Combined admixture mapping and association analysis identifies a novel blood pressure genetic locus on 5p13: contributions from the CARe consortium.

Admixture mapping based on recently admixed populations is a powerful method to detect disease variants with substantial allele frequency differences in ancestral populations. We performed admixture mapping analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP), followed by trait-marker association analysis, in 6303 unrelated African-American participants of the Candidate Gene Association Resource (CARe) consortium. We identified five genomic regions (P< 0.001) harboring genetic variants contributing to inter-individual BP variation. In follow-up association analyses, correcting for all tests performed in this study, three loci were significantly associated with SBP and one significantly associated with DBP (P< 10(-5)). Further analyses suggested that six independent single-nucleotide polymorphisms (SNPs) contributed to the phenotypic variation observed in the admixture mapping analysis. These six SNPs were examined for replication in multiple, large, independent studies of African-Americans [Women's Health Initiative (WHI), Maywood, Genetic Epidemiology Network of Arteriopathy (GENOA) and Howard University Family Study (HUFS)] as well as one native African sample (Nigerian study), with a total replication sample size of 11 882. Meta-analysis of the replication set identified a novel variant (rs7726475) on chromosome 5 between the SUB1 and NPR3 genes, as being associated with SBP and DBP (P< 0.0015 for both); in meta-analyses combining the CARe samples with the replication data, we observed P-values of 4.45 × 10(-7) for SBP and 7.52 × 10(-7) for DBP for rs7726475 that were significant after accounting for all the tests performed. Our study highlights that admixture mapping analysis can help identify genetic variants missed by genome-wide association studies because of drastically reduced number of tests in the whole genome.

Resistin, but not adiponectin and leptin, is associated with the risk of ischemic stroke among postmenopausal women: results from the Women's Health Initiative.

BACKGROUND AND PURPOSE: Adipose tissue is considered an endocrine organ that secretes adipokines, which possibly mediate the effects of obesity on the risk of cardiovascular disease. However, there are yet limited prospective data on the association between circulating adipokine levels and the risk of ischemic stroke. We aimed to examine the associations of 3 adipokines (adiponectin, leptin, and resistin) with the risk of ischemic stroke. METHODS: We conducted a prospective nested case-control study (972 stroke cases and 972 matched control subjects) within the Women's Health Initiative Observational Study cohort. The control subjects were matched to cases on age, race/ethnicity, date of study enrollment, and follow-up time. RESULTS: Adipokine levels were associated with established stroke risk factors such as obesity and systolic blood pressure. Adjusted for body mass index, the ORs for incident ischemic stroke comparing the highest (Quartile 4) with the lowest quartile (Quartile 1) were 0.81 (95% CI, 0.61 to 1.08; P trend=0.068) for adiponectin, 1.15 (95% CI, 0.83 to 1.59; P trend=0.523) for leptin, and 1.57 (95% CI, 1.18 to 2.08; P trend=0.002) for resistin. The association for resistin remained significant even after accounting for established stroke risk factors (OR, 1.39; 95% CI, 1.01 to 1.90; P trend=0.036). Further adjustment for markers for inflammation, angiogenesis, and endothelial function also did not affect our results. CONCLUSIONS: Circulating levels of resistin, but not those of adiponectin or leptin, are associated with an increased risk of incident ischemic stroke in postmenopausal women, independent of obesity and other cardiovascular disease risk factors.

Family history of myocardial infarction predicts incident coronary heart disease in postmenopausal women with diabetes: the Women's Health Initiative Observational Study.

BACKGROUND: Diabetes is a risk factor for coronary heart disease (CHD) but CHD does not occur in all diabetic individuals. The goal of this study was to assess the relationship between family history of myocardial infarction (MI) and incident CHD in diabetic postmenopausal women. METHODS: We conducted a prospective cohort study among 2642 diabetic postmenopausal women without CHD at baseline in the Women's Health Initiative Observational Study. Family history was defined as a proband report of MI in first-degree relatives. Incident CHD was defined as non-fatal MI, coronary revascularization, or CHD death. RESULTS: During 7.3 ( +/- 1.8) years of follow-up, 14.3% of the participants had incident CHD. The risk of incident CHD was 50% higher (HR = 1.50, 95% CI: 1.20-1.87, p = 0.0003) in those with a family history of an MI in at least one first-degree relative, and 79% higher (HR = 1.79, 95% CI: 1.36-2.35, P < 0.0001) if two or more first-degree relatives had an MI, compared to participants without a family history, after adjustment for covariates. The CHD risk increased with elevated systolic blood pressure (SBP) (HR = 1.01, 95% CI: 1.003-1.02, p = 0.001) but decreased with elevated diastolic BP (HR = 0.98, 95% CI: 0.97-0.999, p = 0.005) and with two or more episodes per week of physical activity (HR = 0.70, 95% CI: 0.52-0.93, p = 0.02). CONCLUSIONS: The results suggest that a family history of MI predicts CHD in diabetic postmenopausal women. Close attention should be paid to BP control and physical activity in these women.

