Genome-wide association study of metabolic syndrome in Korean populations.
ABSTRACT: Metabolic syndrome (MetS) which is caused by obesity and insulin resistance, is well known for its predictive capability for the risk of type 2 diabetes mellitus and cardiovascular disease. The development of MetS is associated with multiple genetic factors, environmental factors and lifestyle. We performed a genome-wide association study to identify single-nucleotide polymorphism (SNP) related to MetS in large Korean population based samples of 1,362 subjects with MetS and 6,061 controls using the Axiom® Korean Biobank Array 1.0. We replicated the data in another sample including 502 subjects with MetS and 1,751 controls. After adjusting for age and sex, rs662799 located in the APOA5 gene were significantly associated with MetS. 15 SNPs in GCKR, C2orf16, APOA5, ZPR1, and BUD13 were associated with high triglyceride (TG). 14 SNPs in APOA5, ALDH1A2, LIPC, HERPUD1, and CETP, and 2 SNPs in MTNR1B were associated with low high density lipoprotein cholesterol (HDL-C) and high fasting blood glucose respectively. Among these SNPs, 6 TG SNPs: rs1260326, rs1260333, rs1919127, rs964184, rs2075295 and rs1558861 and 11 HDL-C SNPs: rs4775041, rs10468017, rs1800588, rs72786786, rs173539, rs247616, rs247617, rs3764261, rs4783961, rs708272, and rs7499892 were first discovered in Koreans. Additional research is needed to confirm these 17 novel SNPs in Korean population.
Project description:BACKGROUND:Cholesteryl ester transfer protein (CETP) is involved in reverse cholesterol transport by exchanging cholesteryl esters for triglycerides between high-density lipoprotein and low-density lipoprotein particles, effectively decreasing high-density lipoprotein cholesterol levels. Variants within a large haplotype block upstream of CETP (rs247616, rs173539) have been shown to be significantly associated with reduced expression; however, the underlying mechanism has not been identified. METHODS:We analyzed the linkage structure of our top candidate single-nucleotide polymorphism (SNP), rs247616, and assessed each SNP of the haplotype block for potential interactions with transcription factor binding sites. We then used a reporter gene assay to assess the effect of three SNPs (rs247616, rs173539, and rs1723150) on expression in vitro. RESULTS:Several variants in the upstream haplotype, including rs247616, rs173539, and rs1723150, disrupt or generate transcription factor binding sites. In reporter gene assays, rs247616 and rs173539 were found to significantly affected expression in HepG2 cells, whereas rs17231506 had no effect. rs247616 decreased expression by 1.7-fold (P<0.0001), whereas rs173539 increased expression by 2.2-fold (P=0.0006). CONCLUSION:SNPs rs247616 and rs173539 are in high linkage disequilibrium (R=0.96, D'=1.00) and have the potential to regulate CETP expression. Although opposing effects suggest that regulation of CETP expression could vary between tissues, the minor allele of rs247616 and SNPs in high linkage with it were found to be associated with reduced expression across all tissues.
Project description:Genome-wide association studies have been used extensively to identify genetic variants linked to metabolic syndrome (MetS), but most of them have been conducted in non-Asian populations. This study aimed to evaluate the association between MetS and previously studied single nucleotide polymorphisms (SNPs), and their interaction with health-related behavior in Korean men.Seventeen SNPs were genotyped and their association with MetS and its components was tested in 1193 men who enrolled in the study at Seoul National University Hospital.We found that rs662799 near APOA5 and rs769450 in APOE had significant association with MetS and its components. The SNP rs662799 was associated with increased risk of MetS, elevated triglyceride (TG) and low levels of high-density lipoprotein, while rs769450 was associated with a decreased risk of TG. The SNPs showed interactions between alcohol drinking and physical activity, and TG levels in Korean men.We have identified the genetic association and environmental interaction for MetS in Korean men. These results suggest that a strategy of prevention and treatment should be tailored to personal genotype and the population.
