The effect of APOA5 and APOC3 variants on lipid parameters in European Whites, Indian Asians and Afro-Caribbeans with type 2 diabetes

Common variants in APOA5 and APOC3 have been associated with differences in plasma triglyceride (TG) levels in healthy individuals. The aim of this study was to examine the association of APOA5 (-1131T>C, S19W) and APOC3 (-482C>T, 1100C>T) polymorphisms in patients with type 2 diabetes (T2D) of European White (EW) (n=931), Indian Asian (IA) (n=610) and Afro-Caribbean (AC) (n=167) origin, with lipid and T2D parameters. Rare allele frequencies and linkage disequilibrium differed significantly amongst ethnic groups. Compared to APOA5 -1131T and 19S homozygotes, -1131C and 19W carriers had higher TGs in all groups, but this effect was only statistically significant for the -1131C in the EWs (P=0.04) and 19W in the IAs (P<0.001). APOC3 SNPs showed no significant association with lipid levels in any ethnic group. While haplotypes carrying -1131C allele showed significant TG-raising in the EWs only, the 19W defined haplotype showed significant TG-raising in both IAs and EWs. Comparing all four SNPs in EW T2D subjects with healthy EWs (n=2579), the APOC3 1100C>T frequency was significantly higher in T2D [0.26 (0.24, 0.28)] vs. healthy EWs [0.22 (0.20, 0.23)], P=0.001. While the variable size effects of the two APOA5 SNPs on TG levels may result from ethnically different gene-gene or gene-environment interactions, APOA5 and APOC3 variants did not affect parameters of T2D. However, comparison between EWs with T2D and healthy EWs suggest APOC3 1100C>T is associated with increased risk of diabetes probably through mechanisms other than direct effects on TG.     

?1131T>C and SW19 polymorphisms in APOA5 gene and lipid levels in type 2 diabetic patients

Type 2 diabetes mellitus is a metabolic, vascular, and neuropathic disease with a high risk of atherosclerotic events due to dyslipidemic states. Polymorphisms in Apolipoprotein A5 gene (APOA5) have been associated with increased triglyceride levels in many different populations. This study aimed to identify the frequencies of the APOA5 -1131T>C and SW19 polymorphisms and evaluate their effects on lipid levels in patients with type 2 diabetes. Genotyping of APOA5 -1131T>C and SW19 polymorphisms was performed by PCR-RFLP in 146 diabetic patients and in controls (n = 173), from 30 to 80 years of age. Diabetic patients were divided into two groups: patients not treated with lipid lowering drugs (group G1; n = 62) and those treated with lipid lowering drugs (group G2, n = 84). Lipids and lipoproteins were determined enzymatically. Among participants not treated with lipid-lowering drugs (diabetics G1 and controls; n = 235), the -1131C was associated with lower LDLc levels (p = 0.015). In the diabetic patients, the 19W allele was associated with higher triglyceride levels (p = 0.004). In G1 diabetic patients, the combined analysis of APOA5 -1131T>C and SW19 polymorphisms showed that [TC or CC] + SS carriers presented lower total cholesterol levels than did other genotype combinations (p = 0.049). It could therefore be concluded that APOA5 -1131T>C and SW19 polymorphisms influence lipid levels in type 2 diabetic patients.     

Increased concentrations of circulating vitamin E in carriers of the apolipoprotein A5 gene - 1131T>C variant and associations with plasma lipids and lipid peroxidation

