Abate N, Chandalia M, Satija P, Adams-Huet B, Grundy SM, Sandeep S, Radha V, Deepa R, Mohan V.

Genetic susceptibility modulates the impact of obesity on risk for type 2 diabetes. The present study evaluates the role of ENPP1 K121Q polymorphism in prediction of type 2 diabetes in three populations that differ in susceptibility to diabetes and environmental exposure. The three cohorts included 679 nonmigrant South Asians living in Chennai, India (223 with type 2 diabetes); 1,083 migrant South Asians living in Dallas, Texas (121 with type 2 diabetes); and 858 nonmigrant Caucasians living in Dallas, Texas (141 with type 2 diabetes). Patients with type 2 diabetes were included in these cohorts if they had diabetes onset before the age of 60 years. The prevalence of subjects carrying the polymorphic ENPP1 121Q allele was 25% in the nondiabetic group and 34% in the diabetic group of South Asians living in Chennai (P = 0.01). The prevalence in the nondiabetic and diabetic groups were 33 and 45% (P = 0.01) for the South Asians living in Dallas and 26 and 39% (P = 0.003) for the Caucasians. Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that ENPP1 121Q predicts genetic susceptibility to type 2 diabetes in both South Asians and Caucasians.

de Lemos JA, Zirlik A, Schonbeck U, Varo N, Murphy SA, Khera A, McGuire DK, Stanek G, Lo HS, Nuzzo R, Morrow DA, Peshock R, Libby P.

OBJECTIVE: The purpose of this study was to evaluate the associations between plasma levels of soluble CD40 ligand (sCD40L), atherosclerosis risk factors, and evidence of subclinical atherosclerosis. METHODS AND RESULTS: Plasma levels of sCD40L were measured in 2811 subjects from the Dallas Heart Study, a multiethnic population-based cross-sectional study. Electron Beam Computed Tomography measurements of coronary artery calcium (CAC) and MRI measurements of aortic plaque were performed in 2198 and 1965 subjects, respectively. No association was observed between quartiles of sCD40L and age, sex, race, body mass index, diabetes, smoking, creatinine clearance, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or C-reactive protein. In contrast, weak but statistically significant associations were observed between sCD40L and total cholesterol and triglycerides. The prevalence of detectable CAC (CAC score > or =10) and aortic plaque did not differ across sCD40L quartiles, and individuals with CAC scores <10, > or =10 to 100, >100 to 400, and >400 had similar sCD40L levels. CONCLUSIONS: In a large and representative multiethnic population-based sample, sCD40L was not associated with most atherosclerotic risk factors or with subclinical atherosclerosis. These findings suggest that sCD40L will not be useful as a tool to screen for the presence of subclinical atherosclerosis in the population. Further evaluation of this biomarker should focus on settings in which platelet activation is common, such as following acute coronary syndromes or coronary revascularization procedures.

Abdullah SM, Khera A, Das SR, Stanek HG, Canham RM, Chung AK, Morrow DA, Drazner MH, McGuire DK, de Lemos JA.

Elevated plasma levels of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-pro-BNP) are seen in the setting of cardiac ischemia and are associated with adverse outcomes in patients with coronary artery disease. The mechanisms leading to natriuretic peptide elevation in patients with coronary artery disease, including the contribution of coronary atherosclerosis itself, have not been fully elucidated. Measurement of NT-pro-BNP, electron beam computed tomography, and cardiac magnetic resonance imaging were performed in 2,445 subjects from the Dallas Heart Study who were free of heart failure and renal insufficiency. Electron beam computed tomography-determined coronary artery calcium scores were categorized as none (<10), mild (>/=10 to <100), moderate (>/=100 to <400), and severe (>/=400). NT-pro-BNP levels increased significantly across increasing coronary artery calcium score categories (p <0.0001 for trend). In multivariate models adjusted for age, gender, race, body mass index, hypertension, history of myocardial infarction, angina, angiotensin-converting enzyme inhibitor use, beta-blocker use, left ventricular (LV) ejection fraction, and LV mass, higher coronary artery calcium scores remained independently associated with higher log NT-pro-BNP levels (p = 0.03). This association persisted in similar models excluding patients with low LV ejection fractions, LV hypertrophy, angina pectoris, and a history of myocardial infarction. In conclusion, these findings support the hypothesis that coronary atherosclerosis may directly influence the activation of the cardiac neurohormonal system.

