The effects of biological sex and cardiovascular disease on COVID-19 mortality.

Cardiovascular disease (CVD) is a common comorbidity observed in patients with coronavirus disease 2019 (COVID-19), which is associated with increased severity and mortality. However, the effects of biological sex on CVD-associated mortality in patients with COVID-19 are poorly established, particularly among Hispanic/Latin Americans. We examined the association of preexisting CVD with COVID-19 mortality in hospitalized Latin American men and women. This multicenter study included Mexican patients hospitalized with a positive diagnosis of COVID-19. The main outcome was in-hospital mortality. Multivariable regression analyses were used to calculate the adjusted odds ratio with 95% confidence interval for mortality in women and men. Of 81,400 patients with a positive diagnosis for SARS-CoV-2 infection, 28,929 (35.54%) hospitalized patients were evaluated. Of these, 35.41% (10,243) were women. In-hospital death was higher in men than in women. In relation to CVD between the sexes, women had a higher incidence of CVD than men (4.69 vs. 3.93%, P = 0.0023). The adjusted logistic regression analyses showed that CVD was significantly associated with COVID-19 mortality in women but not men. We then stratified by sex according to age <52 and ≥52 yr old. Similar significant association was also found in prespecified analysis in women ≥52 yr old but not in men of similar age. We conclude that CVD's effect on mortality among patients hospitalized with COVID-19 is dependent on biological sex and age in this Latin American cohort. These results suggest that therapeutic strategies for Latin American women with CVD and COVID-19 should include particular attention to their cardiovascular health.NEW & NOTEWORTHY CVD's effect on COVID-19 mortality is dependent on biological sex and age. CVD in women but not men with COVID-19 is associated with significantly unfavorable outcomes.

Genetic variation at the coronary artery disease risk locus GUCY1A3 modifies cardiovascular disease prevention effects of aspirin.

AIMS: Efficacy of aspirin in primary prevention of cardiovascular disease (CVD) may be influenced by a common allele in guanylate cyclase GUCY1A3, which has been shown to modify platelet function and increase CVD risk. METHODS AND RESULTS: We investigated whether homozygotes of the GUCY1A3 rs7692387 risk (G) allele benefited from aspirin in two long-term, randomized placebo-controlled trials of aspirin in primary CVD prevention: the Women's Genome Health Study (WGHS, N = 23 294) and a myocardial infarction (MI, N = 550) and stroke (N = 382) case-control set from the Physician's Health Study (PHS, N = 22 071). Bleeding risk was evaluated in the WGHS. In the placebo group of the WGHS, the GUCY1A3 risk (G) allele was confirmed to increase CVD risk [hazard ratio 1.38; 95% confidence interval (CI) 1.08-1.78; P = 0.01]. Random-effects meta-analysis of the WGHS and PHS revealed that aspirin reduced CVD events among risk allele homozygotes [G/G: odds ratio (OR) 0.79; 95% CI 0.65-0.97; P = 0.03] but increased CVD events among non-risk allele carriers (e.g. G/A: OR 1.39; 95% CI 1.03-1.87; P = 0.03) thus implying an interaction between genotype stratum and aspirin intake (Pinteraction = 0.01). Bleeding associated with aspirin increased in all genotype groups, with higher risks in heterozygotes. CONCLUSION: In two randomized placebo-controlled trials in the setting of primary prevention, aspirin reduced the incidence of CVD events in individuals homozygous for the GUCY1A3 risk (G) allele, whereas heterozygote individuals had more events when taking aspirin.

Biological, clinical and population relevance of 95 loci for blood lipids.

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Gene variations of ROCKs and risk of ischaemic stroke: the Women's Genome Health Study.