The aim of this study was to investigate the effects of the apolipoprotein A5 (APOA5) 1131T>C gene variant on vitamin E status and lipid profile. The gene variant was determined in 297 healthy nonsmoking men aged 20-75 years and recruited in the VITAGE Project. Effects of the genotype on vitamin E in plasma, LDL, and buccal mucosa cells (BMC) as well as on cholesterol and triglyceride (TG) concentrations in plasma and apolipoprotein A-I (apoA-I), apoB, apoE, apoC-III, and plasma fatty acids were determined. Plasma malondialdehyde concentrations as a marker of in vivo lipid peroxidation were determined. C allele carriers showed significantly higher TG, VLDL, and LDL in plasma, higher cholesterol in VLDL and intermediate density lipoprotein, and higher plasma fatty acids. Plasma alpha-tocopherol (but not gamma-tocopherol, LDL alpha- and gamma-tocopherol, or BMC total vitamin E) was increased significantly in C allele carriers compared with homozygote T allele carriers (P = 0.02), but not after adjustment for cholesterol or TG. Plasma malondialdehyde concentrations did not differ between genotypes. In conclusion, higher plasma lipids in the TC+CC genotype are efficiently protected against lipid peroxidation by higher alpha-tocopherol concentrations. Lipid-standardized vitamin E should be used to reliably assess vitamin E status in genetic association studies.     

Ⅱ型糖尿病患者APOA5-1131T/C基因多态性与血脂代谢和胰岛素抵抗的关系研究

为了探讨载脂蛋白A5基因(APOA5)-1131T/C多态性在中国镇江地区的频率分布及其与血浆脂质代谢和Ⅱ型糖尿病患者胰岛素抵抗的关系, 采用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)结合琼脂糖凝胶电泳技术检测152例健康人及71例Ⅱ型糖尿病患者APOA5 -1131T/C基因型及等位基因频率分布, 同时采用生化方法测定所有研究对象的血脂、血糖和胰岛素水平。结果显示: 糖尿病组APOA5 -1131C等位基因频率显著高于对照组(0.430 vs 0.296, P = 0.006)。CC纯合子患糖尿病的风险是TT纯合子的3.75倍(OR = 3.75, 95% CI: 1.57~8.92), 且经Logistic回归分析, 校正年龄、BMI和血浆HDL-c、LDL-c及ApoB水平等其他混杂因素影响后, 这种差异仍具有显著性意义(OR = 2.70, 95%CI: 1.24 ~ 5.86)。糖尿病组C等位基因携带者TG水平显著高于非C等位基因携带者(P < 0.01), TC水平和LDL-c水平亦明显升高(P < 0.05)。但是在两组中, 不同基因型患者 胰岛素抵抗相关指标均无显示差异。提示APOA5-1131T/C单核苷酸多态性对人群血浆TG水平有影响, -1131C等位基因与血浆TG、TC和LDL-c水平增高有关, 但是与糖尿病患者胰岛素相关指标无关; APOA5 -1131C等位基因可能与人群糖尿病的发生相关联。     

Contribution of APOA5 gene variants to plasma triglyceride determination and to the response to both fat and glucose tolerance challenges

The aim of this study was to investigate the influence of APOA5 variants on fasting lipids and to the response to both an oral fat tolerance test (OFTT) and an oral glucose tolerance test (OGTT). The association of two APOA5 SNPs [S19W (SNP5), -1131T>C (SNP3)] and an APOA4/A5 intergenic SNP [-12238T>C (SNP4)] were examined in healthy young men (n=774) who had undergone both an OFTT and an OGTT. Both -1131T>C and S19W rare alleles were associated with triglyceride (TG)-raising effects (11%, P=0.008; 21% (in cases), P<0.026, respectively) and showed additive effects on TG. None of the variants influenced the responsiveness to the OFTT after correcting for baseline TG. Homozygosity for the -12238T>C rare allele was associated with higher waist to hip ratio (P<0.0006), systolic blood pressure (P=0.012) and AUC and peak of insulin after OGTT (P=0.003 and P=0.027, respectively), traits that define the metabolic syndrome. Our results strongly support the role of APOA5 in determining plasma TG levels in an age-independent manner and highlight the importance of the APOC3/A4/A5 gene cluster in both TG and metabolic homeostasis.     

