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1.  Effect of Positive Well-Being on Incidence of Symptomatic Coronary Artery Disease 
The American journal of cardiology  2013;112(8):1120-1125.
While negative emotions and psychiatric morbidity have often been found to increase incident coronary artery disease (CAD) risk, fewer studies have shown positive emotions to be protective against CAD; none have been performed in high-risk healthy populations, taking risk factors into account. Thus, we examined the impact of positive well-being on incident CAD in both a high-risk initially healthy population and in a national probability sample. We screened healthy siblings of probands with documented early-onset CAD from 1985 to 2007 in the GeneSTAR (Genetic Study of Atherosclerosis Risk) population and examined sociodemographics, risk factors, and positive well-being using the General Well Being Schedule (GWBS). We further classified siblings into high, intermediate and low risk strata based on the Framingham Risk Score (FRS) and followed them for 5 to 25 years. Siblings (n=1483) with higher baseline GWBS total scores were significantly less likely to develop CAD (hazard ratio [HR]=0.67, 95% confidence interval [CI] 0.58–0.79), independent of age, sex, race, and traditional risk factors. Protection was strongest in the high FRS stratum (HR=0.52, 95% CI 0.30–0.90). Findings were replicated in the first National Health and Nutrition Examination Survey and Epidemiologic Follow-up Study (n=5992; HR=0.87, 95% CI 0.83–0.93). In conclusion, positive well-being was associated with nearly a third reduction in CAD in a high-risk population with family history, a nearly 50% reduction in incident CAD in the highest risk stratum in those with family history, and a 13% reduction in incident CAD in a national probability sample, independent of traditional CAD risk factors.
PMCID: PMC3788860  PMID: 23810324
coronary artery disease; epidemiology; cardiovascular risk factors; psychosocial factors
2.  Relation of Subclinical Coronary Artery Atherosclerosis to Cerebral White Matter Disease in Healthy Individuals from Families with Early-Onset Coronary Artery Disease 
The American journal of cardiology  2013;112(6):747-752.
White matter disease (WMD) of the brain is associated with incident stroke. Similarly subclinical calcified coronary artery plaque has been associated with incident coronary artery disease (CAD) events. Although atherogenesis in both vascular beds may share some common mechanisms, the extent to which subclinical CAD is associated with WMD across age ranges in individuals with a family history of early onset CAD remains unknown. We screened 405 apparently healthy participants in the Genetic Study of Atherosclerotic Risk (GeneSTAR) for CAD risk factors, and for the presence of noncalcified and calcified coronary plaque using dual-source multi-detector cardiac CT angiography. The presence and volumes of WMD were assessed by 3 Tesla brain MRI. Participants were 60% female, 36% African American; mean age 51.6 ± 10.6 years. The prevalence of coronary plaque overall was 43.0%. Individuals with coronary plaque had significantly higher WMD volumes (median 1222 mm3, IQR [448 to 3871]) compared to those without coronary plaque (median 551 mm3, IQR [105 to 1523], p<0.001). In multivariable regression analysis, adjusting for age, sex, race, traditional risk factors, total brain volume, and intrafamilial correlations, the presence of coronary plaque was independently associated with WMD volume (p=0.05). This study shows a significant association between WMD and noncalcified and calcified coronary plaque in healthy individuals, independent of age and risk factors. In conclusion, these findings support the premise of possible shared causal pathways in two vascular beds in families at increased risk for early-onset vascular disease.