White PC.

CONTEXT: Apparent cortisone reductase deficiency (ACRD) is a rarely ascertained condition characterized by signs of androgen excess in women or children and decreased urinary excretion of cortisol metabolites compared with cortisone metabolites. These findings suggest a deficiency of 11beta-hydroxysteroid dehydrogenase type 1 (11-HSD1; encoded by the HSD11B1 gene), which normally converts cortisone to cortisol. Common polymorphisms in both HSD11B1 and the hexose-6-phosphate dehydrogenase (H6PD) gene encoding hexose-6-phosphate dehydrogenase have been found together in ACRD patients, who carry three of a possible four minor alleles at the two loci.

OBJECTIVE: The objective of this study was to confirm the postulated digenic inheritance mechanism for ACRD. DESIGN: This was a population-based association study (Dallas Heart Study). Subjects were genotyped for the 1971T>G polymorphism in intron 3 of HSD11B1 and the R453Q polymorphism in H6PD.

SUBJECTS: The study comprised 3551 individuals in a population-based sample (50% black, 35% white, and 15% Hispanic).

MAIN OUTCOME MEASURE: The main outcome measure was association between genotypes and risk for polycystic ovarian syndrome.

RESULTS: Both polymorphisms occurred more frequently than previously reported. Thus, ACRD genotypes (at least three of four minor alleles) occurred in 7.0% of subjects. There were no associations between genotype and body mass index; waist/hip ratio; visceral adiposity; measures of insulin sensitivity; levels of testosterone, FSH, or LH (in females); or risk of polycystic ovarian syndrome. There was no genotype effect on urinary free cortisol/cortisone or corticosteroid metabolite ratios, which were measured in 10 subjects, each carrying zero, three, or four minor alleles.

CONCLUSIONS: Previously reported associations of ACRD with HSD11B1 and H6PD alleles represent ascertainment bias. However, rare severe mutations in these genes cannot be ruled out.

Das SR, Drazner MH, Dries DL, Vega GL, Stanek HG, Abdullah SM, Canham RM, Chung AK, Leonard D, Wians FH Jr, de Lemos JA.

BACKGROUND: The association between higher body mass index (BMI) and lower B-type natriuretic peptide (BNP) level is thought to be mediated by expression of the natriuretic peptide clearance receptor (NPR-C) in adipose tissue. To explore this association, we tested 2 hypotheses: (1) that N-terminal (NT)-proBNP, which is not believed to bind NPR-C, would not be associated with BMI and (2) that lower BNP would be more closely associated with fat mass than with lean mass.

METHODS AND RESULTS: Measurements of BNP, NT-proBNP, and body composition by direct dual energy x-ray absorptiometry (DEXA) were performed in 2707 subjects from the Dallas Heart Study. The associations between obesity and low BNP (<4 ng/L) or low NT-proBNP (lowest sex-specific quartile) were evaluated with multivariable logistic regression models stratified by sex and adjusted for age, race/ethnicity, hypertension, left ventricular mass, and end-diastolic volume. Higher BMI was independently associated with lower BNP and NT-proBNP (all P<0.001). When BMI was replaced with both DEXA-derived lean and fat mass, greater lean mass, but not fat mass, was associated with low BNP and NT-proBNP levels.

CONCLUSIONS: In a large, population-based cohort, we confirm the previously described association between higher BMI and lower BNP and demonstrate a similar inverse association between BMI and NT-proBNP. Interestingly, both BNP and NT-proBNP are more closely associated with lean mass than with fat mass. These findings do not support the hypothesis that the lower BNP levels seen in obesity are driven by enhanced BNP clearance mediated via NPR-C.

Dries DL, Victor RG, Rame JE, Cooper RS, Wu X, Zhu X, Leonard D, Ho SI, Wu Q, Post W, Drazner MH.

