The TM6SF2 rs58542926 T allele is significantly associated with non-alcoholic fatty liver disease in Chinese
Authors: Xiaoliang Wang, Zhipeng Liu, Zhihai Peng, Wanqing Liu
Journal: Journal of Hepatology (2015)

A recent study has identified that a missense variant in TM6SF2 gene (rs58542926: C>T, NP_001001524.2:p. E167K) is significantly associated with non-alcoholic fatty liver disease (NAFLD) [[1]Kozlitina J. Smagris E. Stender S. Nordestgaard B.G. Zhou H.H. Tybjaerg-Hansen A. et al.Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2014; 46: 352-356Crossref PubMed Scopus (794) Google Scholar]. Further analyses suggested that this variant is also significantly associated with NAFLD disease progression [2Liu Y.L. Reeves H.L. Burt A.D. Tiniakos D. McPherson S. Leathart J.B. et al.TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease.Nat Commun. 2014; 5: 4309Crossref PubMed Scopus (430) Google Scholar, 3Dongiovanni P. Petta S. Maglio C. Fracanzani A.L. Pipitone R. Mozzi E. et al.TM6SF2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease.Hepatology. 2015; 61: 506-514Crossref PubMed Scopus (384) Google Scholar]. However, most of the studies thus far were performed in non-Asian populations, leaving out the question as to whether this variant also confers a risk of NAFLD in Asians (particularly East Asians), the largest population in the world. A most recent study led by Wong and colleagues examined the impact of TM6SF2 variant on NAFLD in a Chinese cohort, where the TM6SF2 167K allele was concluded to have a limited effect on NAFLD [[4]Wong V.W. Wong G.L. Tse C.H. Chan H.L. Prevalence of the TM6SF2 variant and non-alcoholic fatty liver disease in Chinese.J Hepatol. 2014; 61: 708-709Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar]. This was deemed to be attributed to the low minor allele frequency (MAF = 7% in their study) as well as the confounding effect of the PNPLA3 I148M variant, another significant risk factor for NAFLD that are replicated among all major human populations [[5]Romeo S. Kozlitina J. Xing C. Pertsemlidis A. Cox D. Pennacchio L.A. et al.Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (2309) Google Scholar]. In order to further verify the effect of this newly discovered allele in NAFLD, we conducted a case-control study in a community-based Han Chinese population. The rs58542926 polymorphism was genotyped in blood DNA samples from NAFLD patients (n = 384) and healthy controls (n = 384) that were collected in the health examination center of Shanghai Jiao Tong University Affiliated First People's Hospital (Shanghai, China). Genotyping was conducted using a Taqman-based assay (Life Technologies, CA, USA). Both the case and control groups consisted of 229 males and 155 females, with a mean age of 45 ± 13 years. The NAFLD diagnosis was made based on ultrasonographic examinations according to the guideline defined by the Chinese National Consensus Workshop on NAFLD [[6]Zeng M.D. Fan J.G. Lu L.G. Li Y.M. Chen C.W. Wang B.Y. et al.Guidelines for the diagnosis and treatment of nonalcoholic fatty liver diseases.J Dig Dis. 2008; 9: 108-112Crossref PubMed Scopus (160) Google Scholar]. The examination was performed by one experienced operator who was blinded to both clinical and biochemical evaluations of the patients. No histological data based on liver biopsy were available for these patients. For each individual, detailed data for ultrasonographic examination of the upper abdominal organs, clinical data for a comprehensive physical examination as well as a questionnaire for demographic, disease history, family history, smoking and alcohol intake information were all collected. The NAFLD patients were selected by excluding the cases with other known causes of steatosis, including heavy alcohol intake (>20 g/day), the use of medications known to contribute to hepatic steatosis, and hepatitis B and C virus infection. Patients with a high likelihood to have other known liver diseases were also excluded. Randomly selected healthy volunteers from the same population with normal liver enzymes, liver ultrasound and without any major illnesses were chosen as controls. The cases and controls were 1:1 matched according to their gender and age information. All enrolled individuals are self-reported Han Chinese and reside in the Shanghai metropolitan area. Informed consent was obtained from all participants. The study was approved by the