PMCID: PMC3759559  PMID: 23742943
coronary artery disease; brain white matter disease; subclinical
3.  Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes 
Ng, Maggie C. Y. | Shriner, Daniel | Chen, Brian H. | Li, Jiang | Chen, Wei-Min | Guo, Xiuqing | Liu, Jiankang | Bielinski, Suzette J. | Yanek, Lisa R. | Nalls, Michael A. | Comeau, Mary E. | Rasmussen-Torvik, Laura J. | Jensen, Richard A. | Evans, Daniel S. | Sun, Yan V. | An, Ping | Patel, Sanjay R. | Lu, Yingchang | Long, Jirong | Armstrong, Loren L. | Wagenknecht, Lynne | Yang, Lingyao | Snively, Beverly M. | Palmer, Nicholette D. | Mudgal, Poorva | Langefeld, Carl D. | Keene, Keith L. | Freedman, Barry I. | Mychaleckyj, Josyf C. | Nayak, Uma | Raffel, Leslie J. | Goodarzi, Mark O. | Chen, Y-D Ida | Taylor, Herman A. | Correa, Adolfo | Sims, Mario | Couper, David | Pankow, James S. | Boerwinkle, Eric | Adeyemo, Adebowale | Doumatey, Ayo | Chen, Guanjie | Mathias, Rasika A. | Vaidya, Dhananjay | Singleton, Andrew B. | Zonderman, Alan B. | Igo, Robert P. | Sedor, John R. | Kabagambe, Edmond K. | Siscovick, David S. | McKnight, Barbara | Rice, Kenneth | Liu, Yongmei | Hsueh, Wen-Chi | Zhao, Wei | Bielak, Lawrence F. | Kraja, Aldi | Province, Michael A. | Bottinger, Erwin P. | Gottesman, Omri | Cai, Qiuyin | Zheng, Wei | Blot, William J. | Lowe, William L. | Pacheco, Jennifer A. | Crawford, Dana C. | Grundberg, Elin | Rich, Stephen S. | Hayes, M. Geoffrey | Shu, Xiao-Ou | Loos, Ruth J. F. | Borecki, Ingrid B. | Peyser, Patricia A. | Cummings, Steven R. | Psaty, Bruce M. | Fornage, Myriam | Iyengar, Sudha K. | Evans, Michele K. | Becker, Diane M. | Kao, W. H. Linda | Wilson, James G. | Rotter, Jerome I. | Sale, Michèle M. | Liu, Simin | Rotimi, Charles N. | Bowden, Donald W.
PLoS Genetics  2014;10(8):e1004517.
Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15×10−94
Author Summary
Despite the higher prevalence of type 2 diabetes (T2D) in African Americans than in Europeans, recent genome-wide association studies (GWAS) were examined primarily in individuals of European ancestry. In this study, we performed meta-analysis of 17 GWAS in 8,284 cases and 15,543 controls to explore the genetic architecture of T2D in African Americans. Following replication in additional 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry, we identified two novel and three previous reported T2D loci reaching genome-wide significance. We also examined 158 loci previously reported to be associated with T2D or regulating glucose homeostasis. While 56% of these loci were shared between African Americans and the other populations, the strongest associations in African Americans are often found in nearby single nucleotide polymorphisms (SNPs) instead of the original SNPs reported in other populations due to differential genetic architecture across populations. Our results highlight the importance of performing genetic studies in non-European populations to fine map the causal genetic variants.
PMCID: PMC4125087  PMID: 25102180
There traditional lipid profile differs by sex hormone levels. However, associations of sex hormones with lipoprotein subfractions, which may more accurately represent metabolic pathways to atherosclerosis, are not well studied. We quantified the cross-sectional associations of endogenous sex hormones with lipoprotein subfractions in 3143 men and 2038 postmenopausal women who were not on hormone replacement therapy, aged 45–84 years, in the Multi-Ethnic Study of Atherosclerosis baseline examination. Particle sizes and numbers of Very Low Density (VLDL), Low Density (LDL) and High Density (HDL) Lipoproteins were measured by Nuclear Magnetic Resonance. In both men and women, after multivariable adjustment, higher Sex Hormone Binding Globulin (SHBG) levels are associated with smaller, fewer VLDL, larger, fewer LDL, and larger, more numerous HDL particles; while higher endogenous estradiol levels are associated with smaller VLDL, and smaller, more numerous HDL and LDL particles (all p < 0.05). Testosterone (adjusted for SHBG) is associated with a smaller VLDL particles in men but not women (sex difference p = 0.040). Higher dehydroepiandrosterone (DHEA) levels are associated with more numerous, smaller VLDL particles only in women (sex difference p = 0.030, 0.004, respectively). In conclusion, we found sex differences in the association of endogenous androgens with lipoprotein particle sizes and numbers. Higher endogenous estradiol, but lower SHBG is associated with a more atherogenic lipoprotein particle profile. These findings highlight the potential to improve the lipoprotein profile with sex hormones, but emphasize the intricacies of the interactions.
PMCID: PMC4017356  PMID: 18502260
In single-nucleotide polymorphism (SNP) scans, SNP-phenotype association hypotheses are tested, however there is biological interpretation only for genes that span multiple SNPs. We demonstrate and validate a method of combining gene-wide evidence using data for high-density lipoprotein cholesterol (HDLC).
In a family based study (N=1782 from 482 families), we used 1000 phenotype-permuted datasets to determine the correlation of z-test statistics for 592 SNP-HDLC association tests comprising 14 genes previously reported to be associated with HDLC. We generated gene-wide p-values using the distribution of the sum of correlated z-statistics.
