Lucia A. Hindorff

Family history of diabetes as a potential public health tool

Given the substantial morbidity and mortality associated with type 2 diabetes, it is important that public health seek ways to delay or prevent the onset of this condition. Risk factors for type 2 diabetes are well established and include underlying genetic susceptibility. Despite this knowledge, as well as significant advances in understanding the human genome, the prevalence of type 2 diabetes continues to rise at an alarming rate. Because type 2 diabetes is a complex condition involving a combination of genetic and environmental factors, DNA testing for susceptibility genes is not yet warranted. However, because family history reflects genetic susceptibility in addition to other factors, it may be a useful public health tool for disease prevention. When evaluating family history as a public health tool, several important issues need to be considered, including the analytic and clinical validity and the clinical utility of using family history as a screening tool. These issues as well as a review of the epidemiologic evidence evaluating family history as a risk factor will be reviewed.Overall, a family history approach appears to be a promising new public health tool to fight the growing epidemic of diabetes in the United States. Adequate levels of funding to further evaluate this approach and to develop appropriate tools should be made available for research activities focused on this important area.

The Association of PAI-1 Promoter 4G/5G Insertion/Deletion Polymorphism with Myocardial Infarction and Stroke in Young Women

Background The plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G insertion/deletion polymorphism has been associated with increased risk of myocardial infarction (MI) and decreased risk of cerebrovascular events. Whether these results apply to young women is not known. Methods We genotyped 78 MI cases, 106 stroke cases and 385 age-matched controls from a population-based case–control study of MI and stroke in women < 45 years old. Results The risk of MI was significantly decreased in carriers of the 4G allele compared with 5G/5G homozygotes, and the association persisted upon adjustment for other risk factors (age- and race-adjusted OR 0.50, 95% CI 0.29–0.85). Carrying the 4G allele was not associated with stroke, either overall or according to subtype. The association of this polymorphism with MI or stroke did not vary significantly by presence or absence of established cardiovascular risk factors, assessed on either an additive or multiplicative scale. Conclusions These data suggest a decreased risk of MI among young women carrying the 4G allele of the PAI-1 4G/5G polymorphism. Although this result contrasts with those of previous studies of older adults and young men, it may highlight the influence of genetic factors on the development of MI within the context of particular hormonal or environmental influences.

Angiotensin II type 1 receptor polymorphisms in the cardiovascular health study: relation to blood pressure, ethnicity, and cardiovascular events

BACKGROUNDnThe angiotensin II type 1 receptor A1166C polymorphism has been associated with increased risks of hypertension and myocardial infarction in several small studies. We examined the association between this polymorphism and new-onset hypertension, blood pressure (BP) control, and incident cardiovascular events in a large population-based cohort of older adults.nnnMETHODSnEight hundred self-identified African Americans and 1,371 randomly selected white participants in the Cardiovascular Health Study were genotyped. The median duration of follow-up was 8.1 years.nnnRESULTSnThe A1166C polymorphism was not associated with new-onset hypertension, with BP control, or with incident cardiovascular events in the overall population. In white participants, the CC genotype was associated with higher baseline systolic BP and pulse pressure, compared to the AC or AA genotype. In whites with treated hypertension at baseline, compared to the AA genotype, the CC genotype was associated with increased risks of incident congestive heart failure (hazard ratio = 2.5, 95% confidence interval [CI] 1.3-4.9) and incident ischemic stroke (hazard ratio = 2.6, 95% CI 1.1-6.0). These associations were not observed among white participants without treated hypertension, but the interaction of genotype with treated hypertension on ischemic stroke and heart failure was only marginally significant.nnnCONCLUSIONSnOn the whole, in this large cohort of older adults, the A1166C polymorphism was not associated with BP control or incident cardiovascular events. The subgroup findings in treated hypertensives need to be confirmed in additional studies.

Cholesterol Ester Transfer Protein, Interleukin-8, Peroxisome Proliferator Activator Receptor Alpha, and Toll-Like Receptor 4 Genetic Variations and Risk of Incident Nonfatal Myocardial Infarction and Ischemic Stroke