Project description:BACKGROUND:To investigate the association of systemic, serum lipids and genetic variants in the high-density lipoprotein (HDL) metabolic pathway with polypoidal choroidal vasculopathy (PCV) in China. METHODS:The case-control study was included 150 controls and 66 cases with PCV. Serum levels of total cholesterol (TC), low-density lipoprotein (LDL), HDL, triglycerides (TG), apolipoprotein A1 (APOA1), apolipoprotein B (APOB) together with systemic risk factors including gender, hyperlipidemia, diabetes mellitus (DM), hypertension, coronary artery disease (CAD) and asthma were identified. All subjects were genotyped for four single nucleotide polymorphisms (SNPs) from three genes in the HDL metabolic pathway: rs10468017 of hepatic lipase (LIPC), rs12678919 of lipoprotein lipase (LPL), rs3764261 and rs173539 of cholesterol ester transfer protein (CETP) with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Student's t-tests, chi-square tests, anova and logistic regression were used to evaluate associations. RESULTS:Hyperlipidemia was a risk factor (odds ratio (OR) = 1.19, P = 0.001) for PCV. HDL, LDL and APOB levels were associated with PCV (OR = 0.001, P = 0.004; OR = 0.099, P = 0.010; OR = 0.839, P = 0.018). Higher level of TC was potently associated with increased risk of PCV (OR = 109.8, P = 0.000). LIPC rs10468017 was a risk factor for PCV (OR = 11.68, P = 0.000). CETP rs3764261 conferred a decreased risk for PCV (OR = 0.08, P = 0.000). No associations of LPL rs12678919 or CETP rs173539 with PCV were found. Mean level of HDL increased with T allele of the CETP gene (p = 0.026): 1.24 mmol/L (±0.31) for the GG genotype and 1.66 mmol/L (±0.54) for the TT genotype. Additionally, T allele was associated with the following increase in APOA1: 136.78 mg/dl (±20.53) for the CC genotype and 149.57 mg/dl (±22.67) for the TT genotype of LIPC and 137.91 mg/dl (±20.36) for the GG genotype and 162.67 mg/dl (±22.50) for the TT genotype of CETP gene. CONCLUSION:Our study suggested that the significant association was found between hyperlipidemia, the serum levels of TC, HDL, LDL and APOB and PCV. The result of present study also showed that the association of LIPC rs10468017 and CETP rs3764261 with PCV.
Project description:Metabolic syndrome (MetS) is a complex and multifactorial disorder characterized by insulin resistance, dyslipidaemia, hyperglycemia, abdominal obesity, and elevated blood pressure. The apolipoprotein A5 (APOA5) gene variants have been reported to correlate with two major components of MetS, including low levels of high density lipoprotein cholesterol (HDL-C) and high levels of triglyceride. In the present study, we explored the associations between five single nucleotide polymorphisms (SNPs) of APOA5 gene and the MetS risk.In a case-control design, 120 Iranian children and adolescents with/without MetS were genotyped by polymerase chain reaction-sequencing for these SNPs. Then, we investigated the association of SNPs, individually or in haplotype constructs, with MetS risk.The rs34089864 variant and H1 haplotype (harboring the two major alleles of rs619054 and rs34089864) were associated with HDL-C levels. However, there was no significant association between different haplotypes/individual SNPs and MetS risk.These results presented no association of APOA5 3'UTR SNPs with MetS. Further studies, including other polymorphisms, are required to investigate the involvement of APOA5 gene in the genetic susceptibility to MetS in the pediatric age group.
