Several candidate gene studies on the metabolic syndrome (MetS) have been conducted. However, for most single nucleotide polymorphisms (SNPs) no systematic review on their association with MetS exists. A systematic electronic literature search was conducted until the 2nd of June 2010, using HuGE Navigator. English language articles were selected. Only genes of which at least one SNP–MetS association was studied in an accumulative total population =4000 subjects were included. Meta-analyses were conducted on SNPs with three or more studies available in a generally healthy population. In total 88 studies on 25 genes were reviewed. Additionally, for nine SNPs in seven genes (GNB3, PPARG, TCF7L2, APOA5, APOC3, APOE, CETP) a meta-analysis was conducted. The minor allele of rs9939609 (FTO), rs7903146 (TCF7L2), C56G (APOA5), T1131C (APOA5), C482T (APOC3), C455T (APOC3) and 174G>C (IL6) were more prevalent in subjects with MetS, whereas the minor allele of Taq-1B (CETP) was less prevalent in subjects with the MetS. After having systematically reviewed the most studied SNP–MetS associations, we found evidence for an association with the MetS for eight SNPs, mostly located in genes involved in lipid metabolism

Genetic variants and the metabolic syndrome: a systematic review

Apolipoprotein A-V (apoA-V) was discovered in 2001 both by comparative sequencing and as a liver regeneration protein. The gene is a located at the APOA1/C3/A4/A5 gene cluster on chromosome 11q23, a locus well known for playing a major role in regulating plasma cholesterol and triglyceride (TG) levels. ApoA-V is produced in the liver and has very low plasma concentrations (0.1-0.4 mug/ml). Mice lacking apoA-V have 4-fold increased TG levels, whereas apoA-V overexpression leads to 40% plasma TG reduction. Based on metabolic studies in vivo, apoA-V enhances the catabolism of TG rich lipoproteins rather than affecting their intestinal or hepatic production. By activating proteoglycans-bound lipoprotein lipase (LPL), apoA-V can accelerate TG hydrolysis from VLDL and chylomicrons independent from other apoproteins. Several variants at the APOA5 gene locus have been detected in humans. Some single nucleotide polymorphisms (SNPs) are associated with significantly higher plasma TG levels in patients (e.g., -1131T > C, S19W, G185C). In addition, these SNPs may affect fibrate response and obesity. However, data for a possible association of APOA5 variants with coronary heart disease are not consistent. Severe structural mutations (Q139X, Q148X, IVS3 + 3G > C) predispose to familial hypertriglyceridaemia and late-onset chylomicronaemia. Thus, despite its low plasma concentration, apoA-V is a major regulator of plasma TG metabolism in humans. However, the precise mechanism of its function is not yet clear.

Apoprotein A‐V: An important regulator of triglyceride metabolism

Variations in gene allele frequencies can contribute to differences in the prevalence of some common complex diseases among populations. Natural selection modulates the balance in allele frequencies across populations. Population differentiation (FST) can evidence environmental selection pressures. Such genetic information is limited in Puerto Ricans, the second largest Hispanic ethnic group in the US, and a group with high prevalence of chronic disease. We determined allele frequencies and population differentiation for 101 single nucleotide polymorphisms (SNPs) in 30 genes involved in major metabolic and disease-relevant pathways in Puerto Ricans (n = 969, ages 45–75 years) and compared them to similarly aged non-Hispanic whites (NHW) (n = 597). Minor allele frequency (MAF) distributions for 45.5% of the SNPs assessed in Puerto Ricans were significantly different from those of NHW. Puerto Ricans carried risk alleles in higher frequency and protective alleles in lower frequency than NHW. Patterns of population differentiation showed that Puerto Ricans had SNPs with exceptional FST values in intronic, non-synonymous and promoter regions. NHW had exceptional FST values in intronic and promoter region SNPs only. These observations may serve to explain and broaden studies on the impact of gene polymorphisms on chronic diseases affecting Puerto Ricans.