BACKGROUND: The natriuretic peptide system contributes to blood pressure regulation. Atrial and brain natriuretic peptides are cleaved into smaller biologically active molecules by corin, a transmembrane serine protease expressed in cardiomyocytes.

METHOD AND RESULTS: This genotype-phenotype genetic association study included replication samples and genomic control to correct for population stratification. Sequencing of the human corin gene identified 2 nonsynonymous, nonconservative single nucleotide polymorphisms (Q568P and T555I) in near-complete linkage disequilibrium, thus describing a single minor I555 (P568) corin gene allele. This allele was present in the heterozygote state in &12% of blacks but was extremely rare in whites (<0.5% were homozygous for the minor allele). In our primary population sample, the Dallas Heart Study, after adjustment for potential confounders, including population stratification, the corin I555 (P568) allele remained independently associated with increased risk for prevalent hypertension (odds ratio, 1.63; 95% CI, 1.11 to 2.38; P=0.013). The corin I555 (P568) allele also was associated with higher systolic blood pressure in subjects not using antihypertensive medication in unadjusted (133.7+/-20.7 versus 129.4+/-17.4 mm Hg; P=0.029) and adjusted (132.5+/-1.6 versus 128.9+/-0.6 mm Hg; P=0.029) analyses. The independent association of the minor corin allele with increased risk for prevalent hypertension was confirmed in the Multi-Ethnic Study of Atherosclerosis (odds ratio, 1.50; 95% CI, 1.09 to 2.06; P=0.014). In addition, the association of the minor corin I555 (P568) allele with higher systolic blood pressure was confirmed in adjusted analysis in the Chicago Genetics of Hypertension Study (125.8+/-1.9 versus 121.4+/-0.7 mm Hg; P=0.03).

CONCLUSIONS: The corin I555 (P568) allele is common in blacks and is associated with higher blood pressure and an increased risk for prevalent hypertension.

Reingold JS, McGavock JM, Kaka S, Tillery T, Victor RG, Szczepaniak LS.

The primary aim of this investigation was to determine the reliability and sensitivity of 1H magnetic resonance spectroscopy (1H-MRS) as a method for quantifying myocardial triglyceride (TG) content in humans over time and in response to metabolic perturbations. Three separate experiments were designed to quantify myocardial TG content 1) over a 90-day period, 2) after a high-fat meal, and 3) after a 48-h fast. Proton spectra were collected from a 10 x 20 x 30-mm3 voxel placed within the intraventricular septum, with measurements acquired at end-systole and end-expiration, using cardiac triggering and respiratory gating. Minimal variation was observed between myocardial TG content determined 90 days apart (r = 0.98, CV = 5%), whereas TG values were unaffected by a high-fat meal despite a significant twofold increase (P < 0.05) in serum TG. In contrast, myocardial TG content increased threefold (P < 0.05) after a 48-h fast despite a 25% reduction in serum TG. Body mass index was significantly related to myocardial TG (r = 0.58, P < 0.05) and the change in myocardial TG after a 48-h fast (r2 = 0.60). 1H-MRS is a reliable method for the determination of myocardial TG in humans and is relatively unaffected by the consumption of one high-fat meal but sensitive to changes following a prolonged fast.

Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9
Nature Genetics, Volume 37 No 2, February 2005, Pages 161 - 165

Jonathan Cohen, Alexander Pertsemlidis, Ingrid K Kotowski, Randall Graham, Christine Kim Garcia & Helen H Hobbs

The low-density lipoprotein receptor (LDLR) prevents hypercholesterolemia and atherosclerosis by removing low-density lipoprotein (LDL) from circulation. Mutations in the genes encoding either LDLR1 or its ligand (APOB)2 cause severe hypercholesterolemia. Missense mutations in PCSK9, encoding a serine protease in the secretory pathway3, also cause hypercholesterolemia4. These mutations are probably gain-of-function mutations, as overexpression of PCSK9 in the liver of mice produces hypercholesterolemia5, 6, 7 by reducing LDLR number. To test whether loss-of-function mutations in PCSK9 have the opposite effect, we sequenced the coding region of PCSK9 in 128 subjects (50% African American) with low plasma levels of LDL and found two nonsense mutations (Y142X and C679X). These mutations were common in African Americans (combined frequency, 2%) but rare in European Americans (<0.1%) and were associated with a 40% reduction in plasma levels of LDL cholesterol. These data indicate that common sequence variations have large effects on plasma cholesterol levels in selected populations.

