Multiple genotype–phenotype association study reveals intronic variant pair on SIDT2 associated with metabolic syndrome in a Korean population

Abstract

BackgroundMetabolic syndrome is a risk factor for type 2 diabetes and cardiovascular disease. We identified common genetic variants that alter the risk for metabolic syndrome in the Korean population. To isolate these variants, we conducted a multiple-genotype and multiple-phenotype genome-wide association analysis using the family-based quasi-likelihood score (MFQLS) test. For this analysis, we used 7211 and 2838 genotyped study subjects for discovery and replication, respectively. We also performed a multiple-genotype and multiple-phenotype analysis of a gene-based single-nucleotide polymorphism (SNP) set.ResultsWe found an association between metabolic syndrome and an intronic SNP pair, rs7107152 and rs1242229, in SIDT2 gene at 11q23.3. Both SNPs correlate with the expression of SIDT2 and TAGLN, whose products promote insulin secretion and lipid metabolism, respectively. This SNP pair showed statistical significance at the replication stage.ConclusionsOur findings provide insight into an underlying mechanism that contributes to metabolic syndrome.Electronic supplementary materialThe online version of this article (10.1186/s40246-018-0180-4) contains supplementary material, which is available to authorized users.

The Variant rs1784042 of the SIDT2 Gene is Associated with Metabolic Syndrome through Low HDL-c Levels in a Mexican Population

“…Gombojav et al identified in more than 8000 Korean individuals, several functional loci in 11q23.3 and found that SIDT2 is associated with an effect on plasma TG levels [ 14 ]. These data are consistent with the findings from Moon et al, who carried out a multiple genotype-phenotype association study in more than 10,000 Korean subjects and identified that the variant rs1784042 was associated with MetS and its components [ 16 , 52 ]. In addition, Kulminsky et al in a GWAS with more than 26,000 individuals from five longitudinal studies identified that the rs1784042 variant was associated with TC levels [ 17 ].…”

“…The variant rs1784042, which is located within the SIDT2 gene on chromosome 11, was the strongest signal ( p GWAS = 0.006) for HDL-c ( Supplementary Figure S1 and Supplementary Table S4 ). The variant rs1784042 (A allele) has been recently associated with risk of MetS in a Korean population [ 16 ] and with high TG levels in cohorts from Nigeria and the Philippines [ 15 ], suggesting a potential association with MetS and related components in certain ethnic groups. In addition, due to the proximity to the variant rs1784042, we also included the missense variant p.V636I (rs17120425) and because, according to the 1000 genomes project, the rs17120425 is rare in several populations (MAF < 1.0%).…”

“…Other studies have identified a role of Sidt2 also in lipid metabolism. Sidt2 -deficient mice developed an increase in serum of TG, FFAs and liver transaminases, indicating an impaired of liver function [ 16 , 19 , 22 ]. Recently, Mendez-Acevedo et al suggested that SIDT2 is involved in cholesterol transport, but not in RNA transport [ 21 ].…”

“…GWAS in Asian populations [ 14 , 15 ] have shown that the SIDT1 transmembrane family member 2 ( SIDT2 ) gene, encodes a SIDT2-lysosomal membrane protein and is associated with plasma triglyceride (TG) levels. Moreover, Moon et al reported an association between SIDT2 and MetS and its components, specifically with high density lipoprotein (HDL-c) and TG levels [ 16 ]. Recently, a meta-analysis conducted in a Korean population found that the SNP rs1784042 in SIDT2 gene was associated with total cholesterol (TC) levels [ 17 ].…”

Genetic Diversity of Insulin Resistance and Metabolic Syndrome

“…More recently, a multiple-genotype and multiple-phenotype analysis of a genebased SNP set has been performed to identify new susceptible variants associated with MetS in 10,049 Korean individuals [29]. In this study, 27 SNP pairs were associated with MetS in the discovery stage and also replicated.…”