Genetic variation of the androgen receptor and risk of myocardial infarction and ischemic stroke in women.

BACKGROUND AND PURPOSE: Androgen receptors (AR) are expressed in endothelial cells and vascular smooth-muscle cells. Some studies suggest an association between AR gene variation and risk of cardiovascular disease (CVD) in men; however, the relationship has not been examined in women. METHODS: Six haplotype block-tagging single nucleotide polymorphisms (rs962458, rs6152, rs1204038, rs2361634, rs1337080, rs1337082), as well as the cysteine, adenine, guanine (CAG) microsatellite in exon 1, of the AR gene were evaluated among 300 white postmenopausal women who developed CVD (158 myocardial infarctions and 142 ischemic strokes) and an equal number of matched controls within the Women's Health Study. RESULTS: Genotype distributions were similar between cases and controls, and genotypes were not significantly related to risk of CVD, myocardial infarctions or ischemic stroke in conditional logistic regression models. Seven common haplotypes were observed, but distributions did not differ between cases and controls nor were significant associations observed in logistic regression analysis. The median CAG repeat length was 21. In conditional logistic regression, there was no association between the number of alleles with CAG repeat length >or=21 (or >or=22) and risk of CVD, myocardial infarctions or ischemic stroke. CONCLUSIONS: No association between AR genetic variation, as measured by haplotype-tagging single nucleotide polymorphisms and CAG repeat number, and risk of CVD was observed in women.

Polymorphisms and haplotypes of the estrogen receptor-beta gene (ESR2) and cardiovascular disease in men and women.

BACKGROUND: Cohort studies suggest an association between variation in the estrogen receptor-alpha gene (ESR1) and cardiovascular disease (CVD), but data are lacking for the effect of variation in the estrogen receptor-beta gene (ESR2). METHODS: Three polymorphisms of the ESR2 gene, and their associated haplotypes, were evaluated in 296 white women from the Women's Health Study and 566 white men from the Physicians' Health Study who developed CVD [myocardial infarction (MI) or ischemic stroke], each matched 1:1 to a member of the cohort study who remained free from CVD. Blood samples and cardiovascular risk information were collected at baseline. RESULTS: Women, but not men, who developed CVD or MI, but not ischemic stroke, were more likely to have the rs1271572 polymorphism variant T allele (P = 0.05 and 0.02) and less likely to have the rs1256049 polymorphism variant A allele (P = 0.003 and 0.004). No associations were observed for rs4986938. In conditional logistic multivariate regression, the rs1271572 variant was associated with increased odds of CVD [odds ratio (OR) = 1.49, 95% CI: 1.10-2.01] and MI (OR = 1.46, 95% CI: 0.96-2.23), whereas the rs1256049 variant was associated with decreased odds of CVD (OR = 0.37, 95% CI: 0.17-0.79) and MI (OR = 0.25, 95% CI: 0.09-0.73) in women. A common haplotype that included the rs1271572 variant was associated with a 7-fold increased risk of MI in women. CONCLUSIONS: Two tightly linked polymorphisms of ESR2 were associated with risk of CVD, particularly MI, in women but not men. Additional studies of ESR2 genetic variation and risk of CVD are warranted.

Association of adiponectin gene variations with risk of incident myocardial infarction and ischemic stroke: a nested case-control study.

BACKGROUND: Adiponectin (ADIPOQ) gene variations are associated with risk of cardiovascular disease in patients with diabetes. No prospective data are available, however, on the risk of atherothrombotic disorders in persons with ADIPOQ variations who do not have diabetes. METHODS: From a group of DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we assessed the presence of 5 ADIPOQ genetic variants (rs266729, rs182052, rs822396, rs2241766, and rs1501299) in samples from 600 Caucasian men who subsequently suffered an atherothrombotic event (incident myocardial infarction or ischemic stroke) and from 600 age- and smoking-matched Caucasian men who remained free of reported vascular disease during follow-up (controls). RESULTS: Genotype distributions for the variations tested were in Hardy-Weinberg equilibrium. Marker-by-marker conditional logistic regression analysis, adjusted for potential risk factors, showed an association of rs266729 [recessive: odds ratio (OR), 0.26; 95% confidence interval (CI), 0.10-0.64; P=0.004] and rs182052 (recessive: OR, 0.40; 95% CI, 0.21-0.76; P=0.006) with decreased risk of ischemic stroke. These findings remained significant after Bonferroni correction. Haplotype-based (constituted by rs266729, rs182052, and rs822396) conditional logistic regression analysis, adjusted for the same potential risk factors, showed an association of haplotype G-A-G (OR, 0.28; 95% CI, 0.09-0.87; P=0.03) with decreased risk of ischemic stroke. Prespecified analysis limited to participants without baseline diabetes showed similar significant findings. CONCLUSIONS: The present prospective investigation provides further evidence for a protective role of adiponectin gene variation in the risk of ischemic stroke that was independent of the presence of diabetes.