The Dallas Heart Study: a population-based probability sample for the multidisciplinary study of ethnic differences in cardiovascular health
The American Journal of Cardiology, Volume 93, Issue 12 , 15 June 2004, Pages 1473-1480

Ronald G. Victor MD, Robert W. Haley MD, DuWayne L. Willett MS, MD, Ronald M. Peshock MD, Patrice C. Vaeth DrPH, David Leonard PhD, Mujeeb Basit BS, Richard S. Cooper MD, Vincent G. Iannacchione MS, Wendy A. Visscher PhD, Jennifer M. Staab MPH, Helen H. Hobbs MD and Dallas Heart Study Investigators

The decrease in cardiovascular death rates in the United States has been slower in blacks than whites, especially in patients <65 years of age. The Dallas Heart Study was designed as a single-site, multiethnic, population-based probability sample to (1) produce unbiased population estimates of biologic and social variables that pinpoint ethnic differences in cardiovascular health at the community level and (2) support hypothesis-driven research on the mechanisms causing these differences using genetics, advanced imaging modalities, social sciences, and clinical research center methods. A probability-based sample of Dallas County residents aged 18 to 65 years was surveyed with an extensive household health interview. The subset of participants 30 to 65 years of age provided in-home fasting blood and urine samples and underwent multiple imaging studies, including cardiac magnetic resonance imaging and electron beam computed tomography. Completed interviews were obtained for 6,101 subjects (54% black), phlebotomy visits for 3,398 (52% black), and clinic visits for 2,971 (50% black). Participation rates were 80.4% for interviews, 75.1% for phlebotomy visits, and 87.4% for clinic visits. Weighted population estimates of many measured variables agreed closely with those of the United States census and were relatively stable from the interview sample to the phlebotomy and clinic subsamples. Thus, the Dallas Heart Study provides a phenotypically well-characterized probability sample for multidisciplinary research that will be used to improve the mechanistic understanding and prevention of cardiovascular disease, especially in black Americans.

African Americans and Caucasians have a similar prevalence of coronary calcium in the Dallas Heart Study
Journal of the American College of Cardiology Volume 44, Issue 5 , 1 September 2004, Pages 1011-1017

Mortality from coronary heart disease (CHD) is higher in African Americans (blacks) than in non-Hispanic Caucasians (whites), especially among women. The higher prevalence of hypertension, left ventricular hypertrophy, diabetes, and chronic renal failure, as well as a reduced access to medical care, are likely contributors to the higher rate of CHD mortality in blacks. It remains controversial whether blacks have a greater coronary atherosclerotic burden than whites. In post-mortem and angiographic studies, blacks have been reported to have less or equivalent amounts of coronary atherosclerosis when compared with whites.

Coronary atherosclerosis can be assessed noninvasively by measuring the amount of coronary artery calcium (CAC), either by fluoroscopy or by electron beam computed tomography (EBCT). Coronary calcium measurements are proportional to coronary atherosclerotic burden. In several previous studies, the prevalence of CAC in blacks was found to be significantly lower than in whites. The exceptions are two studies that reported a similar prevalence of EBCT-detected coronary calcium in blacks and whites-one in young adults and the other in postmenopausal women.