Haplotype analyses of the APOA5 gene in patients with familial combined hyperlipidemia

BACKGROUND: Familial combined hyperlipidemia (FCH) is the most common genetic lipid disorder with an undefined genetic etiology. Apolipoprotein A5 gene (APOA5) variants were previously shown to contribute to FCH. The aim of the present study was to evaluate the association of APOA5 variants with FCH and its related phenotypes in Dutch FCH patients. Furthermore, the effects of variants in the APOA5 gene on carotid intima-media thickness (IMT) and cardiovascular disease (CVD) were examined. MATERIALS AND METHODS: The study population consisted of 36 Dutch families, including 157 FCH patients. Two polymorphisms in the APOA5 gene (-1131T>C and S19W) were genotyped. RESULTS: Haplotype analysis of APOA5 showed an association with FCH (p=0.029), total cholesterol (p=0.031), triglycerides (p<0.001), apolipoprotein B (p=0.011), HDL-cholesterol (p=0.013), small dense LDL (p=0.010) and remnant-like particle cholesterol (p=0.001). Compared to S19 homozygotes, 19W carriers had an increased risk of FCH (OR=1.6 [1.0-2.6]; p=0.026) and a more atherogenic lipid profile, reflected by higher triglyceride (+22%) and apolipoprotein B levels (+5%), decreased HDL-cholesterol levels (-7%) and an increased prevalence of small dense LDL (16% vs. 26%). In carriers of the -1131C allele, small dense LDL was more prevalent than in -1131T homozygotes (29% vs. 16%). No association of the APOA5 gene with IMT and CVD was evident. CONCLUSION: In Dutch FCH families, variants in the APOA5 gene are associated with FCH and an atherogenic lipid profile.     

Influence of apoA-V gene variants on postprandial triglyceride metabolism: impact of gender

Although apolipoprotein A-V (apoA-V) polymorphisms have been consistently associated with fasting triglyceride (TG) levels, their impact on postprandial lipemia remains relatively unknown. In this study, we investigate the impact of two common apoA-V polymorphisms (-1131 T>C and S19W) and apoA-V haplotypes on fasting and postprandial lipid metabolism in adults in the United Kingdom (n = 259). Compared with the wild-type TT, apoA-V -1131 TC heterozygotes had 15% (P = 0.057) and 21% (P = 0.002) higher fasting TG and postprandial TG area under the curve (AUC), respectively. Significant (P = 0.038) and nearly significant (P = 0.057) gender x genotype interactions were observed for fasting TG and TG AUC, with a greater impact of genotype in males. Lower HDL-cholesterol was associated with the rare TC genotype (P = 0.047). Significant linkage disequilibrium was found between the apoA-V -1131 T>C and the apoC-III 3238 C>G variants, with univariate analysis indicating an impact of this apoC-III single nucleotide polymorphism (SNP) on TG AUC (P = 0.015). However, in linear regression analysis, a significant independent association with TG AUC (P = 0.007) was only evident for the apoA-V -1131 T>C SNP, indicating a greater relative importance of the apoA-V genotype.     

Influence of the APOA5 locus on plasma triglyceride, lipoprotein subclasses, and CVD risk in the Framingham Heart Study

Several polymorphisms in the APOA5 gene have been associated with increased plasma triglyceride (TG) concentrations. However, associations between APOA5 and lipoprotein subclasses, remnant-like particles (RLPs), and cardiovascular disease (CVD) risk have been less explored. We investigated associations of five APOA5 single-nucleotide polymorphisms (SNPs; -1131T>C, -3A>G, 56C>G IVS3+ 476G>A, and 1259T>C) with lipoprotein subfractions and CVD risk in 1,129 men and 1,262 women participating in the Framingham Heart Study. Except for the 56C>G SNP, the other SNPs were in significant linkage disequilibria, resulting in three haplotypes (11111, 22122, and 11211) representing 98% of the population. SNP analyses revealed that the -1131T>C and 56C>G SNPs were significantly associated with higher plasma TG concentrations in both men and women. For RLP and lipoprotein subclasses, we observed gender-specific association for the -1131T>C and 56C>G SNPs. Female carriers of the -1131C allele had higher RLP concentrations, whereas in males, significant associations for RLPs were observed for the 56G allele. Moreover, haplotype analyses confirmed these findings and revealed that the 22122 and 11211 haplotypes exhibited different associations with HDL cholesterol concentrations. In women, the -1131C allele was associated with a higher hazard ratio for CVD (1.85; 95% confidence interval, 1.03-3.34; P = 0.04), in agreement with the association of this SNP with higher RLPs.     