Polymorphisms of the phosphodiesterase 4D, cAMP-specific (PDE4D) gene and risk of ischemic stroke: a prospective, nested case-control evaluation.

BACKGROUND AND PURPOSE: In an Icelandic population, gene variants of the phosphodiesterase 4D, cAMP-specific (PDE4D) gene were reported to be risk predictors for ischemic stroke. Case-control studies in other populations have yielded mixed evidence for association. A recent analysis in a prospective, non-Icelandic study found an association with stroke after stratification by hypertension. METHODS: We evaluated nine PDE4D single nucleotide polymorphisms (SNPs) among 259 incident ischemic stroke cases and 259 controls were matched on age and smoking status and length of follow up since randomization, all drawn from initially healthy white males within the Physicians' Health Study cohort who were prospectively followed for first-ever stroke events. RESULTS: Genotype and allele distributions were similar between cases and controls. Results from single-marker conditional logistic regression analysis adjusting for traditional stroke risk factors showed significant association of SNP56 with risk of ischemic stroke (recessive odds ratio [OR], 2.26; 95% confidence interval [CI], 1.11 to 4.61; P=0.03). Among the participants without baseline hypertension, SNP42 (additive OR, 1.68; 95% CI, 0.99 to 2.86, P=0.06), SNP45 (dominant odds ratio, 2.24; 95% CI, 1.00 to 5.00, P=0.05), and SNP56 (additive odds ratio, 1.77; 95% CI, 1.02 to 3.10, P=0.04) showed modest association with increased risk of ischemic stroke. CONCLUSIONS: We found modest associations between several PDE4D gene polymorphisms and risk of incident ischemic stroke in men without baseline hypertension in this prospective, non-Icelandic study. Although of borderline statistical significance, the direction and magnitude of the effect for SNP42 parallels that observed in a recent study evaluating women from an independent, nested case-control study.

Genetic variants of arachidonate 5-lipoxygenase-activating protein, and risk of incident myocardial infarction and ischemic stroke: a nested case-control approach.

BACKGROUND AND PURPOSE: Recent findings have implicated specific gene polymorphisms of arachidonate 5-lipoxygenase-activating protein (ALOX5AP), and 2 at-risk haplotypes (HapA, HapB) in myocardial infarction and stroke. To date, no prospective data are available. METHODS: We evaluated 10 specific Icelandic ALOX5AP gene variants among 600 male participants with incident atherothrombotic events (myocardial infarction [MI] or ischemic stroke) and among 600 age- and smoking-matched male participants, all white, who remained free of reported cardiovascular disease during follow-up within the Physicians' Health Study cohort. RESULTS: Overall allele, genotype, and haplotype distributions were similar between cases and controls. Single-marker conditional logistic regression analysis adjusted for potential risk factors found no association with risk of atherothrombotic events. Further investigation using a haplotype-based approach showed similar null findings with MI (HapA: odds ratio [OR]=1.18, 95% CI, 0.76 to 1.85; P=0.46; HapB: odds ratio=0.62, 95% CI, 0.36 to 1.07; P=0.08), and with ischemic stroke (HapA: odds ratio=1.11, 95% CI, 0.65 to 1.89; P=0.71; HapB: odds ratio=0.82, 95% CI, 0.47 to 1.42; P=0.47). CONCLUSIONS: We found no evidence for an association of the specific Icelandic ALOX5P gene variants/at-risk haplotypes tested with risk of incident MI nor ischemic stroke in this prospective, non-Icelandic study.