Association between Chronic Kidney Disease and Coronary Artery Calcification: The Dallas Heart Study
Articles in Press. Journal of th American Society of Nephrology (February 1, 2005). 16: 507-513, 2005

Holly Kramer, Robert Toto, Ronald Peshock, Richard Cooper and Ronald Victor

The hypothesis that chronic kidney disease (CKD) is associated with increased coronary artery calcification (CAC) was tested using data from the Dallas Heart Study, a representative sample of Dallas County residents aged 30 to 65 yr. CKD was defined as presence of microalbuminuria and GFR =60 ml/min per 1.73 m2 (stage 1 to 2), or GFR <60 ml/min per 1.73 m2 (stage 3 to 5), excluding end-stage kidney disease. Logistic regression was used to examine the association between stages of CKD and CAC scores >10, >100, and >400 versus scores =10 compared with no CKD while adjusting for covariates. Analyses were repeated after stratifying by presence of diabetes. The mean age was 43.9 yr, and hypertension and diabetes were noted in 31.0 and 9.8%, respectively. No association was noted between stage 1 to 2 CKD and increased CAC scores. Compared with no CKD, stage 3 to 5 CKD was associated with CAC scores >100 (odds ratio, 2.85; 95% confidence interval, 0.92 to 8.80) and >400 (odds ratio, 8.35; 95% confidence interval, 1.94 to 35.95) in the total population after adjustment for covariates, but these associations were substantially reduced after exclusion of participants with diabetes. Participants with diabetes and stage 3 to 5 CKD had a ninefold increased odds of CAC scores >10 versus scores =10 compared with participants with diabetes and without CKD, whereas no association was noted between stage 3 to 5 CKD and CAC scores >10 in the nondiabetic population. In conclusion, stage 3 to 5 CKD is associated with increased CAC scores, but this association may be substantially stronger among adults with diabetes. These findings need to be confirmed in study populations that include adults >65 yr of age and a larger number of CKD cases..

Level of Acculturation and Hypertension among Dallas County Hispanics: Findings from the Dallas Heart Study
Annals of Epidemiology, Volume 15, Issue 5, May 2005, Pages 373-380 (doi:10.1016/j.annepidem.2004.11.003)

The purpose of this study is to examine whether the prevalence of hypertension differs by acculturation status among Hispanics in Dallas County, Texas. The authors test the hypothesis that compared with those of low acculturation, those of mid- and high-level acculturation will be at greater risk for having hypertension.

The purpose of this study is to examine whether the prevalence of hypertension differs by acculturation status among Hispanics in Dallas County, Texas. The authors test the hypothesis that compared with those of low acculturation, those of mid- and high-level acculturation will be at greater risk for having hypertension.

Methods- Conducted from July 2000 through October 2002, the Dallas Heart Study (DHS) is a general population cross-sectional study of cardiovascular risk factors among Dallas County residents. These analyses focus on the 1163 DHS participants who self-reported Hispanic ethnicity, completed a household interview, and had blood pressures measured. Acculturation was assessed with a validated 12-item scale that measured the following dimensions of cultural adaptation: language; media preference; social interaction; and ease of relationships with those of other ethnicities.

Results- The majority of participants were born in Mexico (57.5%) and ranged in age from 18 to 65 years (mean age 33 years). Women made up just under half of the sample (47.81%). The unadjusted prevalence of hypertension was 9.78%. When age-adjusted for the 2000 US Standard Population, the prevalence was 17.27%. The ?2 analysis showed that those of low acculturation were significantly less likely to have hypertension (6.05%) than those of mid- and high-level acculturation (10.78% and 12.80%, respectively). After controlling for the effects of possible confounders (i.e., sociodemographic factors, health care access and utilization, health behaviors, and health status), logistic regression showed that when compared with Hispanics of low acculturation, those of middle and high acculturation were at greater risk of having hypertension (OR = 3.04, 95% CI, 1.27, 7.29 and OR = 2.62, 95% CI, 1.04, 6.59, respectively).

Conclusion- hese findings demonstrate that acculturation is significantly associated with hypertensive status.

Lipoprotein(a) and Apolipoprotein(a) Isoforms
No Association With Coronary Artery Calcification in The Dallas Heart Study
Circulation. American Heart Association, Inc. (March 21,2005) Pages 1471-1479. (doi:10.1161/01.CIR.0000159263.50305.BD)

Background- Elevated plasma levels of lipoprotein(a) [Lp(a)] are an independent risk factor for cardiovascular disease in whites. Blacks have 2- to 3-fold higher plasma levels of Lp(a) than whites and yet do not have a correspondingly higher rate of coronary events. It remains unclear whether elevated plasma levels of Lp(a) are an independent risk factor for coronary atherosclerosis in individuals of African descent.