Variations in candidate genes participating in oxidative stress, inflammation, and their interactions are potentially associated with diseases of atherosclerotic origin. We investigated independent and joint associations of variations in cholesterol ester transfer protein (CETP), interleukin-8 (IL8), peroxisome proliferator activator receptor-alpha (PPARA), and Toll-like receptor 4 (TLR4) genes with incident nonfatal myocardial infarction (MI) or ischemic stroke. In a population-based case-control study, patients (848 with MI and 368 with ischemic stroke) and controls (2,682) were recruited from postmenopausal women and hypertensive men/women who were members of Group Health in western Washington State. Common tag single-nucleotide polymorphisms (SNPs; n=34) representing gene-wide variations were selected from gene sequencing data using pairwise linkage disequilibrium. Haplotypes were inferred using a modified expectation maximization algorithm. Multivariate logistic regression evaluated individual haplotype and SNP-disease associations in log-additive models. Global haplotype tests assessed overall gene-disease associations. Logic regression was used to evaluate gene-gene interactions. False discovery rates and permutation tests were used for multiple testing adjustment in evaluating independent associations and interactions, respectively. Overall, gene-wide variations in PPARA and TLR4 genes were associated with MI. The minor allele of the PPARA SNP, rs4253623, was associated with a higher risk of MI (odds ratio 1.25, 95% confidence interval 1.08 to 1.46), whereas the minor allele of the TLR4 SNP, rs1927911, was associated with a lower risk of MI (odds ratio 0.88, 95% confidence interval 0.77 to 0.99). No within-gene or gene-gene interaction was associated with MI or ischemic stroke risk. In conclusion, potential SNP-disease associations identified in the present study are novel and need further investigation.

Common variation in cytochrome P450 epoxygenase genes and the risk of incident nonfatal myocardial infarction and ischemic stroke.

Objective The biologically active epoxyeicosatrienoic acids have protective vascular effects. CYP2J2, CYP2C8, and CYP2C9 are known to be a source of epoxyeicosatrienoic acids in cardiac tissues. We conducted a population-based, case–control study at Group Health to determine whether common genetic variation in the CYP2J2, CYP2C8, and CYP2C9 genes was associated with the risk of myocardial infarction and ischemic stroke. Methods We used publicly available single nucleotide polymorphism discovery data from a mixed race panel of 90 individuals to select 30 tag-single nucleotide polymorphisms that were genotyped in 856 myocardial infarction cases, 368 stroke cases and 2688 controls. We used logistic regression to estimate additive associations. To account for multiple testing, we report q values alongside findings with P<0.05. Results Variation in CYP2J2 was associated with myocardial infarction risk (P=0.027, q=0.081). Two intronic CYP2J2 tag-single nucleotide polymorphisms, rs10889160 and rs11572325 were associated with an increased risk of myocardial infarction (odds ratio: 1.24, 95% confidence interval: 1.07–1.43, P=0.004, q=0.090, and odds ratio: 1.27, 95% confidence interval: 1.08–1.51, P=0.006, q=0.090, respectively). No evidence of an association was found between variation in CYP2J2 and stroke and there was no association between variation in CYP2C8 or CYP2C9 and myocardial infarction or stroke. Conclusion Common variation in CYP2J2 is associated with the risk of myocardial infarction.

β1- and β2-adrenergic receptor gene variation, β-blocker use and risk of myocardial infarction and stroke

BACKGROUNDnThe benefits of beta-blocker therapy may depend on underlying genetic susceptibility.nnnMETHODSnWe investigated the interaction of common variation in beta1 and beta2 adrenergic receptor (AR) genes with beta-blocker use on the risks of myocardial infarction (MI) and ischemic stroke in a case-control study. Participants were treated pharmacologically for hypertension, aged 30-79 years, with incident MI (n = 659) or ischemic stroke (n = 279) between 1995 and 2004, and 2,249 matched controls.nnnRESULTSnWe observed an interaction of beta-blocker use with beta1-AR gene variation on MI risk (P value, 6 degrees of freedom: 0.01) and ischemic stroke risk (P value, 6 degrees of freedom: 0.04). Compared with use of other antihypertensive medications, beta-blocker use was associated with higher MI risk in carriers of one or two copies of rs#17875422 (Odds ratio (OR): 2.66, 95% confidence interval (CI); 1.26-5.60) but not in homozygous carriers of the common allele (OR: 0.88, 95% CI: 0.73-1.07). Another variant, rs#2429511, interacted with beta-blocker use on both MI and ischemic stroke risks. beta-blocker use was associated with higher risk of combined MI and ischemic stroke in carriers of rs#2429511 (OR: 1.24, 95% CI: 1.03-1.50) but not in homozygous carriers of common allele (OR: 0.70, 95% CI: 0.51-0.94). beta-blocker use did not interact with beta2-AR gene variation on the risks of MI and ischemic stroke.nnnCONCLUSIONSnThese results, which require replication, suggest genetic variants in the beta1-AR gene may determine whether to use beta-blockers in hypertension for the primary prevention of cardiovascular disease.