Project description:Fenofibrate therapy reduces serum triglycerides (TG) and increases high-density lipoprotein-cholesterol (HDL-C) and thus addresses the atherogenic dyslipidemia associated with metabolic syndrome (MetS). Our hypothesis is that genetic factors contribute to the variability of lipid response to fenofibrate differently in subjects with MetS and without MetS.We investigated the association in 25 candidate genes with lipid responses to a 3-weeks trial on fenofibrate in subjects with and without MetS. We employed growth curve mixed models to generate the response phenotypes to fenofibrate in TG, HDL-C, and low-density lipoprotein-cholesterol (LDL-C) and examined the genetic associations accounting for family dependencies.After correcting for multiple testing (p<0.05) and accounting for significant differences in the association effect sizes between subjects with and without MetS (p<0.05), variants of APOA5 (rs662799) and APOE (rs429358) were associated with HDL-C and LDL-C responses in MetS subjects, while APOA4 (rs675) was associated with TG response in non-MetS subjects. There was also suggestive evidence that MetS may interact with APOA4 (p=0.017), APOA5 (p=0.06), and APOE (p=0.09) to the variation to lipid responses.Genetic effects that contributed to the variability of lipid responses to fenofibrate may differ in subjects with and without MetS. This research may provide guidance for more personalized and effective therapies.
Project description:BACKGROUND:Single-nucleotide polymorphisms (SNPs) around the apolipoprotein A5 gene (APOA5) have pleiotropic effects on the levels of triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C). APOA5 SNPs have also been associated with metabolic syndrome (MS). Here, we constructed haplotypes with SNPs spanning APOA5 and ZNF259, which are approximately 1.3 kb apart, to perform association analyses with the risk for MS and the levels of TG and HDL-C in terms of a TG:HDL-C ratio. METHODS:The effects of three constructed haplotypes (TAA, CGG, and CGA, in the order of rs662799, rs651821, and rs6589566) on the TG:HDL-C ratio and MS were estimated using multiple regression analyses in 2,949 Koreans and in each gender separately (1,082 men and 1,867 women). RESULTS:The haplotypes, CGG and CGA, were associated with the TG:HDL-C ratio and the risk of MS development in both genders. That is, the minor alleles of the rs662799 and rs651821 in APOA5, irrespective of which allele was present at rs6589566, had the marked effects. Interestingly, a C-G-A haplotype at these three SNPs had the most marked effects on the TG:HDL-C ratio and the risk of MS development in women. CONCLUSIONS:We have identified the novel APOA5-ZNF259 haplotype manifesting sex-dependent effects on elevation of the TG:HDL-C ratio as well as the increased risk for MS.
Project description:APOA5 -1131T > C and S19W single nucleotide polymorphisms (SNP) have been consistently associated with plasma lipid concentration and metabolic syndrome (MetS), alone and in modulation by dietary factors. Puerto Ricans have a high prevalence of metabolic conditions and high minor allele frequency for these SNP, suggesting a possible role in disease for this population. We aimed to determine the association of APOA5 -1131T > C and S19W with plasma lipids and markers of MetS, alone and in interaction with total fat intake, as a percent of total energy intake, in Puerto Ricans. Anthropometric and demographic data, FFQ, and blood samples were collected at baseline from participants in the Boston Puerto Rican Health Study (n = 802, 45-75 y). APOA5 S19W was associated with plasma HDL cholesterol (HDL-C) (P = 0.044); minor allele carriers had lower HDL-C [1.12 +/- 0.03 (mean +/- SE)] than those with the common variant (1.18 +/- 0.01 mmol/L), even after adjustment for plasma triglycerides (TG) (P = 0.012). Neither polymorphism was associated with TG or other lipids. Interaction of the -1131T > C SNP with total fat energy intake was observed for plasma TG (P = 0.032) and total cholesterol (P = 0.034). APOA5 S19W interacted with total fat intake in association with systolic (P = 0.002) and diastolic (P = 0.007) blood pressure. Neither SNP was associated with MetS in the overall analysis or after stratifying by total energy intake as fat. In conclusion, Puerto Ricans present a distinctive lipid profile in association with APOA5 polymorphisms. Dietary fat intake seems to modulate these associations. The results contribute to the understanding of health disparities in this population.