Panic attacks, daily life ischemia, and chest pain in postmenopausal women.

BACKGROUND: Chest pain is a common symptom of panic attacks, but little is known about the relationship in older women among panic attacks, chest pain, and daily life ischemia. METHODS: The authors conducted a cross-sectional survey of 3063 community-dwelling, generally healthy postmenopausal women enrolled between 1997 and 2000 in the Myocardial Ischemia and Migraine Study in 10 clinical centers of the 40-center Women's Health Initiative. Participants, ages 50 to 79 years, completed a questionnaire about occurrence of panic attacks in the previous 6 months and underwent 24-hour ambulatory electrocardiogram monitoring (AECG); 2705 women had valid AECG recordings and panic attack questionnaires. ST depression on AECG, heart rate variability (HRV), and chest pain episodes were compared among women with and without a 6-month history of panic attack. RESULTS: There was no difference in overall prevalence of ischemic episodes during AECG between women with and without panic attacks. Women with a recent history of panic were more likely to experience chest pain during AECG after controlling for potential confounders (odds ratio [OR] = 2.01; 95% confidence interval [CI] = 1.40-2.88), including both nonischemic (OR = 1.83; 95% CI = 1.26-2.65) and ischemic chest pain (OR = 4.94; 95% CI = 1.41-17.30). Although mean HRV was lower in those with panic attacks (p = .017), this was not significant after controlling for confounders. CONCLUSIONS: Postmenopausal women with a recent history of panic attacks do not appear to have more daily life ischemia as measured by occurrence of ST depression during 24-hour monitoring, but do have more chest pain and possibly lower HRV, suggesting that even sporadic panic attacks may be related to cardiovascular risk.

An updated meta-analysis of genome scans for hypertension and blood pressure in the NHLBI Family Blood Pressure Program (FBPP).

A meta-analysis of the results from a multicenter genome-wide linkage study for hypertension and blood pressure (BP) based on an initial sample of 6,245 individuals was published in 2003. We report here a combined linkage analysis of hypertension and BP using the complete Family Blood Pressure Program (FBPP) dataset, which includes a total of 12,028 genotyped individuals. Genome-wide linkage analyses for hypertension and BP were first performed in each of the studied ethnic group within each network and the results were combined with a meta-analysis using a modified Fisher's method of combining P values. Our meta-analysis of genome scans for the latest FBPP dataset reveals suggestive linkage for hypertension and BP at several regions on the human genome. Strong evidence for linkage at two of these regions, 2p14 and 3p14.1, have also been published in previous meta-analyses, making them good candidate locations for susceptibility variants.

Genome-wide linkage analysis of lipids in nondiabetic Chinese and Japanese from the SAPPHIRe family study.

BACKGROUND: Lipid levels are recognized as major risk factors for coronary heart disease (CHD). Discovery of major loci underlying quantitative lipid traits could help to elucidate the genetics of CHD. METHODS: We performed a genome-wide search for quantitative trait loci linked to lipid phenotypes in 1538 Chinese subjects (509 families) and 625 Japanese subjects (204 families) not taking lipid-lowering medications from the Stanford-Asian Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe) study. The multipoint variance-components method was used to test for linkage between marker loci and each trait by maximum likelihood methods adjusted for effects of age, age(2), gender, body mass index (BMI), smoking, alcohol drinking, physical activity, and field center. RESULTS: The highest logarithm of odds (LOD) score detected was 3.22 for logarithmically transformed HDL-cholesterol on chromosome 12 at 113 cM in Chinese subjects. This score overlaps the positive findings for HDL reported in Mexican Americans (chromosome 12 at 96 cM). Although no strong evidence for linkage was found in Japanese subjects, some modest peaks (LOD score >==1.5) were found in several regions that have been reported in other published genome scans. For example, the Japanese SAPPHIRe peak for HDL (chromosome 1 at 167 cM; LOD = 1.54) was very close to the quantitative trait loci (QTL) for HDL reported in the scan of white American HyperGEN (chromosome 1 at 159.9 cM). CONCLUSIONS: Genome-wide scan for genes influencing lipid phenotypes was conducted and we found significant linkage of HDL to a locus on chromosome 12 in Chinese subjects and no linkage signal exceeding 1.68 was found in the Japanese subjects.