https://open.bu.edu/bitstream/handle/2144/3069/1471-2156-10-45.pdf?sequence=1

Disparities in allele frequencies and population differentiation for 101 disease-associated single nucleotide polymorphisms between Puerto Ricans and non-Hispanic whites

The apolipoprotein A5 (APOA5) gene −1131T>C (rs662799) has been suggested to be involved in the pathway of lipid homeostasis and the development of metabolic syndrome (MetS) However, the findings are not consistent To systematically evaluate the associations between −1131T>C polymorphism and fasting lipid parameters and the risk of MetS, we conducted a case-control study in a Chinese population and a meta-analysis The findings from 1840 Chinese participants indicated that the C allele carriers had significantly higher fasting total cholesterol (TC), triglycerides (TG) and lower HDL-cholesterol (HDL-C) than the TT homozygotes carriers The −1131C allele was also found to be significantly associated with increased risk of MetS (OR  =  140, 95% confidence interval (CI)  =  115, 169) compared to the TT homozygotes In the meta-analysis of 51,868 participants from 46 East Asian studies, 26 European studies and 19 studies of other ethnic groups, the −1131C allele was associated with higher fasting TC (weighted mean difference (WMD)  =  008 mmol/L, 95% CI  =  005, 010, P = 174×10−9), TG (WMD  =  030 mmol/L, 95% CI  =  026, 033, P =  187×10−55), LDL-cholesterol (LDL-C) (WMD  =  004 mmol/L, 95% CI  =  002, 007, P = 0002), and lower HDL-C (WMD  =  −005 mmol/L, 95% CI  =  −006,−004, P = 188×10−21), respectively Based on 12 studies with 5,573 MetS cases and 8,290 controls from 5 East Asian studies, 5 European studies and 2 studies of other ethnic groups, the −1131C allele was associated with increased risk of MetS with an OR (95% CI)  =  133 (116, 153) in the overall population, 143 (129, 158) in East Asian and 130 (094, 178) in European populations In conclusion, the −1131C allele may be associated with elevated levels of fasting TG, TC, LDL-C and decreased HDL-C, and increased risk of MetS, especially in East Asians

/pdf/effects-of-apoa5-1131t-c-rs662799-on-fasting-plasma-lipids-3w3pg1619d.pdf

Effects of APOA5 -1131T>C (rs662799) on fasting plasma lipids and risk of metabolic syndrome: evidence from a case-control study in China and a meta-analysis.

Associations of polymorphisms in the apolipoprotein A1/C3/A4/A5 gene cluster with familial combined hyperlipidaemia in Hong Kong Chinese.

The −1131C is a naturally occurring variant of the apolipoprotein A5 (ApoA5) gene, which has been shown to associate with increased triglyceride levels. This variant has also been shown to confer risk for development of ischemic heart disease and stroke. The gene is in linkage disequilibrium with factors known to correlate with impaired glucose homeostasis. These observations prompted us to study the prevalence of the ApoA5 –1131C allele in patients with metabolic syndrome. A total of 201 metabolic syndrome patients and 210 controls were studied. In both groups the triglyceride levels of patients with −1131C allele were significantly increased compared to the subjects with −1131T allele (3.22 ±0.43 mmol/1 vs. 2.24 ±0.12 mmol/1, p<0.01 in the metabolic syndrome patients; 2.10 ±0.19 mmol/1 vs. 1.22 ±0.05 mmol/1, p<0.01 in the controls). In metabolic syndrome patients the prevalence of the ApoA5 –1131C variant was increased compared to the healthy controls (11% vs. 6.20%). Multiplex regression analysis model adjusted for age, gender, serum total cholesterol levels, acute myocardial infarction and stroke events revealed that the examined ApoA5 variant confers risk for the development of metabolic syndrome: the odds ratio at 95% confidence interval was 3.622 (1.200–10.936), p=0.02. Our findings strongly suggest that this variant is a risk factor for the development of hypertriglyceridemia and metabolic syndrome.

Márion Mohás

Papers

Apolipoprotein A5 T-1131C variant confers risk for metabolic syndrome.