Abstract 563: Variants of Neurocan , A Nonalcoholic Fatty Liver Disease Risk Allele, are Associated with Plaque Development in the Carotid Artery Over 5 Years and Metabolic Factors

Abstract

Introduction: Nonalcoholic fatty liver disease (NAFLD) genetic risk alleles are associated with lipid metabolism. However, the association between those variants and atherosclerosis has not yet been fully evaluated. Hypothesis: We hypothesized that NAFLD risk alleles are associated with the progression of atherosclerosis. Methods: A total of 1,150 Japanese men and women (median age 55 years) free of CVD, dyslipidemia, hypertension, and diabetes were studied. As NAFLD risk SNPs, variants of patatin-like phospholipase domain containing 3 ( PNPLA3 ), transmembrane 6 superfamily member 2 ( TM6SF2 ), glucokinase regulator ( GCKR ), and neurocan ( NCAN ) were assessed. Plasma total cholesterol, LDL cholesterol, small dense LDL cholesterol, LDL-triglycerides, HDL cholesterol, triglycerides, remnant-like particle cholesterol (RLP-C), fasting blood glucose (FBS), HbA1c, and high sensitivity CRP (hsCRP) were also measured. At baseline and after a five-year follow-up, carotid intima-media thickness (cIMT) was assessed using ultrasonography. Atherosclerosis was defined as cIMT over 1.1mm or the presence of a plaque. Univariate and multivariate analyses and chi-square and Fisher’s exact tests were performed to examine the associations between NAFLD risk SNPs, lipoproteins, and the progression of atherosclerosis. Results: Among 944 participants without atherosclerosis at baseline, the rate of plaque development was 13.1%, with the major allele (CC) of NCAN being significantly higher than non-CC alleles (13.8% vs. 4.7%, P = 0.04, Fisher’s exact test). Participants with the non-CC alleles of NCAN had significantly lower RLP-C at baseline than those with the CC allele (7.6 vs. 10.5 mg/dl, P = 0.02). In addition, participants with the non-CC alleles of NCAN had favorable metabolic parameters, lower blood pressure, triglycerides, small dense LDL cholesterol, and hsCRP, and higher HDL cholesterol than those with the CC allele (not significant). Conclusions: A NCAN variant, one of the NAFLD risk SNPs, was associated with plaque development among healthy Japanese participants, possibly mediated by favorable metabolism induced by the minor allele of NCAN .