Interaction of SAMM50-rs738491,PARVB-rs5764455 and PNPLA3-rs738409 Increases Susceptibility to Nonalcoholic Steatohepatitis

Background and Aims:Previous studies have reported that the single nucleotide polymorphisms(SNPs)of SAMM50-rs738491,PARVB-rs5764455 and PNPLA3-rs738409 are associated with nonalcoholic fatty liver disease(NAFLD).However,no studies have examined the effect of interactions between these three genotypes to affect liver disease severity.We assessed the effect of these three SNPs on nonalcoholic steatohepatitis(NASH)and also examined the gene-gene interactions in a Chinese population with biopsy-confirmed NAFLD.Methods:We enrolled 415 consecutive adult individuals with biopsy-proven NAFLD.Multivariable logistic regres-sion analysis was undertaken to test associations between NASH and SNPs in SAMM50-rs738491,PARVB-rs5764455 and PNPLA3-rs738409.Gene-gene interactions were ana-lyzed by performing a generalized multifactor dimensionality reduction(GMDR)analysis.Results:The mean±standard deviation age of these 415 patients was 41.3±12.5 years,and 75.9%were men.Patients with SAMM50-rs738491 TT,PARVB-rs5764455 AA or PNPLA3-rs738409 GG genotypes had a higher risk of NASH,even after adjustment for age,sex and body mass index.GMDR analysis showed that the combination of all three SNPs was the best model for predicting NASH.Additionally,the odds ratio of the haplotype T-A-G for predicting the risk of NASH was nearly three times higher than that of the haplotype G-C-C.Conclusions:NAFLD patients carrying the SAMM50-rs738491 TT,PARVB-rs5764455 AA or PNPLA3-rs738409 GG genotypes are at greater risk of NASH.These three SNPs may synergistically interact to increase susceptibility to NASH.

PNPLA3 rs738409 C>G Variant Influences the Association Between Visceral Fat and Significant Fibrosis in Biopsyproven Nonalcoholic Fatty Liver Disease

Background and Aims:Intra-abdominal visceral fat accumulation and patatin-like phospholipase domain containing 3(PNPLA3)rs738409 G/C gene polymorphism confer a greater susceptibility to nonalcoholic fatty liver disease(NAFLD).We examined whether the relationship between visceral fat accumulation and liver disease severity may be influenced by PNPLA3 rs738409 polymorphism.Methods:The variant of PNPLA3 rs738409 was genotyped within 523 Han individuals with biopsy-confirmed NAFLD.Visceral fat area(VFA)was measured by bioelectrical impedance.Significant liver fibrosis(SF),defined as stage F≥2 on histology,was the outcome measure of interest.Results:The distribution of PNPLA3 genotypes was CC:27.5%,CG:48.2%,and GG:24.3%.Higher VFA was associated with greater risk of having SF(adjusted-odds ratio[OR]:1.03;95%confidence interval[CI]:1.02–1.04,p<0.05),independent of potential confounders.Among subjects with the same VFA level,the risk of SF was greater among carriers of the rs738409 G genotype than among those who did not.Stratified analysis showed that PNPLA3 rs738409 significantly influenced the association between VFA and SF.VFA remained significantly associated with SF only among the rs738409 G-allele carriers(adjusted-OR:1.05;95%CI:1.03–1.08 for the GG group;and adjusted-OR:1.03;95%CI:1.01–1.04 for the GC group).There was a significant interaction between VFA and PNPLA3 rs738409 genotype(Pinteraction=0.004).Conclusions:PNPLA3 rs738409 G allele has a moderate effect on the association between VFA and risk of SF in adult individuals with biopsy-proven NAFLD.Existence of the PNPLA3 rs738409 G allele and VFA interact to increase risk of SF。