APOA5 variants and metabolic syndrome in Caucasians

Apolipoprotein A5 (APOA5) gene variants were reported to be associated with two components of metabolic syndrome (MetS): higher TG levels and lower HDL levels. Moreover, a recent Japanese case-control study found variant -1131T>C associated with MetS itself. Thus, our study systematically analyzed the APOA5 gene for association with lipid parameters, any other features of MetS, including waist circumference, glucose-related parameters, blood pressure, uric acid, and MetS itself in Caucasians. Ten polymorphisms were analyzed in a large fasting sample of the population-based Cooperative Health Research in the Region of Augsburg (KORA) survey S4 (n = 1,354; southern Germany) and in a second fasting sample, the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) study (n = 1,770; Austria). Minor alleles of variants -1131T>C, -3A>G, c.56C>G, 476G>A, and 1259T>C were significantly associated with higher TG levels in single polymorphism (P < 0.001) and haplotype (P G was associated with higher risk for MetS [odds ratio (95% confidence interval) = 1.43 (1.04, 1.99), P = 0.03 for KORA and 1.48 (1.10, 1.99), P = 0.009 for SAPHIR). Our study confirms the association of the APOA5 locus with TG and HDL levels in humans. Furthermore, the data suggest a different mechanism of APOA5 impact on MetS in Caucasians, as variant c.56C>G (not analyzed in the Japanese study) and not -1131T>C, as in the Japanese subjects, was associated with MetS.     

Apolipoprotein A5 polymorphisms in Turkish population: association with serum lipid profile and risk of ischemic stroke

Atherosclerosis, a major cause of ischemic stroke, may be associated with variability of triglyceride (TG) levels. Apolipoprotein A5 (APOA5) genetic polymorphisms are associated with altered TG levels. The objective of this study was to investigate the coding region polymorphisms S19W (rs3135506) and G185C (rs2075291) and the promoter region polymorphism ?1131T>C (rs662799) of the APOA5 gene as risk factors for ischemic stroke in Turkish population. Study group consisted of 272 ischemic stroke patients and 123 controls. Genotypes were determined by real-time polymerase chain reaction (PCR) for S19W and PCR-restriction fragment length polymorphism analysis (PCR–RFLP) for ?1131T>C and G185C. 19W allele frequency was 0.090 in stroke patients and 0.062 in controls (P = 0.191). Minor allele frequencies of ?1131T>C and G185C in patients were 0.106 and 0.004, respectively, and were nearly the same in controls. Total cholesterol and LDL-cholesterol levels were significantly higher for stroke patients having at least one 19W allele compared to non-carriers. A significant difference was also found for LDL-cholesterol levels of stroke patients; higher in ?1131C allele carriers compared to wild type patients. There was a trend for higher frequency of ischemic stroke among ?1131C allele carrier hypertensive, diabetic or obese subjects compared to non-carriers. However, APOA5 genotypes were not associated with the risk of ischemic stroke by logistic regression analysis. The present study demonstrated that carrying rare alleles of APOA5 S19W, ?1131T>C and G185C alone do not constitute a risk for ischemic stroke in the studied Turkish subjects.     

Lipid metabolism response to a single, prolonged bout of endurance exercise in healthy young men