Methods and Results- The relationship between plasma levels of Lp(a), apolipoprotein(a) isoform sizes, and the presence of coronary calcium was examined in 761 blacks and 527 whites (men aged >40 years, women aged >45 years) from a population-based sample. No relationship was found between plasma levels of Lp(a), apolipoprotein(a) isoform size, or a combination of these 2 variables and coronary artery calcium (CAC) in whites or blacks. No correlation was observed between plasma levels of Lp(a) and coronary calcium scores in any group, although all black men with very high plasma levels of Lp(a) (>300 µmol/L; n=7) were CAC-positive. Whites with high plasma levels of Lp(a) plus elevated plasma levels of LDL cholesterol (men) or reduced levels of HDL cholesterol (men and women) or who smoked (women) had a higher prevalence of CAC. In contrast, no joint effects between plasma levels of Lp(a) and other cardiovascular risk factors on coronary calcium were found in blacks.

Conclusions- No consistent independent relationship between plasma levels of Lp(a) or apolipoprotein(a) isoform size and coronary calcium was found in whites or blacks.

Left Ventricular Hypertrophy Is More Prevalent in Blacks Than Whites in the General Population
Hypertension. American Heart Association, Inc. (June 6, 2005) Pages 46-124. (doi:10.1161/01.HYP.0000169972.96201.8e)

Although recent studies have suggested that blacks compared with whites have an increased prevalence of left ventricular hypertrophy, it remains uncertain whether this is true despite adjustment for body composition (fat mass and fat-free mass) and when assessed by cardiac MRI in the general population. The Dallas Heart Study is a population-based study of Dallas County in which 1335 black and 858 white participants 30 to 67 years of age underwent detailed assessment including dual-energy x-ray absorptiometry scan to measure body composition and cardiac MRI. Left ventricular hypertrophy, whether defined by indexation to body surface area (P<0.001), fat-free mass (P=0.002), or height2.7 (P<0.001) was 2- to 3-fold more common in black versus white women. Similar results were seen when comparing black and white men (P<0.001 when left ventricular hypertrophy was indexed to body surface area or height2.7 and P=0.05 when indexed to fat-free mass). Ethnic disparities in left ventricular mass persisted in multivariable models despite adjustment for fat mass, fat-free mass, systolic blood pressure, age, gender, and measures of socioeconomic status. We conclude that blacks compared with whites have increased left ventricular mass and a 2- to 3-fold higher prevalence of left ventricular hypertrophy in the general population, as assessed by cardiac MRI. The ethnic differences in left ventricular mass are independent of differences in body composition.

An expression screen reveals modulators of class II histone deacetylase phosphorylation
PNAS | June 7, 2005 | vol. 102 | no. 23 | 8120-8125

Class II histone deacetylases (HDACs) repress transcription by associating with a variety of transcription factors and corepressors. Phosphorylation of a set of conserved serine residues in the N-terminal extensions of class II HDACs creates binding sites for 14-3-3 chaperone proteins, which trigger nuclear export of these HDACs, thereby derepressing specific target genes in a signal-dependent manner. To identify intracellular signaling pathways that control phosphorylation of HDAC5, a class II HDAC, we designed a eukaryotic cDNA expression screen in which a GAL4-dependent luciferase reporter was expressed with the DNA-binding domain of GAL4 fused to the N-terminal extension of HDAC5 and the VP16 transcription activation domain fused to 14-3-3. The transfection of COS cells with cDNA expression libraries results in activation of luciferase expression by cDNAs encoding HDAC5 kinases or modulators of such kinases that enable phosphorylated GAL4-HDAC5 to recruit 14-3-3-VP16 with consequent reconstitution of a functional transcriptional complex. Our results reveal a remarkable variety of signaling pathways that converge on the signal-responsive phosphorylation sites in HDAC5, thereby enabling HDAC5 to connect extracellular signals to the genome.