 'Van Meurs|Krisa P|KP|', 'Johnson|Karen J|KJ|', 'Levy|Joshua|J|', 'McDonald|Scott A|SA|', 'Zaterka-Baxter|Kristin M|KM|', 'Kennedy|Kathleen A|KA|', 'Sánchez|Pablo J|PJ|', 'Duara|Shahnaz|S|', 'Walsh|Michele C|MC|', 'Shankaran|Seetha|S|', 'Wynn|James L|JL|http://orcid.org/0000-0001-7052-4836', 'Cotten|C Michael|CM|', '|||']
D018528:ATP-Binding Cassette Transporters D048868:Adaptor Proteins, Signal Transducing D015331:Cohort Studies D010450:Endopeptidases D005260:Female D051858:Forkhead Transcription Factors D020690:GTPase-Activating Proteins D055106:Genome-Wide Association Study D005838:Genotype D006801:Humans D062071:Infant, Extremely Premature D007231:Infant, Newborn D007473:Ion Channels D008297:Male D008840:Microfilament Proteins D020641:Polymorphism, Single Nucleotide D018805:Sepsis
extreme prematurity Genetics ELBW infection