High-throughput genotyping of single nucleotide polymorphisms using new biplex invader technology.

The feasibility of large-scale genome-wide association studies of complex human disorders depends on the availability of accurate and efficient genotyping methods for single nucleotide polymorphisms (SNPs). We describe a new platform of the invader assay, a biplex assay, where both alleles are interrogated in a single reaction tube. The assay was evaluated on over 50 different SNPs, with over 20 SNPs genotyped in study cohorts of over 1500 individuals. We assessed the usefulness of the new platform in high-throughput genotyping and compared its accuracy to genotyping results obtained by the traditional monoplex invader assay, TaqMan genotyping and sequencing data. We present representative data for two SNPs in different genes (CD36 and protein tyrosine phosphatase 1beta) from a study cohort comprising over 1500 individuals with high or low-normal blood pressure. In this high-throughput application, the biplex invader assay is very accurate, with an error rate of <0.3% and a failure rate of 1.64%. The set-up of the assay is highly automated, facilitating the processing of large numbers of samples simultaneously. We present new analysis tools for the assignment of genotypes that further improve genotyping success. The biplex invader assay with its automated set-up and analysis offers a new efficient high-throughput genotyping platform that is suitable for association studies in large study cohorts.

Combined analysis of genomewide scans for adult height: results from the NHLBI Family Blood Pressure Program.

A combined analysis of genome scans was performed for adult height in the NHLBI Family Blood Pressure Program. Height data were available on 6752 individuals. Linkage analysis was performed first separately for each of the eight ethnic groups in the four networks using the variance component method. To increase the power to detect the common genetic components affecting height for all the individuals, a linkage analysis was performed subsequently for the combined data set by pooling the average allele-sharing IBD () for all groups. By combining the data, we replicated evidence for a QTL influencing adult height on chromosome 7 (7q31) (LOD=2.46), which has been reported in two previous studies. Suggestive linkage (LOD>1) was found in another six regions in our combined analysis. Evidence for linkage for two of these regions (2p12, 20p11) has also been reported previously.

A genome scan for hypertension susceptibility loci in populations of Chinese and Japanese origins.

BACKGROUND: Our understanding of genes that predispose to essential hypertension is poor. METHODS: A genome-wide scan for linkage at approximately 10 cM resolution was done on 1425 sibpairs of Chinese and Japanese origins that were concordant for hypertension (N = 661), low-normal blood pressure (BP) (N = 184), or discordant for BP (N = 580). RESULTS: There was no significant evidence of linkage to a single locus in the genome. There was suggestive evidence of linkage to chromosome 10p, with a LOD score of 2.5. CONCLUSIONS: We can exclude the possibility that a single gene accounts for at least 15% of the variance in hypertension in this population.

Clustering and heritability of insulin resistance in Chinese and Japanese hypertensive families: a Stanford-Asian Pacific Program in Hypertension and Insulin Resistance sibling study.