To discover the alterations in lipid metabolism linked to postexercise hypotriglyceridemia, we measured lipid kinetics, lipoprotein subclass distribution and lipid transfer enzymes in seven healthy, lean, young men the day after 2 h of cycling and rest. Compared with rest, exercise increased fatty acid rate of appearance and whole body fatty acid oxidation by approximately 65 and 40%, respectively (P < 0.05); exercise had no effect on VLDL-triglyceride (TG) secretion rate, increased VLDL-TG plasma clearance rate by 40 +/- 8%, and reduced VLDL-TG mean residence time by approximately 40 min and VLDL-apolipoprotein B-100 (apoB-100) secretion rate by 24 +/- 8% (all P < 0.05). Exercise also reduced the number of VLDL but almost doubled the number of IDL particles in plasma (P < 0.05). Muscle lipoprotein lipase content was not different after exercise and rest, but plasma lipoprotein lipase concentration increased by approximately 20% after exercise (P < 0.05). Plasma hepatic lipase and lecithin:cholesterol acyltransferase concentrations were not affected by exercise, whereas cholesterol ester transfer protein concentration was approximately 10% lower after exercise than after rest (P = 0.052). We conclude that 1) greater fatty acid availability after exercise does not stimulate VLDL-TG secretion, probably because of the increase in fatty acid oxidation and possibly also fatty acid use for restoration of tissue TG stores; 2) reduced secretion of VLDL-apoB-100 lowers plasma VLDL particle concentration; and 3) increased VLDL-TG plasma clearance maintains low plasma TG concentration but is not accompanied by similar increases in subsequent steps of the delipidation cascade. Acutely, therefore, the cardioprotective lowering of plasma TG and VLDL concentrations by exercise is counteracted by a proatherogenic increase in IDL concentration.     

Apolipoprotein A-V: a potential modulator of plasma triglyceride levels in Turks

The apolipoprotein A-V gene (APOA5) plays an important role in determining plasma triglyceride levels. We studied the effects of APOA5 polymorphisms on plasma triglyceride levels in Turks, a population with low levels of HDL cholesterol and a high prevalence of coronary artery disease. We found 15 polymorphisms, three of which were novel. Seven haplotype-tagging single nucleotide polymorphisms (SNPs) were chosen and genotyped in approximately 3,000 subjects. The rare alleles of the -1464T>C, -1131T>C, S19W, and 1259T>C SNPs were significantly associated with increased triglyceride levels (19-86 mg/dl; P < 0.05) and had clear gene-dose effects. Haplotype analysis of the nine common APOA5 haplotypes revealed significant effects on triglyceride levels (P < 0.001). Detailed analysis of haplotypes clearly showed that the -1464T>C polymorphism had no effect by itself but was a marker for the -1131T>C, S19W, and 1259T>C polymorphisms. The -1131T>C and 1259T>C polymorphisms were in a strong but incomplete linkage disequilibrium and appeared to have independent effects. Thus, the APOA5 -1131T>C, S19W, and 1259T>C rare alleles were associated with significant increases in plasma triglyceride levels. At least one of these alleles was present in approximately 40% of the Turks. Similar associations were observed for -1131T>C and S19W in white Americans living in San Francisco, California.     

Apolipoprotein B metabolism and the distribution of VLDL and LDL subfractions

Apolipoprotein B (apoB) metabolism was investigated in 20 men with plasma triglyceride 0.66-2.40 mmol/l and plasma cholesterol 3.95-6. 95 mmol/l. Kinetics of VLDL(1) (S(f) 60-400), VLDL(2) (S(f) 20-60), IDL (S(f) 12-20), and LDL (S(f) 0;-12) apoB were analyzed using a trideuterated leucine tracer and a multicompartmental model which allowed input into each fraction. VLDL(1) apoB production varied widely (from 5.4 to 26.6 mg/kg/d) as did VLDL(2) apoB production (from 0.18 to 8.4 mg/kg/d) but the two were not correlated. IDL plus LDL apoB direct production accounted for up to half of total apoB production and was inversely related to plasma triglyceride (r = -0.54, P = 0.009). Percent of direct apoB production into the IDL/LDL density range (r = 0.50, P < 0.02) was positively related to the LDL apoB fractional catabolic rate (FCR). Plasma triglyceride in these subjects was determined principally by VLDL(1) and VLDL(2) apoB fractional transfer rates (FTR), i.e., lipolysis. IDL apoB concentration was regulated mainly by the IDL to LDL FTR (r = -0.71, P < 0.0001). LDL apoB concentration correlated with VLDL(2) apoB production (r = 0.48, P = 0.018) and the LDL FCR (r = -0.77, P < 0. 001) but not with VLDL(1), IDL, or LDL apoB production. Subjects with predominantly small, dense LDL (pattern B) had lower VLDL(1) and VLDL(2) apoB FTRs, higher VLDL(2) apoB production, and a lower LDL apoB FCR than those with large LDL (pattern A). Thus, the metabolic conditions that favored appearance of small, dense LDL were diminished lipolysis of VLDL, resulting in a raised plasma triglyceride above the putative threshold of 1.5 mmol/l, and a prolonged residence time for LDL. This latter condition presumably permitted sufficient time for the processes of lipid exchange and lipolysis to generate small LDL particles.     

