The dual and opposite role of the TM6SF2-rs58542926 Variant in Protecting against Cardiovascular Disease and Conferring Risk for Non-alcoholic fatty liver: A meta-analysis

CARLOS JOSE PIROLA; SILVIA SOOKOIAN

San Francisco

Congreso; The 66th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2015; 2015

American Association for the Study of Liver Diseases AASLD

Background: The nonsynonymous p.Glu167Lys (rs58542926 C/T, E167K) variant, located in TM6SF2 (transmembrane 6 superfamily member 2) gene, was associated not only with blood lipid levels, including serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), but also myocardial infarction risk and NAFLD susceptibility. This variant, which has a relatively low frequency not only in Caucasian population (0.09)but globally (0.07), presents a clinical paradox, as the C (Glu167) allele was shown to be associated with increased CVD risk, while the T allele (Lys167) was associated with NAFLD.Objective: to examine the evidence provided in the available literature to estimate the strength of the effect of rs58542926 on both circulating lipid traits and NAFLD across different populations. In addition, we assessed whetherassociations are consistent across studies in magnitude and direction for all explored traits.Methods/design: We performed a systematic review by a meta-analysis; literature searches identified eleven studies.Results: The rs58542926 exerts a significant role in modulating lipid traits, including TC, LDL-C, TG, and NAFLD.However, this influence on lipids and NAFLD is opposite between genotypes in the dominant model of inheritance.Pooled estimates of random effects in 193,931 individuals showed that, compared with carriers of the minor K allele (EK+KK individuals), subjects homozygous for the ancestral C allele (EE genotype) are at risk of having higher levelsof TC, LDL-C and TG; the differences in mean±SE (mg/dL) are 7.4±2.3, 3.7±0.9 and 9.4±2.1, respectively. The rs58542926 was not associated with HDL-C in a large sample (n =91,937). Of note, the EE genotype is associated with a relatively large effect on blood levels of TC (about 2-3% increase on an upper limit of 200 mg/dL), LDL-C (about 1-2% increase on an upper limit of 150 mg/dL), and TG (about 6.4% increase on an upper limit of 150 mg/dL) for a single variant influencing a polygenic trait. In contrast, homozygous EE subjects appear to be protected against NAFLD (OR 0.469, 95% CI 0.300-0.734, p = 0.0009, n = 3273), while carriers of the K allele show about~ 2.2% higher lipid fat content when compared with homozygous EE (n = 3,413), and have 2.13-fold higher risk of developing NAFLD.Conclusion: The rs58542926 appears to be an important modifier of blood lipid traits in different populations. As a challenge for the personalized medicine, the ?major? C-allele, which has a frequency as high as 93%, is associated with CVD risk, while the ?minor?-low frequency T allele confers risk for NAFLD; in turn, CVD and NAFLD are strongly related outcomes.