The clustering between hypertension and other metabolic abnormalities related to insulin resistance syndrome (IRS) has been investigated in cross-sectional and prospective studies. Offspring studies have revealed that the clustering characteristics of IRS have familial components. However, it is not known whether the clustering also occurs in siblings (sibs) with different levels of blood pressure (BP). In addition, the genetic susceptibility accounting for the clustering in hypertensive families has not been determined. Siblings with Japanese or Chinese ancestry and having either similar BP levels (concordant sibs) or different BP levels (discordant sibs) were recruited. The delta method and variance component model were applied to analyze the differences in metabolic variables between hypertension (HTN) and low BP (LBP) sibs, and to compute the polygenic heritabilities for these metabolic variables and insulin sensitivity. After adjustment for age, gender and body mass index (BMI), HTN (n=393) sibs had higher levels of triglyceride (p < 0.0001), VLDL-cholesterol (p<0.0001), fasting insulin (p < 0.05), and homeostasis model assessment of insulin resistance (HOMAir) (p < 0.05) than LBP sibs (n = 389), but there were no differences in fasting glucose or high density lipoprotein (HDL)-cholesterol. The HTN sibs also had higher plasma glucose and insulin levels at 2 h after 75 g oral glucose loading (p<0.001 and p<0.01, respectively). The heritability estimates for fasting glucose, fasting insulin and HOMAir were 0.58, 0.43 and 0.46, respectively; for triglyceride, HDL-cholesterol, and BMI they were 0.60, 0.63 and 0.54, respectively. In hypertensive families, sibs with extreme levels of BP have significant differences in IRS-associated metabolic variables. The clustering characteristics and the significance of heritability estimation for these metabolic variables indicate that IRS is familial in nature and heritable in Chinese and Japanese hypertensive families.

Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.

CONTEXT: Despite decades of use and considerable research, the role of estrogen alone in preventing chronic diseases in postmenopausal women remains uncertain. OBJECTIVE: To assess the effects on major disease incidence rates of the most commonly used postmenopausal hormone therapy in the United States. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled disease prevention trial (the estrogen-alone component of the Women's Health Initiative [WHI]) conducted in 40 US clinical centers beginning in 1993. Enrolled were 10 739 postmenopausal women, aged 50-79 years, with prior hysterectomy, including 23% of minority race/ethnicity. INTERVENTION: Women were randomly assigned to receive either 0.625 mg/d of conjugated equine estrogen (CEE) or placebo. MAIN OUTCOME MEASURES: The primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death). Invasive breast cancer incidence was the primary safety outcome. A global index of risks and benefits, including these primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture, and deaths from other causes, was used for summarizing overall effects. RESULTS: In February 2004, after reviewing data through November 30, 2003, the National Institutes of Health (NIH) decided to end the intervention phase of the trial early. Estimated hazard ratios (HRs) (95% confidence intervals [CIs]) for CEE vs placebo for the major clinical outcomes available through February 29, 2004 (average follow-up 6.8 years), were: CHD, 0.91 (0.75-1.12) with 376 cases; breast cancer, 0.77 (0.59-1.01) with 218 cases; stroke, 1.39 (1.10-1.77) with 276 cases; PE, 1.34 (0.87-2.06) with 85 cases; colorectal cancer, 1.08 (0.75-1.55) with 119 cases; and hip fracture, 0.61 (0.41-0.91) with 102 cases. Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01-1.24); total cancer, 0.93 (0.81-1.07); total fractures, 0.70 (0.63-0.79); total mortality, 1.04 (0.88-1.22), and the global index, 1.01 (0.91-1.12). For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10 000 person-years and an absolute risk reduction of 6 fewer hip fractures per 10 000 person-years. The estimated excess risk for all monitored events in the global index was a nonsignificant 2 events per 10 000 person-years. CONCLUSIONS: The use of CEE increases the risk of stroke, decreases the risk of hip fracture, and does not affect CHD incidence in postmenopausal women with prior hysterectomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women.

Improvement in stroke risk prediction: role of C-reactive protein and lipoprotein-associated phospholipase A2 in the women's health initiative.

BACKGROUND: Classification of risk of ischemic stroke is important for medical care and public health reasons. Whether addition of biomarkers adds to predictive power of the Framingham Stroke Risk or other traditional risk factors has not been studied in older women. METHODS: The Hormones and Biomarkers Predicting Stroke Study is a case-control study of blood biomarkers assayed in 972 ischemic stroke cases and 972 controls, nested in the Women's Health Initiative Observational Study of 93, 676 postmenopausal women followed for an average of eight-years. We evaluated additive predictive value of two commercially available biomarkers: C-reactive protein and lipoprotein-associated phospholipase A2 to determine if they added to risk prediction by the Framingham Stroke Risk Score or by traditional risk factors, which included lipids and other variables not included in the Framingham Stroke Risk Score. As measures of additive predictive value, we used the C-statistic, net reclassification improvement, category-less net reclassification improvement, and integrated discrimination improvement index. RESULTS: Addition of C-reactive protein to Framingham risk models or additional traditional risk factors overall modestly improved prediction of ischemic stroke and resulted in overall net reclassification improvement of 6·3%, (case net reclassification improvement=3·9%, control net reclassification improvement=2·4%). In particular, high-sensitivity C-reactive protein was useful in prediction of cardioembolic strokes (net reclassification improvement=12·0%; 95% confidence interval 4·3-19·6%) and in strokes occurring in less than three-years (net reclassification improvement=7·9%, 95% confidence interval 0·8-14·9%). Lipoprotein-associated phospholipase A2 was useful in risk prediction of large artery strokes (net reclassification improvement=19·8%, 95% confidence interval 7·4-32·1%) and in early strokes (net reclassification improvement=5·8%, 95% confidence interval 0·4-11·2%). CONCLUSIONS: C-reactive protein and lipoprotein-associated phospholipase A2 can improve prediction of certain subtypes of ischemic stroke in older women, over the Framingham stroke risk model and traditional risk factors, and may help to guide surveillance and treatment of women at risk.

