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Genetic variants in PNPLA3 and risk of non-alcoholic fatty liver disease in a Han Chinese population.

ABSTRACT: We investigated the possible association between genetic variants in the Patatin like phospholipase-3 (PNPLA3) gene and nonalcoholic fatty liver disease (NAFLD) in a Han Chinese population. We evaluated twelve tagging single-nucleotide polymorphisms (tSNPs) of the PNPLA3 gene in a frequency matched case-control study from Fuzhou city of China (553 cases, 553 controls). In the multivariate logistic regression analysis, the rs738409 GG or GC, and rs139051 TT genotypes were found to be associated with increased risk of NAFLD, and a significant trend of increased risk with increasing numbers of risk genotype was observed in the cumulative effect analysis of these single nucleotide polymorphisms. Furthermore, haplotype association analysis showed that, compared with the most common haplotype, the CAAGAATGCGTG and CGAAGGTGTCCG haplotypes conferred a statistically significant increased risk for NAFLD, while the CGGGAACCCGCG haplotype decreased the risk of NAFLD. Moreover, rs738409 C>G appeared to have a multiplicative joint effect with tea drinking (P<0.005) and an additive joint effect with obesity (Interaction contrast ratio (ICR)?=?2.31, 95% CI: 0.7-8.86), hypertriglyceridemia (ICR?=?3.07, 95% CI: 0.98-5.09) or hypertension (ICR?=?1.74, 95% CI: 0.52-3.12). Our data suggests that PNPLA3 genetic polymorphisms might influence the susceptibility to NAFLD development independently or jointly in Han Chinese.

SUBMITTER: Peng XE

PROVIDER: S-EPMC3511464 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Genetic variants in PNPLA3 and risk of non-alcoholic fatty liver disease in a Han Chinese population.

Peng Xian-E XE Wu Yun-Li YL Lin Shao-Wei SW Lu Qing-Qing QQ Hu Zhi-Jian ZJ Lin Xu X

PloS one 20121130 11

We investigated the possible association between genetic variants in the Patatin like phospholipase-3 (PNPLA3) gene and nonalcoholic fatty liver disease (NAFLD) in a Han Chinese population. We evaluated twelve tagging single-nucleotide polymorphisms (tSNPs) of the PNPLA3 gene in a frequency matched case-control study from Fuzhou city of China (553 cases, 553 controls). In the multivariate logistic regression analysis, the rs738409 GG or GC, and rs139051 TT genotypes were found to be associated w ...[more]

PMID: 23226254

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Project description:ObjectiveSeveral single-nucleotide polymorphisms have been identified to be disadvantageous or protective in regard to disease severity in patients with non-alcoholic fatty liver disease (NAFLD). However, it is unclear, whether including genetic risk factor(s) either alone or combined into risk stratification algorithms for NAFLD actually provides incremental benefit over clinical risk factors.DesignPatients with biopsy-proven NAFLD were genotyped for the PNPLA3-rs738409(minor allele:G), TM6SF2-rs58542926(minor allele:T) and HSD17B13- rs72613567 (minor allele:TA) variants. The NAFLD activity score (NAS) and fibrosis stage (F0-F4) were used to grade and stage all liver biopsy samples. Patients from seven centers throughout Central Europe were considered for the study.Results703 patients were included: NAS ≥ 5:173(24.6%); Fibrosis: F3-4:81(11.5%). PNPLA3 G/G genotype was associated with a NAS ≥ 5(aOR 2.23, p = 0.007) and advanced fibrosis (aOR-3.48, p < 0.001).TM6SF2 T/- was associated with advanced fibrosis (aOR 1.99, p = 0.023). HSD17B13 TA/- was associated with a lower probability of NAS ≥ 5(TA/T: aOR 0.65, p = 0.041, TA/TA: aOR 0.40, p = 0.033). Regarding the predictive capability for NAS ≥ 5, well-known risk factors (age, sex, BMI, diabetes, and ALT; baseline model) had an AUC of 0.758, Addition of PNPLA3(AUC 0.766), HSB17B13(AUC 0.766), and their combination(AUC 0.775), but not of TM6SF2(AUC 0.762), resulted in a higher diagnostic accuracy of the model. Addition of genetic markers for the prediction of advanced fibrosis (baseline model: age, sex, BMI, diabetes: AUC 0.777) resulted in a higher AUC if PNPLA3(AUC 0.789), and TM6SF2(AUC 0.786) but not if HSD17B13(0.777) were added.ConclusionIn biopsy-proven NAFLD, PNPLA3 G/-, TM6SF2 T/- and HSD17B13 TA/- carriage are associated with severity of NAFLD. Incorporating these genetic risk factors into risk stratification models might improve their predictive accuracy for severity of NAFLD and/or advanced fibrosis on liver biopsy.

Project description:BackgroundGenome-wide association studies have shown that rs738491, rs2143571, and rs3761472 in the sorting and assembly machinery component 50 homolog (SAMM50) gene are significantly associated with susceptibility to nonalcoholic fatty liver disease (NAFLD).ObjectivesThe present study evaluated the association between the three genetic variants in the SAMM50 gene and susceptibility to NAFLD in a Chinese Han population.Patients and methodsGenotypes for 3 single nucleotide polymorphisms (SNPs), viz rs738491, rs2143571, and rs3761472, in the SAMM50 gene were determined using an improved multiplex ligation detection reaction technique in 340 B-type ultrasonography-diagnosed NAFLD patients and 452 healthy controls. Meanwhile, serum lipid profiles and liver enzymes were estimated using standard clinical laboratory methods. The SNP-SNP interactions were analyzed by performing multifactor dimensionality reduction (MDR) and generalized multifactor dimensionality reduction (GMDR).ResultsThe genotype and allele frequencies of the SAMM50 polymorphisms between the NAFLD group and the control group were significantly different (all Ps < 0.05). In the multivariate analysis adjusted for gender, age, and body mass index, the carriers of the rs738491 T allele, rs2143571 A allele, and rs3761472 G allele had significantly increased susceptibility to NAFLD (OR, 1.507; 95% CI, 1.035 to 2.195; P = 0.032; OR, 1.761; 95% CI, 1.232 to 2.517; P = 0.002; OR, 1.483; 95% CI, 1.039 to 2.115; P = 0.030, respectively). Moreover, the rs738491 T allele carriers had significantly higher levels of alanine aminotransferase (ALT) (P = 0.017) than did the noncarriers. However, differences in the levels of serum triglyceride (TG) and aspartate aminotransferase (AST) were not statistically significant (P = 0.123; P = 0.107). The Rs2143571 A allele and the rs3761472 G allele were both deeply associated with increased levels of serum TG, ALT, and AST (all Ps < 0.05). Furthermore, the MDR and GMDR showed that a synergistic relationship might exist between rs738491, rs2143571, and rs3761472 in the SAMM50 gene and the pathophysiology and genetics of NAFLD.ConclusionsWe first demonstrated that the rs738491 T allele, rs2143571 A allele, and rs3761472 G allele in the SAMM50 gene created susceptibility to NAFLD in a Chinese Han population. The combination of the three SNPs in the SAMM50 gene may have synergism to predict the predisposition to NAFLD.

Dataset Information

Genetic variants in PNPLA3 and risk of non-alcoholic fatty liver disease in a Han Chinese population.

Publications

Genetic variants in PNPLA3 and risk of non-alcoholic fatty liver disease in a Han Chinese population.

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