Abstract
BackgroundThe Neurocan-cartilage intermediate layer protein 2 (NCAN-CILP2) region forms a tight linkage disequilibrium (LD) block and is associated with plasma lipid levels and non-alcoholic fatty liver disease (NAFLD) in individuals of European descent but not in the Malay and Japanese ethnic groups. Recent genome-wide resequence studies identified a missense single-nucleotide polymorphism (SNP) (rs58542926) of the transmembrane 6 superfamily member 2 (TM6SF2) gene in the NCAN-CILP2 region related to hepatic triglyceride content. This study aims to analyze the influences of SNPs in this region on NAFLD and plasma lipid levels in the Asian and Pacific ethnic groups and to reveal the reasons behind positive and negative genetic associations dependent on ethnicity.MethodsSamples and characteristic data were collected from 3,013 Japanese, 119 Palauan, 947 Mongolian, 212 Thai and 401 Chinese people. Hepatic sonography data was obtained from the Japanese individuals. Genotyping data of five SNPs, rs58542926, rs735273, rs1009136, rs1858999, and rs16996148, were used to verify the effect on serum lipid levels by multiple linear regression, and the association with NAFLD in the Japanese population was examined by logistic regression analysis.Resultsrs58542926 showed significant association with the plasma triglyceride (TG) level in Japanese (P = 0.0009, effect size = 9.5 (±3.25) mg/dl/allele) and Thai (P = 0.0008, effect size = 31.6 (±11.7) mg/dl/allele) study subjects. In Mongolian individuals, there was a significant association of rs58542926 with total cholesterol level (P = 0.0003, 11.7 (±3.2) mg/dl/allele) but not with TG level. In multiple comparisons in Chinese individuals, rs58542926 was weakly (P = 0.022) associated with TG levels, although the threshold for statistical significance was not reached. In Palauan individuals, there was no significant association with the studied SNPs. rs58542926 also showed significant association with Japanese NAFLD. The minor allele (t) increased NAFLD risk (OR 1.682, 95 % CI 1.289–2.196, p value 0.00013).ConclusionThis study confirmed the genetic association of missense SNP of TM6SF2, rs58542926, with plasma lipid levels in multiple East Asian ethnic groups and with NAFLD in Japanese individuals.
Highlights
The Neurocan-cartilage intermediate layer protein 2 (NCAN-CILP2) region forms a tight linkage disequilibrium (LD) block and is associated with plasma lipid levels and non-alcoholic fatty liver disease (NAFLD) in individuals of European descent but not in the Malay and Japanese ethnic groups
Through genome-wide association studies (GWAS), abundant genetic variants associated with plasma lipid levels have been identified, among which the Neurocan-cartilage intermediate layer protein 2 (NCAN-CILP2) region has high statistical significance and a relatively large effect size per allele on low-density lipoprotein cholesterol (LDL) and triglyceride (TG) levels [1, 2]
Details of all 5 single-nucleotide polymorphism (SNP) and minor allele frequencies (MAFs) for each population are described in Table 1. rs58542926 showed significant associations with plasma lipid levels in multiple ethnic groups, which persisted after applying the Bonferroni correction for multiple testing (5 SNPs and 4 phenotypes)
Summary
The Neurocan-cartilage intermediate layer protein 2 (NCAN-CILP2) region forms a tight linkage disequilibrium (LD) block and is associated with plasma lipid levels and non-alcoholic fatty liver disease (NAFLD) in individuals of European descent but not in the Malay and Japanese ethnic groups. Through genome-wide association studies (GWAS), abundant genetic variants associated with plasma lipid levels have been identified, among which the Neurocan-cartilage intermediate layer protein 2 (NCAN-CILP2) region has high statistical significance and a relatively large effect size per allele on low-density lipoprotein cholesterol (LDL) and triglyceride (TG) levels [1, 2]. Eleven genes and one miRNA are encoded in this region This locus showed consistent and deep association with serum lipid levels in the subsequent studies for individuals of European and Chinese descent [3,4,5]. The tag SNP in this region, rs16996148, was not correlated with plasma lipids in Malaysian [6] and Japanese populations [7, 8]
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