The effects of the renin-angiotensin-aldosterone system gene polymorphisms on insulin resistance in hypertensive families.

INTRODUCTION: The hereditability of insulin resistance has been demonstrated in both familial and twin studies. The effects of renin-angiotensin-aldosterone system gene polymorphisms on insulin resistance remain inconclusive. METHODS: This is a sibling-based association study. Polymorphisms of renin-angiotensin-aldosterone system genes were examined in 1113 hypertension and 676 normotension siblings from Chinese and Japanese hypertensive families. The generalized estimation equations method was used to compare the differences in metabolic variables between hypertension and normotensive siblings. RESULTS: For the G-6A polymorphism of AGT, GG siblings had lower 2-h insulin than siblings carrying the A allele (p=0.006). Siblings with different variants of the angiotensin II type 1 receptor A1166C had no difference in metabolic variables. Siblings carrying the D allele of the angiotensin converting enzyme gene had higher levels of fasting glucose, fasting insulin, area under the curve of insulin levels and the homeostasis model assessment of insulin resistance than II siblings (all p<0.05). Lower levels of fasting glucose and 2-h glucose were observed in siblings with the T allele than their CC homozygotes for the C-344T polymorphism of CYP11B2 (p<0.05). Siblings carrying three high-risk genotypes of the angiotensin converting enzyme, angiotensinogen and CYP11B2 had higher fasting glucose level than siblings carrying no high-risk genotypes (p=0.011). CONCLUSION: Our comprehensive analysis of renin-angiotensin-aldosterone system gene polymorphisms demonstrates that the angiotensin converting enzyme and CYP11B2 gene polymorphisms are associated with insulin resistance in hypertensive families.

Hypertension in pregnancy as a risk factor for cardiovascular disease later in life.

OBJECTIVE: The association between hypertension in pregnancy and future cardiovascular disease (CVD) increasingly is recognized. We aimed to assess the role of hypertension in pregnancy as an independent risk factor for hypertension, coronary heart disease (CHD), and stroke later in life. METHODS: Women who participated in the Phase 2 (2000-2004) Family Blood Pressure Program study (n = 4782) were categorized into women with no history of pregnancy lasting more than 6 months (n = 718), women with no history of hypertension in pregnancy (n = 3421), and women with a history of hypertension in at least one pregnancy (n = 643). We used Kaplan-Meier and Cox proportional hazard models to estimate and contrast the risks of subsequent diagnoses of hypertension, CHD, and stroke among the groups. RESULTS: Women with a history of hypertension in pregnancy, compared with those without such a history, were at increased risks for the subsequent diagnoses of hypertension (50% hypertensive at the age 53 vs. 60, P < 0.001), CHD (14% estimated event rate vs. 11%, P = 0.009), and stroke (12% estimated event rate vs. 5%, P < 0.001). The increased risk for subsequent hypertension remained significant after controlling for race, family history of CVD, smoking, dyslipidemia, and diabetes mellitus, with an adjusted hazard ratio of 1.88 [95% confidence interval (CI) 1.49-2.39, P < 0.001]. After controlling for traditional risk factors, including subsequent hypertension, the increased risk for stroke remained statistically significant (hazard ratio 2.10, 95% CI 1.19-3.71, P = 0.01), but not for CHD. CONCLUSION: Hypertension in pregnancy may be an independent risk factor for subsequent diagnoses of hypertension and stroke.

