Association of diabetes and PNPLA3 genetic variants with disease severity of patients with chronic hepatitis C virus infection.
BACKGROUND & AIMS
Genetic variants of patatin-like phospholipase domain-containing 3 (PNPLA3) and diabetes are associated with liver disease severity, in patients with chronic hepatitis C (CHC) infection. We aimed at exploring their interaction in determining hepatitis C virus (HCV)-related liver fibrosis.


METHODS
The PNPLA3 genetic polymorphism at rs738409 was verified in 1077 biopsy-proven CHC patients. Other clinical variables, including diabetes status, were analysed for factors associated with bridging fibrosis.


RESULTS
Patients with advanced liver fibrosis had higher proportions of the GG genotype (14.5% vs. 10.4%, p=0.06 in recessive model) and GG/GC genotype carriage (64.0% vs. 56.8%, p=0.03 in dominant model). Stepwise logistic regression analysis revealed that factors predictive of advanced liver fibrosis included age (odds ratio [OR]: 1.02, 95% confidence intervals [CI]: 1.008-1.037, p=0.002), diabetes (OR: 1.81, CI: 1.236-2.653, p=0.002), α-fetoprotein (OR: 1.006, CI: 1.001-1.01, p=0.01), platelet counts (OR: 1.009, CI: 1.006-1.012, p<0.001), and PNPLA3 rs738409 CG/GG genotype (OR: 1.34, CI: 1.006-1.785, p=0.046). When patients were grouped according to their diabetes status, the PNPLA3 genetic variants were associated with advanced liver fibrosis in diabetic patients only, but not in non-diabetic patients. The PNPLA3 gene was the most important predictive factor of bridging fibrosis in diabetic patients, using the recessive model (OR: 4.53, CI: 1.356-15.106, p=0.014) or the dominant model (OR: 2.20, CI: 1.026-4.734, p=0.04). Compared to non-diabetic patients, patients with the diabetes/GG genotype were more likely to have advanced liver fibrosis (OR: 8.79, CI: 2.889-26.719, p<0.001), followed by those with diabetes/non-GG genotype (OR: 1.55, CI: 1.048-2.286, p=0.03).


CONCLUSIONS
The effect of PNPLA3 genetic variants in HCV-related advanced liver fibrosis was enhanced in diabetic patients. The strong genetic-environmental interaction contributed to the high risk of advanced liver disease in CHC patients.
['Huang|Chung-Feng|CF|', 'Dai|Chia-Yen|CY|', 'Yeh|Ming-Lun|ML|', 'Huang|Ching-I|CI|', 'Tai|Chi-Ming|CM|', 'Hsieh|Meng-Hsuan|MH|', 'Liang|Po-Cheng|PC|', 'Lin|Yi-Hung|YH|', 'Hsieh|Ming-Yen|MY|', 'Yang|Hua-Ling|HL|', 'Huang|Jee-Fu|JF|', 'Lin|Zu-Yau|ZY|', 'Chen|Shinn-Cherng|SC|', 'Yu|Ming-Lung|ML|', 'Chuang|Wan-Long|WL|']
D000328:Adult D000368:Aged D015331:Cohort Studies D048909:Diabetes Complications D005260:Female D005799:Genes, Dominant D005808:Genes, Recessive D056726:Genetic Association Studies D020022:Genetic Predisposition to Disease D014644:Genetic Variation D005838:Genotype D019698:Hepatitis C, Chronic D006801:Humans D008049:Lipase D008103:Liver Cirrhosis D008297:Male D008565:Membrane Proteins D008875:Middle Aged D008957:Models, Genetic D020641:Polymorphism, Single Nucleotide D012189:Retrospective Studies D012307:Risk Factors
PNPLA3 CHC Liver fibrosis DM HCV SNP