Recent animal and human studies have demonstrated the importance of the ROCK (RhoA/Rho-associated kinase) pathway in IsST (ischaemic stroke). Whether the genetic variation within ROCK-associated genes modulates the risk of IsST remains elusive. The association between 66 tSNPs [tagging SNPs (single nucleotide polymorphisms)] of three ROCK-associated genes [ROCK1, ROCK2 and ARHGEF10 (Rho guanine-nucleotide-exchange factor 10)] and the incidence of IsST was investigated in 23294 Caucasian female participants of the prospective WGHS (Women's Genome Health Study). All were free of known cancer and cardiovascular disease at baseline. During a 15-year follow-up period, 323 participants developed their first ever IsST. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and risk of IsST assuming an additive genetic model. Haplotype-block analysis was also performed. A total of ten tSNPs were associated with the risk of IsST (three in ARHGEF10 and seven in ROCK1; P<0.050). Further investigation using the haplotype-block analysis revealed a similar significant association of pre-specified haplotypes of ROCK1 with the risk of IsST (P=0.005). If corroborated in other large prospective studies, the findings of the present study suggest that genetic variation within the ROCK-associated pathway gene loci examined, and in particular ROCK1 gene variation, may influence the risk of IsST.

Strain-specific variations in cation content and transport in mouse erythrocytes.

Studies of ion transport pathophysiology in hematological disorders and tests of possible new therapeutic agents for these disorders have been carried out in various mouse models because of close functional similarities between mouse and human red cells. We have explored strain-specific differences in erythrocyte membrane physiology in 10 inbred mouse strains by determining erythrocyte contents of Na(+), K(+), and Mg(2+), and erythrocyte transport of ions via the ouabain-sensitive Na-K pump, the amiloride-sensitive Na-H exchanger (NHE1), the volume and chloride-dependent K-Cl cotransporter (KCC), and the charybdotoxin-sensitive Gardos channel (KCNN4). Our data reveal substantial strain-specific and sex-specific differences in both ion content and trans-membrane ion transport in mouse erythrocytes. These differences demonstrate the feasibility of identifying specific quantitative trait loci for erythroid ion transport and content in genetically standardized inbred mouse strains.

Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels.

BACKGROUND: C-reactive protein (CRP) is a heritable marker of chronic inflammation that is strongly associated with cardiovascular disease. We sought to identify genetic variants that are associated with CRP levels. METHODS AND RESULTS: We performed a genome-wide association analysis of CRP in 66 185 participants from 15 population-based studies. We sought replication for the genome-wide significant and suggestive loci in a replication panel comprising 16 540 individuals from 10 independent studies. We found 18 genome-wide significant loci, and we provided evidence of replication for 8 of them. Our results confirm 7 previously known loci and introduce 11 novel loci that are implicated in pathways related to the metabolic syndrome (APOC1, HNF1A, LEPR, GCKR, HNF4A, and PTPN2) or the immune system (CRP, IL6R, NLRP3, IL1F10, and IRF1) or that reside in regions previously not known to play a role in chronic inflammation (PPP1R3B, SALL1, PABPC4, ASCL1, RORA, and BCL7B). We found a significant interaction of body mass index with LEPR (P<2.9×10(-6)). A weighted genetic risk score that was developed to summarize the effect of risk alleles was strongly associated with CRP levels and explained ≈5% of the trait variance; however, there was no evidence for these genetic variants explaining the association of CRP with coronary heart disease. CONCLUSIONS: We identified 18 loci that were associated with CRP levels. Our study highlights immune response and metabolic regulatory pathways involved in the regulation of chronic inflammation.

Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study.

Although elevated levels of C-reactive protein (CRP) independently predict increased risk of development of metabolic syndrome, diabetes, myocardial infarction, and stroke, comprehensive analysis of the influence of genetic variation on CRP is not available. To address this issue, we performed a genome-wide association study among 6345 apparently healthy women in which we evaluated 336,108 SNPs as potential determinants of plasma CRP concentration. Overall, seven loci that associate with plasma CRP at levels achieving genome-wide statistical significance were found (range of p values for lead SNPs within the seven loci: 1.9 x 10(-)(8) to 6.2 x 10(-)(28)). Two of these loci (GCKR and HNF1A) are suspected or known to be associated with maturity-onset diabetes of the young, one is a gene-desert region on 12q23.2, and the remaining four loci are in or near the leptin receptor protein gene, the apolipoprotein E gene, the interleukin-6 receptor protein gene, or the CRP gene itself. The protein products of six of these seven loci are directly involved in metabolic syndrome, insulin resistance, beta cell function, weight homeostasis, and/or premature atherothrombosis. Thus, common variation in several genes involved in metabolic and inflammatory regulation have significant effects on CRP levels, consistent with CRP's identification as a useful biomarker of risk for incident vascular disease and diabetes.

Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women.

While circulating levels of soluble Intercellular Adhesion Molecule 1 (sICAM-1) have been associated with diverse conditions including myocardial infarction, stroke, malaria, and diabetes, comprehensive analysis of the common genetic determinants of sICAM-1 is not available. In a genome-wide association study conducted among 6,578 participants in the Women's Genome Health Study, we find that three SNPs at the ICAM1 (19p13.2) locus (rs1799969, rs5498 and rs281437) are non-redundantly associated with plasma sICAM-1 concentrations at a genome-wide significance level (P<5x10(-8)), thus extending prior results from linkage and candidate gene studies. We also find that a single SNP (rs507666, P = 5.1x10(-29)) at the ABO (9q34.2) locus is highly correlated with sICAM-1 concentrations. The novel association at the ABO locus provides evidence for a previously unknown regulatory role of histo-blood group antigens in inflammatory adhesion processes.

Genetic variation in sex-steroid receptors and synthesizing enzymes and colorectal cancer risk in women.

OBJECTIVES: Several lines of evidence have suggested that female hormones may lower the risk for developing colorectal cancer. However, the mechanisms by which sex hormones affect colorectal cancer development remain unknown. We sought to determine whether the association may be under genetic control by evaluating genetic variation in estrogen receptors (ESR1 and ESR2), progesterone receptor (PGR), aromatase cytochrome 450 enzyme (CYP19A1), and 17 beta-hydroxysteroid dehydrogenase type 2 gene (HSD17B2). METHODS: We included 158 incident cases of colorectal cancer and 563 randomly chosen control subjects from 28,345 women in the Women's Health Study aged 45 or older who provided blood samples and had no history of cancer or cardiovascular disease at baseline in 1993. All cases and controls were Caucasians of European descent. A total of 63 tagging and putative functional SNPs in the 5 genes were included for analysis. Unconditional logistic regression was used to estimate odds ratio (ORs) and 95% confidence intervals (CIs). RESULTS: There was no association between variation in ESR1, ESR2, PGR, CYP19A1 and HSD17B2 and colorectal cancer risk after correction for multiple comparisons (p values after correction > or =0.25). There was also no association with any of the haplotypes examined (p > or = 0.15) and no evidence of joint effects of variants in the 5 genes (p > or = 0.51). CONCLUSION: Our data offer insufficient support for an association between variation in ESR1, ESR2, PGR, CYP19A1, and HSD17B2 and risk for developing colorectal cancer.

Mean leukocyte telomere length and risk of incident colorectal carcinoma in women: a prospective, nested case-control study.

BACKGROUND: To date, no prospective epidemiological data are available, particularly in women, on mean leukocyte telomere length as a risk predictor. METHODS: Using leukocyte DNA samples collected at baseline in a prospective cohort of over 28,000 initially healthy women, we examined the relationship between mean leukocyte telomere repeat copy number to single gene copy number (TSR) in 134 incident cases of colorectal carcinoma (CRC), and 357 matched controls; all were Caucasian. RESULTS: The observed log(e)-transformed TSRs were similar between cases and controls (p=0.79). Using an adjusted analysis, we found no evidence for an association of the log(e)-TSRs with CRC risk [adjusted odds ratio (OR)=0.943, 95% confidence interval (CI)=0.647-1.376, p=0.762]. Stratified analysis by median follow-up time, or postmenopausal status also showed similar null findings. CONCLUSIONS: In concordance with our previous findings in Caucasian men, the present study in Caucasian women found no evidence for an association of mean leukocyte telomere length with risk of incident CRC, further suggesting that leukocyte telomere length may not be a useful indicator for risk assessment.