Interactions between the APOA5 -1131T>C and the FEN1 10154G>T polymorphisms on ��6 polyunsaturated fatty acids in serum phospholipids and coronary artery disease

We determined the contribution of the combination of FEN1 10154G>T with the most significant association in the analysis of plasma arachidonic acid (AA, 20:4ω6) and the APOA5-1131T>C on phospholipid ω6PUFA and coronary artery disease (CAD). Patients with CAD (n = 807, 27–81 years of age) and healthy controls (n = 1123) were genotyped for FEN1 10154G>T and APOA5-1131T>C. We found a significant interaction between these two genes for CAD risk (P = 0.007) adjusted for confounding factors. APOA5-1131C allele carriers had a higher CAD risk [odds ratio (OR):1.484, 95% confidence interval (CI):1.31–1.96; P = 0.005] compared with APOA5-1131TT individuals in the FEN1 10154GG genotype group but not in the FEN1 10154T allele group (OR:1.096, 95%CI:0.84–1.43; P = 0.504). Significant interactions between these two genes were also observed for the AA proportion (P = 0.04) and the ratio of AA/linoleic acid (LA, 18:2ω6) (P = 0.004) in serum phospholipids of controls. The APOA5-1131C allele was associated with lower AA (P = 0.027) and AA/LA (P = 0.014) only in controls carrying the FEN1 10154T allele. In conclusion, the interaction between these genes suggests that the FEN1 10154T variant allele decreases AA and AA/LA in the serum phospholipids of carriers of the APOA5-1131C allele, but contributes no significant increase in CAD risk for this population subset despite their increased triglylcerides and decreased apoA5.     

Apolipoprotein A5-1131T>C polymorphism, but not APOE genotypes, increases susceptibility for dyslipidemia in children and adolescents

Apolipoprotein A5 (APOA5) and apolipoprotein E (APOE) play important roles in the metabolism of cholesterol and triglycerides. The aim of this study was to determine the allelic and genotypic distributions of the APOA5-1131T>C (rs 662799) and the APOE HhaI polymorphisms and to identify the association of both individual and combined APOA5-APOE genetic variants and the risk for dyslipidemia in children and adolescents. We genotyped 53 dyslipidemic and 77 normolipidemic individuals. The total cholesterol, triglycerides and HDL cholesterol were determined enzymatically. For APOA5 polymorphism, the presence of the allele C confers an individual risk for dyslipidemia (OR = 2.38, 95% CI = 1.15-4.89; P = 0.018). No significant differences were observed for lipid parameters among the APOA5 groups, except for a higher value of HDLc (P = 0.024) in C-carriers. The allelic and genotypic frequencies of APOE polymorphism were similar between groups and did not increase the susceptibility for dyslipidemia. None of the combined APOA5-APOE polymorphisms increased risk for dyslipidemia. We demonstrated an association between APOA5-1131T>C polymorphism and dyslipidemia in children and adolescents. This finding may be useful to guide new studies with genetic markers down a path toward a better characterization of the genetic risk factors for dyslipidemia and atherosclerotic diseases.     