Associations between common fibrinogen gene polymorphisms and cardiovascular disease in older adults - The Cardiovascular Health Study

Elevated plasma fibrinogen is a risk factor for cardiovascular disease (CVD), but associations between fibrinogen single nucleotide polymorphisms (SNPs) and disease risk are inconsistent. We investigated whether common (> or = 5% minor allele frequency) variation in the fibrinogen genes (FGA, FGB, FGG) is associated with fibrinogen concentration, carotid artery intima-medial thickness (IMT) and risk of incident myocardial infarction (MI), ischemic stroke and CVD mortality in European- (EA) and African-descent (AA) adults (> or = 65 years) from the Cardiovascular Health Study. TagSNPs were genotyped in 3,969 EA and 719 AA free of MI or stroke at baseline. Race-specific models included multiple testing correction and adjustment for sex, age and site. Among EA, minor alleles of FGA3807, FGB1437 and FGG902 were associated with higher fibrinogen levels; whereas FGA251, FGA2224, FGA6534 and FGG10034 were associated with lower levels, p<0.004 for each. Strongest associations were seen for FGB1437; each additional copy of the minor allele was associated with 13 mg/dl (95%CI: 9-16) higher fibrinogen level. Similar trends in AA were not significant. Fibrinogen haplotypes were not significantly associated with internal or common carotid IMT. No associations with MI or CVD mortality were seen in EA, though FGB1038 and FGG902 were significantly associated with increased and decreased risk of stroke in men, respectively, as were related haplotypes. FGB1038 was also associated with CVD mortality in AA, HR = 1.9 (95%CI: 1.3-2.7). In conclusion, while fibrinogen genetic variation was strongly associated with fibrinogen levels, there was less evidence of association with the more complex outcomes of IMT and CVD events.

No clear link between VKORC1 genetic polymorphism and the risk of venous thrombosis or peripheral arterial disease

No clear link between VKORC1 genetic polymorphism and the risk of venous thrombosis or peripheral arterial disease -

Common VKORC1 variants are not associated with arterial or venous thrombosis

The vitamin K epoxide receptor complex subunit 1 (VKORC1) plays a crucial role in the regulation of several vitamin Kdependent proteins relevant to hemostasis and, perhaps, atherosclerosis [1]. Common polymorphisms and haplotypes of the VKORC1 gene have recently been shown to predict warfarin response [2,3] and arterial disease [4]. The latter findings have not yet been replicated in a population-based setting. Whether these variants are associated with venous disease in the general population is unknown. The goal of this study was to replicate the recent arterial thrombosis findings and determine whether these variants are additionally associated with venous thrombosis. Participants in this study formed part of three ongoing case– control studies of myocardial infarction (MI), stroke, and venous thrombosis (VT) at Group Health, a large healthcare delivery system based in western Washington State. All participants gave written informed consent. TheMI and stroke cases were either persons with pharmacologically treated hypertension or perimenopausal or postmenopausal women who had an incident non-fatal MI or ischemic stroke during 1995–2002 and were 30–79 years old [5,6]. VT cases were perimenopausal or postmenopausal women who experienced an incident deep vein thrombosis or pulmonary embolism during 1995–2002 and were 30–89 years old [7]. A common control group of randomly selected members of Group Health was frequency matched to MI cases on the basis of age, sex, and treated hypertension. Control participants were eligible for MI or stroke analyses if they did not have a priorMI or stroke, and were eligible for VT analyses if they did not have a prior deep vein thrombosis or pulmonary embolism. Data on characteristics prior to each participant s index date were collected from the Group Health outpatient record, and a venous blood sample was collected at an in-person interview. Single-nucleotide polymorphisms (SNPs) in the VKORC1 gene were identified through the resequencing efforts of SeattleSNPs (http://pga.gs.washington.edu; accessed 10 August 2007). Five tagSNPs (rs17708472, rs9934438, rs8050894, rs2359612 and rs7294) were initially selected and successfully genotyped on the Illumina BeadArray platform; 99.96% of genotypes were successfully called. These SNPs correspond to SeattleSNPs positions 6009, 6484, 6853, 7566, and 9041, respectively. According to SeattleSNPs data, three SNPs (rs9934438, rs8050894, and rs2359612) were in high linkage disequilibrium (r > 0.64); to avoid redundancy, only rs2359612 is presented in this analysis. All SNPs were in Hardy–Weinberg equilibrium. Haplotypes were inferred using PHASE 2.0. Odds ratios and 95% confidence intervals for the association between each SNP and outcome were calculated using logistic regression, and were adjusted for age, sex, treated hypertension, year of identification, and race (three categories). For haplotypes, estimates were derived from weighted logistic regression and robust standard errors, where weights corresponded to the probability for each possible inferred haplotype combination. The most common haplotype was arbitrarily selected as the reference. A Wald test was used to assess the global hypothesis that no haplotype had an association with the outcome that was significantly different from 1. The distribution of age, sex and treated hypertension across the case–control groups was consistent with the study design. The average age of study participants was 66 years for the MI and stroke studies and 68 years for the VT study. Caucasians comprised greater than 91% of the participants. Of the combined MI and stroke controls (n = 2686), MI cases (n = 856), and stroke cases (n = 368), men comprised 42%, Correspondence: Lucia A. Hindorff, Department of Epidemiology, University of Washington, Seattle, WA, USA. Tel.: +1 206 287 2808; fax: +1 206 287 2662; e-mail: lah@u. washington.edu