Gene variation of the transient receptor potential cation channel, subfamily M, member 7 (TRPM7), and risk of incident ischemic stroke: prospective, nested, case-control study.

BACKGROUND AND PURPOSE: Transient receptor potential cation channel, subfamily M, member 7 (TRPM7), has been implicated in ischemic brain damage, a major source of morbidity and mortality in westernized society. We hypothesized that TRPM7 gene variation might play a role in the risk of ischemic stroke. METHODS: From a group of DNA samples collected at baseline in a prospective cohort of 14 916 initially healthy American men, we assessed 16 TRPM7 tag-single-nucleotide polymorphisms (SNPs) (dbSNP: rs11854949, rs4775899, rs11635825, rs12905120, rs16973487, rs7173321, rs7163283, rs17520378, rs17520350, rs4775892, rs7174839, rs17645523, rs3109894, rs616256, rs11070795, and rs313158) from 245 white men who subsequently had an incident ischemic stroke and from 245 age- and smoking habit-matched white men who remained free of reported vascular disease during follow-up (controls). RESULTS: All SNPs examined were in Hardy-Weinberg equilibrium. Overall allele, genotype, and haplotype distributions were similar between cases and controls. Marker-by-marker conditional logistic-regression analysis, adjusted for potential risk factors, showed no evidence for an association between any of the SNPs tested and ischemic stroke. Further investigation with an Entropy Blocker-defined, haplotype-based approach showed similar null findings. Prespecified analysis limited to participants without baseline diabetes and hypertension (ie, low-risk group) again showed similar null findings. CONCLUSIONS: The present prospective investigation provides no evidence of a role for the TRPM7 gene in the risk of incident ischemic stroke.

A meta-analysis of candidate gene polymorphisms and ischemic stroke in 6 study populations: association of lymphotoxin-alpha in nonhypertensive patients.

BACKGROUND AND PURPOSE: Ischemic stroke is a multifactorial disease with a strong genetic component. Pathways, including lipid metabolism, systemic chronic inflammation, coagulation, blood pressure regulation, and cellular adhesion, have been implicated in stroke pathophysiology, and candidate gene polymorphisms in these pathways have been proposed as genetic risk factors. METHODS: We genotyped 105 simple deletions and single nucleotide polymorphisms from 64 candidate genes in 3550 patients and 6560 control subjects from 6 case-control association studies conducted in the United States, Europe, and China. Genotyping was performed using the same immobilized probe typing system and meta-analyses were based on summary logistic regressions for each study. The primary analyses were fixed-effects meta-analyses adjusting for age and sex with additive, dominant, and recessive models of inheritance. RESULTS: Although 7 polymorphisms showed a nominal additive association, none remained statistically significant after adjustment for multiple comparisons. In contrast, after stratification for hypertension, 2 lymphotoxin-alpha polymorphisms, which are in strong linkage disequilibrium, were significantly associated among nonhypertensive individuals: LTA 252A>G (additive model; OR, 1.41 with 95% CI, 1.20 to 1.65; P=0.00002) and LTA 26Thr>Asn (OR, 1.19 with 95% CI, 1.06 to 1.34; P=0.003). LTA 252A>G remained significant after adjustment for multiple testing using either the false discovery rate or by permutation testing. The 2 single nucleotide polymorphisms showed no association in hypertensive subjects (eg, LTA 252A>G, OR, 0.93; 95% CI, 0.84 to 1.03; P=0.17). CONCLUSIONS: These observations may indicate an important role of LTA-mediated inflammatory processes in the pathogenesis of ischemic stroke.

Candidate genetic variants in the fibrinogen, methylenetetrahydrofolate reductase, and intercellular adhesion molecule-1 genes and plasma levels of fibrinogen, homocysteine, and intercellular adhesion molecule-1 among various race/ethnic groups: data from the Women's Genome Health Study.