Of the 14 genes, CETP was significant (p=4.0×10−5 <0.05/14), while PLTP was significant at the borderline (p=6.7×10−3 <0.1/14). These p-values were confirmed using empirical distributions of the sum of χ2 association statistics as a gold standard (2.9×10−6 and 1.8×10−3, respectively). Genewide p-values were more significant than Bonferroni-corrected p-value for the most significant SNP in 11 of 14 genes (p=0.023). Genewide p-values calculated from SNP correlations derived for 20 simulated normally distributed phenotypes reproduced those derived from the 1000 phenotype-permuted datasets were correlated with the empirical distributions (Spearman correlation = 0.92 for both).
We have validated a simple scalable method to combine polymorphism-level evidence into gene-wide statistical evidence. High-throughput gene-wide hypothesis tests may be used in biologically interpretable genomewide association scans. Genewide association tests may be used to meaningfully replicate findings in populations with different linkage disequilibrium structure, when SNP-level replication is not expected.
PMCID: PMC3969754  PMID: 24688980
Bonferroni; hypothesis tests; combining evidence
Dietary guidelines support intake of polyunsaturated fatty acids (PUFAs) in fish and vegetable oils. However, some controversy remains about benefits of PUFAs, and most prior studies have relied on self‐reported dietary assessment in relatively homogeneous populations.
Methods and Results
In a multiethnic cohort of 2837 US adults (whites, Hispanics, African Americans, Chinese Americans), plasma phospholipid PUFAs were measured at baseline (2000–2002) using gas chromatography and dietary PUFAs estimated using a food frequency questionnaire. Incident cardiovascular disease (CVD) events (including coronary heart disease and stroke; n=189) were prospectively identified through 2010 during 19 778 person‐years of follow‐up. In multivariable‐adjusted Cox models, circulating n‐3 eicosapentaenoic acid and docosahexaenoic acid were inversely associated with incident CVD, with extreme‐quartile hazard ratios (95% CIs) of 0.49 for eicosapentaenoic acid (0.30 to 0.79; Ptrend=0.01) and 0.39 for docosahexaenoic acid (0.22 to 0.67; Ptrend<0.001). n‐3 Docosapentaenoic acid (DPA) was inversely associated with CVD in whites and Chinese, but not in other race/ethnicities (P‐interaction=0.01). No significant associations with CVD were observed for circulating n‐3 alpha‐linolenic acid or n‐6 PUFA (linoleic acid, arachidonic acid). Associations with CVD of self‐reported dietary PUFA were consistent with those of the PUFA biomarkers. All associations were similar across racial‐ethnic groups, except those of docosapentaenoic acid.
Both dietary and circulating eicosapentaenoic acid and docosahexaenoic acid, but not alpha‐linolenic acid or n‐6 PUFA, were inversely associated with CVD incidence. These findings suggest that increased consumption of n‐3 PUFA from seafood may prevent CVD development in a multiethnic population.
PMCID: PMC3886748  PMID: 24351702
cardiovascular disease prevention; cardiovascular risk factors; diet; fatty acids
Human heredity  2012;74(1):17-26.
Variance-component analysis (VCA), the traditional method for handling correlations within families in genetic association studies, is computationally intensive for genome-wide analyses, and the computational burden of VCA, a likelihood-based test, increases with family size and the number of genetic markers. Alternative approaches that do not require the computation of familial correlations is preferable, provided that they do not inflate type I error or decrease power. We performed a simulation study to evaluate practical alternatives to VCA that use regression with generalized estimating equations (GEE) in extended family data. We compared the properties of linear regression with GEE applied to an entire extended family structure (GEE-EXT) and GEE applied to nuclear family structures split from these extended families (GEE-SPL) to variance-components likelihood-based methods (FastAssoc). GEE-EXT was evaluated with and without robust variance estimators to estimate the standard errors. We observed similar average type I error rates from GEE-EXT and FastAssoc compared to GEE-SPL. Type I error rates for the GEE-EXT method with a robust variance estimator were marginally higher than the nominal rate when the MAF was < 0.1, but were close to nominal rate when MAF ≥ 0.2. All methods gave consistent effect estimates and had similar power. In summary, the GEE framework with the robust variance estimator, the computationally fastest and least data management intensive, appears to work well in extended families and thus provides a reasonable alternative to full variance components approaches for extended pedigrees in the GWAS setting.
PMCID: PMC3736986  PMID: 23038411
Generalized estimating equation; Variance components analysis; Family-based association study; Genome-wide scan
Menopause (New York, N.Y.)  2012;19(10):1081-1087.
Cardiovascular disease is the number one killer of women. Identifying women at risk of cardiovascular disease has tremendous public health importance. Early menopause is associated with increased cardiovascular disease events in some predominantly white populations, but not consistently. Our objective was to determine if a self-reported early menopause (menopause at an age <46) identifies women as at risk for future coronary heart disease or stroke.