Project description:PURPOSE:This study was conducted to investigate the distributions of the triglyceride (TG) to high-density lipoprotein-cholesterol (HDL-C) ratio and total cholesterol (TC) to HDL-C ratio, and to explore their usefulness as markers of metabolic syndrome (MetS) in Korean adolescents. METHODS:We obtained data for 2,721 adolescents (1,436 boys and 1,285 girls) aged 10-18 years who participated in the Korean National Health and Nutrition Examination Surveys from 2008 to 2010. International Diabetes Federation criteria were used to define MetS. RESULTS:There were no significant gender-related differences in TG/HDL-C or TC/HDL-C ratios. These lipid ratios showed significant associations with homeostatic model assessment for insulin resistance (HOMA-IR) and waist circumference. Areas under the receiver operating characteristic curve to identify MetS were 0.947 for TG/HDL-C and 0.924 for TC/HDL-C, which were higher than that of HOMA-IR (0.822). Optimal cutoff values (sensitivity, specificity) of TG/HDL-C and TC/HDL-C ratios for MetS prediction were 3.3 (85.7%, 89.9%), and 3.8 (92.9%, 82.8%), respectively. Odds ratio (OR; 95% confidence intervals [CIs]) for MetS in adolescents with TC/HDL-C ratio above the cutoff value was 14.8 (2.8-77.4), while that for TG/HDL-C ratio about the cutoff value was 30.6 (6.0-157.6). In adolescents who had both lipid ratios above the cutoff values, the OR (95% CI) for MetS was 36.2 (7.2-186.2). CONCLUSION:TG/HDL-C and TC/HDL-C ratios are useful markers of metabolic syndrome with high predictive value in Korean adolescents.
Project description:Although the association of single nucleotide polymorphisms (SNPs) with metabolic syndrome (MetS) has been reported in various populations in several genome-wide association studies (GWAS), the data is not conclusive. In this GWAS study, we assessed whether SNPs are associated with MetS and its individual components independently and/or through complex interactions in a Taiwanese population.A total of 10,300 Taiwanese subjects were assessed in this study. Metabolic traits such as waist circumference, triglyceride, high-density lipoprotein (HDL) cholesterol, systolic and diastolic blood pressure, and fasting glucose were measured.Our data showed an association of MetS at the genome-wide significance level (P < 8.6 x 10-8) with two SNPs, including the rs662799 SNP in the apolipoprotein A5 (APOA5) gene and the rs16944558 SNP in the collectin subfamily member 12 (COLEC12) gene. Moreover, we identified the effect of APOA5 rs662799 on triglyceride and HDL, the effect of rs1106475 in the actin filament associated protein 1 like 2 (AFAP1L2) gene on systolic blood pressure, and the effect of rs17667932 in the mediator complex subunit 30 (MED30) gene on fasting glucose. Additionally, we found that an interaction between the APOA5 rs662799 and COLEC12 rs16944558 SNPs influenced MetS, high triglyceride, and low HDL.Our study indicates that the APOA5 and COLEC12 genes may contribute to the risk of MetS and its individual components independently as well as through gene-gene interactions.
Project description:Increased risk of developing metabolic syndrome (MetS) has been associated with the APOA5, APOC1, BRAP, BUD13, CETP, LIPA, LPL, PLCG1, and ZPR1 genes. In this replication study, we reassessed whether these genes are associated with MetS and its individual components independently and/or through complex interactions in a Taiwanese population. We also analyzed the interactions between environmental factors and these genes in influencing MetS and its individual components. A total of 3,000 Taiwanese subjects were assessed in this study. Metabolic traits such as waist circumference, triglyceride, high-density lipoprotein (HDL) cholesterol, systolic and diastolic blood pressure, and fasting glucose were measured. Our data showed a nominal association of MetS with the APOA5 rs662799, BUD13 rs11216129, BUD13 rs623908, CETP rs820299, and LIPA rs1412444 single nucleotide polymorphisms (SNPs). Moreover, APOA5 rs662799, BUD13 rs11216129, and BUD13 rs623908 were significantly associated with high triglyceride, low HDL, triglyceride, and HDL levels. Additionally, we found the interactions of APOA5 rs662799, BUD13 rs11216129, BUD13 rs623908, CETP rs820299, LIPA rs1412444, alcohol consumption, smoking status, or physical activity on MetS and its individual components. Our study indicates that the APOA5, BUD13, CETP, and LIPA genes may contribute to the risk of MetS independently as well as through gene-gene and gene-environment interactions.