BACKGROUND: Although inflammation is a core element of atherogenesis and plasma levels of fibrinogen (FGB), homocysteine, and intercellular adhesion molecule-1 (ICAM-1) differ by race/ethnicity, little is known about the role of genetic polymorphisms in the FGB, methylenetetrahydrofolate reductase (MTHFR), and ICAM-1 genes in determining plasma levels of these biomarkers. We examined the relationship between specific polymorphisms in the FGB, homocysteine, and ICAM-1 genes and their respective inflammatory biomarker concentrations at baseline in women from different race/ethnic groups. METHODS: We genotyped specific polymorphisms in FGB (-455G>A/rs1800790), MTHFR (677C>T/rs1801133), and ICAM-1 (Lys56Met/rs5491 and Gly241Arg/rs1799969) at baseline and evaluated their relationship with respective inflammatory biomarker levels in 25,565 white, 476 African-American (black), 277 Hispanic, and 370 Asian women participating in the Women's Genome Health Study. RESULTS: Overall, the minor allele frequencies for -455G>A were similar among white, Hispanic, and Asian women (17.2%-21.9%) but significantly lower in black women (6.6%, P < .001). The minor allele was associated with elevated FGB levels only in whites and Asians. After adjustment for age, body mass index, smoking, postmenopausal status, diabetes, hormone replacement therapy use, hypertension, and education, black women had the highest FGB levels compared to other race/ethnic groups. The minor allele frequency of the MTHFR 677C>T polymorphism was lowest in blacks (blacks 12.1%, whites 33.1%, Hispanics 39.0%, Asians 24.0%), and the T allele was only significantly associated with homocysteine levels in white women. Among whites, Hispanics, and Asians, the Lys56Met polymorphism was rare compared to the frequency in blacks (P < .001). Neither the Lys56Met nor Gly241Arg polymorphisms were common in Asians. Nonetheless, both polymorphisms were generally associated with lower ICAM-1 levels; the lowest levels were observed in black women. CONCLUSION: We found significant associations between certain candidate genetic polymorphisms and baseline plasma levels of FGB, homocysteine, and ICAM-1 in women from various race/ethnic groups. The present investigation is hypothesis generating and suggests genetic determination of differential concentrations of these atherosclerosis-related inflammatory biomarkers differ among various race/ethnic groups.

Association of genetic variants with the metabolic syndrome in 20,806 white women: The Women's Health Genome Study.

BACKGROUND: Candidate genes associated with cardiovascular disease (CVD) represent potential risk factors for the metabolic syndrome (MetS). METHODS: The association between prevalent MetS and a panel of 62 polymorphisms within 42 candidate genes, previously implicated in the pathophysiology of CVD, were investigated in 20,806 white participants of the Women's Health Study. All were free of known CVD and diabetes at baseline. Logistic regression was performed to investigate the relationship between genotype and the MetS assuming an additive model. Stratified analyses by hormone therapy use were also performed. Correction for multiple testing was performed using false discovery rate for polymorphisms and false positive rate probability for stratified analysis, respectively. RESULTS: The prevalence of the MetS was 23%. In a marker-by-marker analysis, the ADRB2 rs180088 (OR 1.22, 95% CI 1.01-1.48) and PAI1 rs1799768 (OR 1.05, 95% CI 1.01-1.10) were associated with an increased MetS risk, whereas the C5 rs17611 (OR 0.95, 95% CI 0.91-1.00) and the CTLA4 rs5742909 (OR 0.91, 95% CI 0.84-0.99) were associated with a decreased risk. In postmenopausal women, an increased MetS risk was found for the ADRB2 rs180088 (OR 1.28, 95% CI 0.99-1.65), PAI1 rs1799768 (OR 1.07, 95% CI 1.01-1.14), SCNN1A rs5742912 (OR 1.22, 95% CI 1.01-1.47), and IL1A rs1800587 (OR 1.07, 95% CI 1.01-1.15), whereas the AGTR1 rs5186 (OR 0.93, 95% CI 0.87-0.99) was associated with decreased risk. However, none remained significant after false discovery rate correction. In a stratified analysis, one or more copies of the variant C allele of SCNN1A rs5742912 were associated with an increased MetS risk among the current users (OR 1.56, 95% CI 1.21-2.01, P interaction .007, false positive rate probability 0.13). CONCLUSIONS: Effect modification of the SCNN1A rs5742912 on the MetS by hormone therapy use warrants further investigation.