Relationship of the polyunsaturated to saturated fatty acid ratio to cardiovascular risk factors and metabolic syndrome in Japanese: the INTERLIPID study.

AIM: There have been few studies on the relationships of the dietary polyunsaturated to saturated fatty acid ratio (P/S) to cardiovascular risk factors and metabolic syndrome. We hypothesized that there would be favorable relationships. METHODS: Metabolic cardiovascular risk factors from dietary nutrient intake were investigated in 1,004 men and women aged 40-59 years from 4 population samples of Japanese. Multiple linear regression analysis was used to examine the relationship of the dietary P/S ratio to the following risk factors: hemoglobin A1c, blood pressure, serum triglycerides, LDL and total cholesterol, and HDL-cholesterol. Adjusted odds ratio of having metabolic syndrome was also calculated. RESULTS: The dietary P/S ratio was significantly and inversely related to serum total and LDL cholesterol with control for possible confounding variables. We did not find any significant relationship between the P/S ratio and single metabolic risk factors or the prevalence of metabolic syndrome. CONCLUSIONS: Managing the P/S ratio is important to control serum LDL-cholesterol; however, increasing the P/S ratio may not improve metabolic risk factors. Other countermeasures, such as weight control, greater physical activity, and smoking cessation should be recommended to prevent and control metabolic syndrome.

Vasomotor symptoms and coronary artery calcium in postmenopausal women.

OBJECTIVE: We assessed whether vasomotor symptoms (VMS) are associated with coronary artery calcium (CAC) and how hormone therapy (HT) may influence this association. METHODS: Participants were a subset of women aged 50 to 59 years with a history of hysterectomy who were enrolled in the Women's Health Initiative (WHI) estrogen-alone clinical trial and underwent a CT scan of the chest at the end of the trial to determine CAC. Participants provided information about VMS (hot flashes and/or night sweats), as well as HT use, on self-administered questionnaires at trial baseline. RESULTS: The sample consisted of 918 women with a mean (SD) age of 55.1 (2.8) years at WHI randomization and 64.8 (2.9) years at CAC ascertainment. The prevalence of a CAC score higher than 0 was 46%, whereas the prevalence of a CAC score of 10 or higher and higher than 100 was 39% and 19%, respectively. At randomization, 77% reported a history of any VMS at any time before or at enrollment in the WHI, whereas 20% reported any VMS present only at enrollment. Compared with those without a history of any VMS and after adjustment for potential confounders, a history of any VMS at any time up to and including WHI enrollment was associated with significantly reduced odds for CAC higher than 0 (odds ratio, 0.66; 95% CI, 0.45-0.98). Moreover, as duration of HT increased, the inverse association between any VMS and CAC moved toward the null. CONCLUSIONS: A history of any VMS was significantly associated with reduced odds for CAC independent of traditional cardiovascular disease risk factors and other relevant covariates. This association seems to be influenced by duration of HT.

Sex disparities in control and treatment of modifiable cardiovascular disease risk factors among patients with diabetes: Translating Research Into Action for Diabetes (TRIAD) Study.

OBJECTIVE: Cardiovascular disease (CVD) mortality has decreased in men but not in women with diabetes. We investigated whether sex differences in control and treatment of CVD risk factors might underlie this disparity. RESEARCH DESIGN AND METHODS: We performed cross-sectional analyses from a cohort of patients with diabetes sampled from 10 U.S. managed care health plans. Study end points included not being in control for CVD risk factors (>or=140 mmHg for systolic blood pressure [SBP], >or=3.35 mmol/l for LDL cholesterol, and >or=8.0% for A1C) and the intensity of medication management (number of medication classes) for patients not in control. Logistic regression models with random intercepts were used to adjust probabilities of control and management for demographics, clinical characteristics, and clustering within health plans. RESULTS: There were 1,315 women and 1,575 men with a history of CVD and 3,415 women and 2,516 men without a history of CVD. Among patients with CVD, adjusted estimated probabilities for not being in control and risk differences varied significantly between men and women for SBP (men 41.2%, women 46.6%; risk difference -5.4% [95% CI -9.5 to -1.3]) and LDL cholesterol (men 22.4%, women 28.3%; risk difference -5.9% [-9.9 to -1.8]). There were no significant sex differences in intensity of medication management for patients not in control. In patients without CVD there were no significant differences in control or intensity of medication management. CONCLUSIONS: In diabetic patients with CVD, poorer control of SBP and LDL cholesterol for women may contribute to the sex disparity in CVD mortality trends.