ethical committees of the Shanghai Jiao Tong University and strictly conforms to the principles of the Declaration of Helsinki. Consistent with Wong's results, the TM6SF2 167K allele has a similarly low frequency in our dataset (MAF = 6.6%). However, we still observed a significant association between TM6SF2 167K allele and NAFLD (p = 0.0007) after adjustment for age, sex, body mass index and status of diabetes (Table 1). Furthermore, to clarify the independent effect of the TM6SF2 allele on NAFLD, we controlled the PNPLA3 rs738409 polymorphism, which was significantly associated with NAFLD in our data (p = 0.0002, data not shown). Our analysis showed that rs58542926 remained to be associated with NAFLD (p = 0.0004) after conditioning on rs738409 (Table 1). Moreover, several genome-wide association studies have shown that a variant in NCAN (rs2228603), whose locus is near TM6SF2, is strongly associated with NAFLD [7Speliotes E.K. Yerges-Armstrong L.M. Wu J. Hernaez R. Kim L.J. Palmer C.D. et al.Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet. 2011; 7: e1001324Crossref PubMed Scopus (715) Google Scholar, 8Gorden A. Yang R. Yerges-Armstrong L.M. Ryan K.A. Speliotes E. Borecki I.B. et al.Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity.Hum Hered. 2013; 75: 34-43Crossref PubMed Scopus (69) Google Scholar]. However, rs2228603 is not significantly associated with NAFLD in our samples (p = 0.1, data not shown). After conditioning on this variant, the TM6SF2 rs58542926 variant still remains significant (p = 0.001) in our data (Table 1).Table 1Association between TM6SF2 rs58542926 variant and NAFLD.*Associations were tested using logistic regression with adjustment for age, sex, BMI and status of diabetes.OR, odds ratio; CI, confidence interval. Open table in a new tab *Associations were tested using logistic regression with adjustment for age, sex, BMI and status of diabetes. OR, odds ratio; CI, confidence interval. In summary, we demonstrated that in a Han Chinese population cohort, the TM6SF2 167K allele has a similar allele frequency as reported in Caucasian populations (∼7%) [1Kozlitina J. Smagris E. Stender S. Nordestgaard B.G. Zhou H.H. Tybjaerg-Hansen A. et al.Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2014; 46: 352-356Crossref PubMed Scopus (794) Google Scholar, 2Liu Y.L. Reeves H.L. Burt A.D. Tiniakos D. McPherson S. Leathart J.B. et al.TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease.Nat Commun. 2014; 5: 4309Crossref PubMed Scopus (430) Google Scholar, 3Dongiovanni P. Petta S. Maglio C. Fracanzani A.L. Pipitone R. Mozzi E. et al.TM6SF2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease.Hepatology. 2015; 61: 506-514Crossref PubMed Scopus (384) Google Scholar] but higher than that in African-Americans (3.4%) [[1]Kozlitina J. Smagris E. Stender S. Nordestgaard B.G. Zhou H.H. Tybjaerg-Hansen A. et al.Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2014; 46: 352-356Crossref PubMed Scopus (794) Google Scholar], Hispanic-Americans (4.7%) [[1]Kozlitina J. Smagris E. Stender S. Nordestgaard B.G. Zhou H.H. Tybjaerg-Hansen A. et al.Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease.Nat Genet. 2014; 46: 352-356Crossref PubMed Scopus (794) Google Scholar], and Argentinians (5.5%) [[9]Sookoian S. Castano G.O. Scian R. Mallardi P. Fernandez Gianotti T. Burgueno A.L. et al.Genetic variation in TM6SF2 and the risk of nonalcoholic fatty liver disease and histological disease severity.Hepatology. 2015; 61: 515-525Crossref PubMed Scopus (161) Google Scholar]. Our data suggests that this variant significantly contributes to increased NAFLD risk in Chinese population, independent of the PNPLA3 rs738409 and NCAN rs2228603 polymorphisms. This observation further highlights the independent and potentially causal role of rs58542926 in the disease biology of NAFLD. However, further investigation is needed in East Asian populations to test whether it is also involved in NAFLD disease progression and severity, especially using biopsy-characterized samples. The authors declared no conflict of interest in relation to this manuscript. We thank Dr. Naga Chalasani for his kind review and comments on this letter. This study was supported in part by the NIH/NIDDK grant (R21 DK090437) (WL), the startup funds from the Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University (WL), and Shanghai Pujiang Program (No. 14PJD029) (XW).