Genetic susceptibility to hepatocellular carcinoma in chromosome 22q13.31, findings of a genome‐wide association study

Abstract

Background and Aim: Chronic hepatitis C virus (HCV) infection, long-term alcohol use, cigarette smoking, and obesity are the major risk factors for hepatocellular carcinoma (HCC) in the United States, but the disease risk varies substantially among individuals with these factors, suggesting host susceptibility to and gene-environment interactions in HCC. To address genetic susceptibility to HCC, we conducted a genome-wide association study (GWAS). Methods: Two case-control studies on HCC were conducted in the United States. DNA samples were genotyped using the Illumian microarray chip with over 710 000 single nucleotide polymorphisms (SNPs). We compared these SNPs between 705 HCC cases and 1455 population controls for their associations with HCC and verified our findings in additional studies. Results: In this GWAS, we found that two SNPs were associated with HCC at P < 5E-8 and six SNPs at P < 5E-6 after adjusting for age, sex, and the top three principal components (PCs). Five of the SNPs in chromosome 22q13.31, three in PNPLA3 (rs2281135, rs2896019, and rs4823173) and two in SAMM50 (rs3761472, rs3827385), were replicated in a small US case-control study and a cohort study in Singapore. The associations remained significant after adjusting for body mass index and HCV infection. Meta-analysis of multiple datasets indicated that these SNPs were significantly associated with HCC. Conclusions: SNPs in PNPLA3 and SAMM50 are known risk loci for nonalcoholic fatty liver disease (NAFLD) and are suspected to be associated with HCC. Our GWAS demonstrated the associations of these SNPs with HCC in a US population. Biological mechanisms underlying the relationship remain to be elucidated.

Risk factors and diagnostic biomarkers for nonalcoholic fatty liver disease-associated hepatocellular carcinoma: Current evidence and future perspectives

“…GG carriers were found to evince a 5-fold increased risk compared to CC carriers[ 51 ]. This association was confirmed by subsequent studies[ 52 , 53 ]. The TM6SF2 rs58542926 polymorphism has been reported to be another risk factor for HCC and advanced fibrosis/cirrhosis[ 54 , 55 ].…”

Contribution of PNPLA3 gene polymorphisms to hepatocellular carcinoma susceptibility in the Chinese Han population

“…We also explored the association of rs3747207, rs4823173 and rs2896019 with HCC susceptibility. One study has also revealed the significant correlation of PNPLA3 rs4823173 and rs2896019 with HCC susceptibility [ 24 ]. Notably, although no association was observed between the alleles and genotypes of rs4823173 and HCC susceptibility, our study demonstrated that the rs2896019 G allele and GG genotype were obviously associated with increased HCC susceptibility.…”

Genetic Variation of SAMM50 Is Not an Independent Risk Factor for Alcoholic Hepatocellular Carcinoma in Caucasian Patients

“…Among others, a common variant in the toll-like receptor 5 , rs5744174, was linked to the development of HCC [ 28 ], while genetic variation in platelet receptors does not seem to play a role [ 29 ]. In the same line, we analysed two polymorphisms in SAMM50 because a recent genome-wide association study linked the genetic variation of SAMM50 to the development of HCC [ 16 ].…”

“…It was suggested that SAMM50 is upregulated in patients with NAFLD, that this upregulation is impaired in the presence of genetic variants in polymorphisms associated with NAFLD and that experimental knock-down of SAMM50 leads to intracellular triglyceride accumulation [ 18 ]. In line with changed expression, both rs3761472 and rs3827385 were reported to affect the binding of transcription factors and were linked to SAMM50 mRNA expression level in adipose tissue [ 16 ].…”

“…New genetic markers that deserve validation are the minor variants at two polymorphisms in the Sorting and assembly machinery component 50 homolog (SAMM50) , rs3761472 T > C and rs3827385 A > G, which were identified in two large cohorts including 705 HCC cases and 1455 controls and were validated using several datasets [ 16 ]. Both polymorphisms are supposed to interfere with transcription factor binding, with SAMM50 expression being increased in the presence of the minor variant in adipocytes [ 16 ]. Rs3761472 [ 17 ] and rs738491/rs2073082 [ 18 ] in SAMM50 were associated with NAFLD before; another polymorphism in SAMM50 (rs2143571) was linked to the serum level of ALT at the population level [ 19 ].…”