Family history of diabetes, autoimmunity, and risk factors for cardiovascular disease among children with diabetes in the SEARCH for Diabetes in Youth Study.

BACKGROUND: While type 1 diabetes and type 2 diabetes (T2D) are considered etiologically distinct, mixed features of autoimmunity and insulin resistance are increasingly common. We explored a familial contribution to this admixture by evaluating diabetes family history (FH) and its relationship to diabetes type, ethnicity, age at diagnosis, and cardiovascular risk factors in SEARCH for Diabetes in Youth Study participants. METHODS: Diabetes FH was assessed by questionnaire, with FH categories defined by relative's(s') age at diagnosis as follows: <25 (early FH), >/=25 (later FH), and both <25 and >/=25 (mixed FH). Diabetes type was classified based on a biochemical algorithm using diabetes autoantibodies and fasting C-peptide (FCP). RESULTS: A positive FH was common in all diabetes types, particularly T2D (83%). Minorities were more likely to have a positive FH than non-Hispanic Whites [odds ratio (OR) 1.96, 95% confidence interval (CI) 1.69-2.27]. The likelihood of having an early FH decreased with age at diagnosis (OR 0.95, 95% CI 0.93-0.98), and the likelihood of having a later/mixed or any positive FH increased with age (OR 1.03, 95% CI 1.01-1.04; OR 1.03, 95% CI 1.02-1.05, respectively). Higher FCP concentrations and less desirable values for almost all cardiovascular risk factors were associated with a later/mixed FH. The association between a later/mixed FH and FCP, body mass index, waist circumference, triglycerides, and high-density lipoprotein remained significant in a subgroup of autoimmune participants. CONCLUSIONS: Later FH confers cardiovascular risk factors in diabetic youth, including those youth with islet cell autoimmunity. This characterization of diabetes FH may provide a better understanding of familial contributors to diabetes.

An investigation of genome-wide associations of hypertension with microsatellite markers in the family blood pressure program (FBPP).

The Family Blood Pressure Program (FBPP) has data on 387 microsatellite markers in 13,524 subjects from four major ethnic groups. We investigated genetic association with hypertension of the linkage markers. Family-based methods were used to test association of the 387 loci with resting blood pressures (BPs) [systolic blood pressure (SBP) and diastolic blood pressure (DBP)] and the hypertension status (HT). We applied a vote-counting approach to pool results across the three correlated traits, network samples, and ethnic groups to refine the selection of susceptibility loci. The association analyses captured signals missed by previous linkage scans. We found 71 loci associated with at least one of the three traits in at least one of the four ethnic groups at the significance level of 0.01. After validation across multiple samples and related traits, we identified by vote-counting 21 candidate loci for hypertension. Two loci, D3S2459 and D10S1412 confirmed findings in Network-specific linkage scans (GENOA and SAPPHIRe). Many of the candidate loci were reported by others in linkage to BPs, body weight, heart disease, and diabetes. We also observed frequent presence of quantitative trait loci (QTLs) involved in autoimmune and neurological disorders (e.g., NOD2). The vote-counting method of pooling results recognizes the potential that a gene may be involved in varying ways among different samples, which we believe is responsible for identifying genes in the less explored inflammatory pathways to hypertension.

Incorporating endophenotypes into allele-sharing based linkage tests.

For a genetic study in which there are concordant and discordant sibpairs for a complex disease trait and the measurements of other endophenotypes/intermediate phenotypes for each of the individuals are also available, we describe an allele-sharing based multipoint linkage test that utilizes nonparametrically the additional endophenotypes/intermediate phenotypes. The usefulness of this method is evaluated in simulation studies, which show that the gain in power is influenced by not only the endophenotypic value but also the correlation between the diagnosis-based phenotype and the endophenotype. In addition to reporting p values, our method also provides an index C(E), derived from the coefficients of the weight function associated with the endophenotype in the proposed statistic, to indicate the relevance of a specific endophenotype/intermediate phenotype in the genetic study. The simulation study indicates that a larger power, in general, corresponds to a larger value of the index C(E). The index C(E) is thus suggested as a quantity to be used in the choice of endophenotypes in linkage study. Data from the Stanford Asian Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe) are used to illustrate the method.