Association between polymorphisms in the beta2-adrenergic receptor gene with myocardial infarction and ischaemic stroke in women.

Results from studies investigating the association between polymorphisms in the beta2-adrenergic receptor gene (ADRB2) and cardiovascular disease (CVD) are controversial. Using haplotype-based analysis, we have previously shown a protective effect of the Gly16-Gln27-Ile164 haplotype on myocardial infarction in men. We sought to replicate these findings in women and further investigated whether the gene variants exert differential effects on myocardial infarction and ischaemic stroke. We performed a prospective study among 25,224 women, participating in the Women's Health Study and free of CVD at study entry. We had information on polymorphisms Gly16Arg, Gln27Glu, and Thr164Ile in the ADRB2. Incident CVD was self-reported and confirmed after medical record review. We used proportional hazards models to investigate the association between genotypes and haplotypes with any myocardial infarction, any ischaemic stroke, and CVD death. During a mean of 11.8 years of follow-up, 274 myocardial infarctions, 299 ischaemic strokes, and 159 CVD deaths occurred. Among the whole cohort genotype- and haplotype-based analyses did not show an association for any of the gene variants with any of the CVD outcomes. When we focused on Caucasian women, the haplotype-based analysis, however, suggested an inverse association of the haplotype Gly16-Gln27-Thr164 with incident myocardial infarction (multivariable-adjusted hazard ratio 0.75; 95% confidence interval 0.58-0.97; p = 0.03). We did not find associations in the haplotype-based analyses with incident ischaemic stroke or CVD death. Our results suggest that the haplotype Gly16-Gln27-Thr164 is associated with reduced risk of incident myocardial infarction but not ischaemic stroke in Caucasian women and suggest differential pathophysiologies for myocardial infarction and stroke.

Association between polymorphisms in the beta2-adrenoceptor gene and migraine in women.

OBJECTIVE: To investigate the role of three common polymorphisms in the beta2-adrenoceptor gene in migraine. BACKGROUND: Migraine has been associated with increased risk of cardiovascular disease and asthma in which beta2-adrenoceptors play an important role; beta-adrenoceptor antagonists are used in migraine prevention. However, the role of variants in the beta2-adrenoceptor gene in migraine is unclear. METHODS: Association study among 23,753 white women, participating in the Women's Health Study, for whom we had information on migraine at baseline and genotype status of the polymorphisms rs1042713 (Gly16Arg), rs1042714 (Gln27Glu), rs1800888 (Thr164Ile). Migraine was self-reported and we distinguished between any history of migraine, active migraine with and without aura, and prior migraine (history of migraine but not active migraine) in our analyses. RESULTS: At baseline 4339 women reported any history of migraine. Of these, 3041 had active migraine (1221 migraine with aura, 1820 migraine without aura) and 1298 prior migraine. No migraine was reported by 19,414 women. Genotype- and haplotype-based analyses did not show an association of any of the gene variants tested with any history of migraine. The multivariable-adjusted odds ratios (ORs) (95% confidence intervals) for any history of migraine in the additive model were 1.0 (0.96-1.05) for rs1042713, 1.0 (0.95-1.05) for rs1042714, and 0.84 (0.68-1.05) for rs1800888. In the haplotype analysis the ORs ranged from 0.83 (0.67-1.03) to 1.01 (0.94-1.07) with Gly16-Glu27-Thr164 as the reference. We also did not find associations in the genotype- and haplotype-based analyses within migraine-specific subgroups. CONCLUSIONS: Our results do not support a role of 3 investigated polymorphisms in the beta2-adrenoceptor gene in migraine pathophysiology.

Polymorphisms in the renin-angiotensin system and migraine in women.