APOA5 polymorphisms influence plasma triglycerides in young, healthy African Americans and whites of the CARDIA Study

Genetic variation in the apolipoprotein A-V gene (APOA5) has been associated with variation in plasma triglyceride (TG) levels in African American and white females and males older than 40 years and/or at increased risk of coronary artery disease. We have examined whether plasma TG levels are associated with 16 APOA5 polymorphisms in young (18-30 years) African American (1,075 females and 783 males) and white (1,041 females and 932 males) individuals of the Coronary Artery Risk Development in Young Adults (CARDIA) Study selected without regard to health. Plasma TG was significantly (P < 0.01) associated with markers 27376 and 28837 (-3A/G) in both white females and males, with 27709 (-1131T/C) and 29085 in white males, with 29009 (S19W) in African American females and white males, and with 30966 in African American females. No statistically significant associations were observed in African American males. These six single-nucleotide polymorphisms individually accounted for 0-0.78% of lnTG variation among white females, 0-2.46% among white males, and 0-0.69% among African American females. The results of our study suggest a small but replicable context-dependent influence of the APOA5 gene region on plasma TG levels in young, healthy individuals.     

Apolipoprotein A5 and Lipoprotein Lipase Interact to Modulate Anthropometric Measures in Hispanics of Caribbean Origin

Apolipoprotein A5 (APOA5) and lipoprotein lipase (LPL) proteins interact functionally to regulate lipid metabolism, and single‐nucleotide polymorphisms (SNPs) for each gene have also been associated independently with obesity risk. Evaluating gene combinations may be more effective than single SNP analyses in identifying genetic risk, but insufficient minor allele frequency (MAF) often limits evaluations of potential epistatic relationships. Populations with multiple ancestral admixtures may provide unique opportunities for evaluating genetic interactions. We examined relationships between LPL m107 (rs1800590) and APOA5 S19W (rs3135506) and lipid and anthropometric measures in Caribbean origin Hispanics (n = 1,019, aged 45–75 years) living in the Boston metropolitan area. Significant interaction terms between LPL m107 and APOA5 S19W were observed for BMI (P = 0.003) and waist circumference (P = 0.019). Higher BMI (P = 0.001), waist (P = 0.011) and hip (P = 0.026) circumference were observed in minor allele (G) carriers for LPL m107 who also carried the APOA5 S19W minor allele (G). Additionally, extreme obesity (BMI ≥ 40 kg/m²) risk was higher (odds ratio = 4.02; 95% confidence interval: 1.81–8.91; global P = 0.008) for minor allele carriers for both SNPs (LPL TG+GG, APOA5 CG+GG) compared to major allele carriers for both SNPs. In summary, we identified significant interactions for APOA5 S19W and LPL m107 for obesity in Caribbean Hispanics. Population‐specific MAFs increase the difficulties of replicating gene–gene interactions, but may support the hypothesis that combinations of frequencies in selected genes could heighten obesity susceptibility in a given population. Analyses of gene–gene interactions may improve understanding of genetically based obesity risk, and underscore the need for further study of groups with multiple ancestral admixtures.     

APOC3/A5 haplotypes, lipid levels, and risk of myocardial infarction in the Central Valley of Costa Rica

Genetic variation in the APOC3 and APOA5 genes has been associated with plasma triglyceride concentrations and may affect the risk of myocardial infarction (MI). To assess whether APOC3/A5 haplotypes are associated with risk of MI, we examined three single-nucleotide polymorphisms (SNPs) in APOC3 (3238C>G, -455T>C, and -482C>T) and six SNPs in the APOA5 gene (-1131T>C, c.-3A>G, c.56C>G, IVS3+476G>A, c.553G>T, and c.1259T>C) in incident cases (n = 1,703) of a first nonfatal MI matched for gender, age, and area of residence with population-based controls (n = 1,703). Conditional logistic regression models, adjusted for potential environmental confounders, were used for analysis. The common APOC3*222 haplotype was more frequent in cases than in controls (17.4% and 13.7%, respectively, P < 0.001) and was associated with increased risk of MI [odds ratio (OR) = 1.27; 95% confidence interval (95% CI), 1.09, 1.48] compared with APOC3*111 wild-type haplotype. This association was independent of the APOA5 SNPs. Although the APOC3 3238G, APOA5 -1131C, APOA5 c.-3G, and APOA5 c.1259C alleles were associated with higher triglyceride plasma concentrations, these effects could not explain the associations with MI in this population. In summary, this study supports the hypothesis that haplotypes in the APOC3 gene but not in the APOA5 gene increase susceptibility to MI.