Tryptophanyl-tRNA synthetase gene polymorphisms and risk of incident myocardial infarction.

Tryptophanyl-tRNA synthetase (WARS) gene polymorphisms have been associated with the patho-physiology of vascular angiogenesis and homeostasis. Data from a recent genome-wide linkage analysis suggested a potential role of WARS in the risk of myocardial infarction. However, no genetic-epidemiological data are available. From a prospective cohort of 14,916 initially healthy American men, we evaluated five common polymorphisms within or close to the WARS locus, all with a minor allele frequency >0.10, amongst 386 individuals who subsequently developed myocardial infarction and 386 matched individuals who remained free of reported cardiovascular events during follow-up. The polymorphisms were: a G > C substitution in the 5'-flanking region (dbSNP rs2273804), an A > G substitution in intron 1 (dbSNP rs941931), a 335T > C substitution in exon 10 (dbSNP rs9453), a C > T substitution in intron 10 (dbSNP rs1570305), and a C > T substitution in the C14orf68 region (dbSNP rs3736951). The observed genotypes were in Hardy-Weinberg equilibrium in the control group. Genotype- and haplotype-frequency distributions were similar between cases and controls. Further investigation using a haplotype-based matched logistic regression analysis, adjusting for age, smoking, randomized treatment-assignment (likelihood ratio test: chi(3)(2) = 3.20, p = 0.36) or with additional adjustment for BMI, hypertension, and diabetes (likelihood ratio test: chi(3)(2) = 2.38, p = 0.50) yielded similar null findings. An alternative haplotype analysis based on evolutionary arguments again yielded null results. In conclusion, we found no evidence for an association between the common polymorphisms or haplotypes of the tryptophanyl-tRNA synthetase gene tested and risk of myocardial infarction.

Toll-like receptor 4 Asp299Gly gene polymorphism and risk of atherothrombosis.

BACKGROUND AND PURPOSE: Recent findings of an association between a functional toll-like receptor 4 (TLR4) D299G gene variant and reduced risk of atherothrombotic disorders have generated great interest. METHODS: We evaluated the TLR4 D299G polymorphism among 695 individuals with incident myocardial infarction (MI) or stroke and among 695 age- and smoking-matched individuals who remained free of reported cardiovascular disease during follow-up within the Physicians' Health Study. RESULTS: Overall, we observed little evidence of association between the D299G polymorphism and risk of any atherothrombotic event (P=0.25), incident MI (P=0.89), or stroke (P=0.09), assuming an additive model. Adjusting for traditional cardiovascular risk factors or assuming a dominant model yielded similar null findings. Whereas the observed carrier frequency of the D299G polymorphism in our data (13.0%) is consistent with those observed in most other studies, it was higher than the 6.8% carrier frequency observed in the initial study that suggested a protective effect for this gene variant. Thus, this former association may have been caused, in part, by an underestimation of the control frequency. CONCLUSIONS: In contrast to previous data, the D299G TLR4 polymorphism was not associated with risk of incident MI or stroke in this large prospective study of US men.

C-reactive protein gene polymorphisms and the incidence of post-angioplasty restenosis.

Recent findings have demonstrated that plasma C-reactive protein levels predict restenosis after coronary angioplasty. Furthermore, C-reactive protein levels have also been shown to be heritable. However, no genetic-epidemiological data are available on the relationship between genetic variants of C-reactive protein (CRP) gene and risk of restenosis after angioplasty. The present study was carried out to examine the possible association of a non-sense exonic 1059G > C and an intronic T > A C-reactive protein gene polymorphisms in a large, previously described, well-characterized cohort of 779 post-angioplasty patients of whom 342 subjects developed restenosis. Genotype distributions were in Hardy-Weinberg equilibrium. Genotype and allele distributions were similar between cases and controls. Haplotype frequency distributions were also similar between cases and controls. Further investigation using a haplotype-based logistic and linear regression analyses, adjusting for potential confounders, yielded similar null results. In conclusion, we found no evidence for an association between the polymorphisms/haplotypes thereof tested and restenosis after angioplasty.