BACKGROUND: Recent findings suggest an association between the renin-angiotensin system and migraine. However, genetic studies are scarce and controversial. OBJECTIVE: To investigate the association between the AGTR1 1166A > C and AGT Met235Thr polymorphisms with migraine and migraine aura status. METHODS: We performed an association study among 25,000 Caucasian US women, participating in the Women's Health Study, with information on the AGTR1 1166A > C and AGT Met235Thr polymorphisms. Migraine and migraine aura status were self-reported. We distinguished between any history of migraine, active migraine with aura, active migraine without aura, and prior migraine (history of migraine, but not in the year prior to baseline). We used logistic regression to investigate the genotype-migraine association. RESULTS: At baseline, 4577 (18.3%) women reported any history of migraine; 39.5% of the 3226 women with active migraine indicated aura. The polymorphisms were not associated with migraine or migraine-specific subgroups. We also did not find a significant interaction between the polymorphisms. CONCLUSIONS: Data from this large cohort of Caucasian women do not suggest an association of polymorphisms in the renin-angiotensin system with migraine or aura status. Future studies should focus on haplotype analyses and additional gene-gene as well as gene-environment interactions.

Quantitative telomerase activity in circulating human leukocytes: utility of real-time telomeric repeats amplification protocol (RQ-TRAP) in a clinical/epidemiological setting.

BACKGROUND: There is accumulating evidence from the epidemiological field of telomere biology that telomere length plays an important role in the pathophysiology of cardiovascular disease. The RNA-dependent DNA polymerase, telomerase, is essential in regulating telomere length by acting as a reverse transcriptase. However, the relationship between telomerase activity and telomere length in cardiovascular disease is unclear. This is due, in part, to the paucity of information on the utility of a quantitative and routine assay for the determination of telomerase activity in circulating blood leukocytes. METHODS: We used a validated, high-sensitive real-time quantitative telomeric repeat amplification protocol (RQ-TRAP) to determine telomerase activity in circulating blood leukocytes. RESULTS: The present investigation demonstrated direct and reliable detection of telomerase activity of circulating blood leukocytes. CONCLUSION: The present investigation suggests the feasibility of using RQ-TRAP assay in routine screening of telomerase activity in blood specimens typically collected in a clinical/epidemiological setting.

Effects of random allocation to vitamin E supplementation on the occurrence of venous thromboembolism: report from the Women's Health Study.

BACKGROUND: Supplementation with vitamin E may antagonize vitamin K in healthy adults, but it is unclear whether intake of vitamin E decreases the risk of venous thromboembolism (VTE). METHODS AND RESULTS: The Women's Health Study randomized 39,876 women > or = 45 years of age to receive 600 IU of natural source vitamin E or placebo on alternate days. Before randomization, 26,779 participants gave blood samples, which were used to determine factor V Leiden, G20210A prothrombin, and 677C>T MTHFR polymorphisms. Documented VTE (including deep vein thrombosis or pulmonary embolism) and unprovoked VTE (no recent surgery, trauma, or cancer diagnosis) were prospectively evaluated, secondary end points of the trial. During a median follow-up period of 10.2 years, VTE occurred in 482 women: 213 in the vitamin E group and 269 in the placebo group, a significant 21% hazard reduction (relative hazard, 0.79; 95% CI, 0.66 to 0.94; P=0.010). For unprovoked VTE, the hazard reduction was 27% (relative hazard, 0.73; 95% CI, 0.57 to 0.94; P=0.016). In subgroup analyses, the 3% of participants who reported VTE before randomization had a 44% hazard reduction (relative hazard, 0.56; 95% CI, 0.31 to 1.00; P=0.048), whereas women without prior VTE had an 18% hazard reduction (relative hazard 0.82; 95% CI, 0.68 to 0.99; P=0.040). Women with either factor V Leiden or the prothrombin mutation had a 49% hazard reduction associated with vitamin E treatment (relative hazard, 0.51; 95% CI, 0.30 to 0.87; P=0.014). CONCLUSIONS: These data suggest that supplementation with vitamin E may reduce the risk of VTE in women, and those with a prior history or genetic predisposition may particularly benefit.

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.