Supplementary Material for: Genetic Variation at NCAN Locus Is Associated with Inflammation and Fibrosis in Non-Alcoholic Fatty Liver Disease in Morbid Obesity

<b><i>Objective:</i></b> Obesity-associated non-alcoholic fatty liver disease (NAFLD) may cause liver dysfunction and failure. In a previously reported genome-wide association meta-analysis, single nucleotide polymorphisms (SNPs) near <i>PNPLA3</i>, <i>NCAN</i>, <i>GCKR</i>, <i>LYPLAL1</i> and <i>PPP1R3B</i> were associated with NAFLD and with distinctive serum lipid profiles. The present study examined the relevance of these variants to NAFLD in extreme obesity. <b><i>Methods:</i></b> In 1,092 bariatric surgery patients, the candidate SNPs were genotyped and association analyses with liver histology and serum lipids were performed. <b><i>Results:</i></b> We replicated the association of hepatosteatosis with <i>PNPLA3</i> rs738409[G] and with <i>NCAN</i> rs2228603[T]. We also replicated the association of rs2228603[T] with hepatic inflammation and fibrosis. rs2228603[T] was associated with lower serum low-density lipoprotein, total cholesterol and triglycerides. After stratification by the presence or absence of NAFLD, these associations were present predominantly in the subgroup with NAFLD. <b><i>Conclusion:</i></b><i>NCAN</i> rs2228603[T] is a risk factor for liver inflammation and fibrosis, suggesting that this locus is responsible for progression from steatosis to steatohepatitis. In this bariatric cohort, rs2228603[T] was associated with low serum lipids only in patients with NAFLD. This supports a NAFLD model in which the liver may sequester triglycerides as a result of either increased triglyceride uptake and/or decreased lipolysis.