The study population came from the Multi-Ethnic Study of Atherosclerosis, a longitudinal, ethnically diverse cohort study of US men and women aged 45 to 84 years enrolled in 2000–2002 and followed up until 2008. The association between a personal history of early menopause (either natural menopause or surgical removal of ovaries at an age <46) and future coronary heart disease and stroke was assessed in 2509 women (ages 45–84, 987 White, 331 Chinese, 641 Black, 550 Hispanic) from the Multi-Ethnic Study Atherosclerosis, who were free of cardiovascular disease at baseline.
693/2509 (28%) of women reported either surgical or natural early menopause. In survival curves, women with early menopause had worse coronary heart disease and stroke-free survival (log rank p=<0.008 and 0.0158). In models adjusted for age, race/ethnicity, Multi-Ethnic Study Atherosclerosis site and traditional cardiovascular disease risk factors, this risk for coronary heart disease and stroke remained (HR 2.08, 95% CI 1.17, 3.70 and 2.19, 95% CI 1.11, 4.32, respectively).
Early menopause is positively associated with coronary heart disease and stroke in a multiethnic cohort, independent of traditional cardiovascular disease risk factors.
PMCID: PMC3443540  PMID: 22692332
Early Menopause; Coronary Heart Disease; Stroke
Waist-to-hip ratio (WHR) is strongly associated with prevalent atherosclerosis. We analyzed the associations of baseline serum levels of testosterone (T), estradiol (E2), sex hormone binding globulin (SHBG), and dehydroepiandrosterone (DHEA) with WHR in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort.
Baseline data was available for 3144 men and 2038 postmenopausal women, who were non-users of hormone therapy, who were 45–84 years of age, and of White, Chinese, Black or Hispanic racial/ethnic groups. Of these, 2708 men and 1678 women also had longitudinal measurements of WHR measured at the second and/or the third study visits (median follow-up 578 days, and 1135 days, respectively).
In cross-sectional analyses adjusted for age, race, and cardiovascular disease risk factors, T was negatively associated with baseline WHR in men, while in both sexes, E2 was positively associated and SHBG was negatively associated with WHR (all p<0.001). In longitudinal analyses, further adjusted for follow-up time and baseline WHR, baseline T was negatively associated with WHR at follow-up (p=0.001) in men, while in both sexes, E2 was positively associated (p=0.004), and SHBG was negatively associated with WHR (p<0.001). The longitudinal association of E2, but not T, was independent of SHBG. In both cross-sectional or longitudinal analyses, there were no associations between DHEA and WHR in either men or women.
Sex hormones are associated with WHR at baseline and also during follow-up above and beyond their baseline association. Future research is needed to determine if manipulation of hormones is associated with changes in central obesity.
PMCID: PMC3342434  PMID: 22270378
Sex Hormones; epidemiology; waist to hip ratio
Journal of Women's Health  2012;21(5):516-520.
Older women have a higher prevalence of systolic hypertension than do men; however, whether or not this relates to arterial properties, such as distensibility coefficient (DC), is not known. We examined whether the association of carotid artery DC with age differed by sex in the Multi-Ethnic Study of Atherosclerosis (MESA).
B-mode ultrasound-measured carotid diameters and brachial pressures were obtained from 6359 participants (53% female, 38% white, 12% Chinese, 27% black, 22% Hispanic, aged 45–85 years) of the MESA baseline examination. The within-individual slopes of 2log(diameter) vs. blood pressure fit using mixed models (MM) are interpreted as the DC, and interaction terms are interpreted as differences in DC. The MM calculation allows for correction of the confounding caused by the association of age, sex, and race with blood pressure, the denominator in the calculation of DC.
DC was associated with age, sex, and race (all p<0.001). Women had a greater age-related lowering of DC compared to men (2.52×10−5 vs. 2.16×10−5/mm Hg lower DC per year of age, p=0.006). Mean diameter of carotid arteries was greater with age (p<0.001); this association also was significantly stronger in women compared to men (0.24% vs. 0.14% larger mean carotid diameter per year of age, p<0.001).
Greater stiffening and enlargement of arteries are seen in older women compared to older men. This implies that the afterload on the heart of older women is likely to be greater than that among older men.
PMCID: PMC3353825  PMID: 22393881
Circulation research  2001;88(3):333-339.
Cardiac arrhythmia is a common and often lethal manifestation of many forms of heart disease. Gap junction remodeling has been postulated to contribute to the increased propensity for arrhythmogenesis in diseased myocardium, although a causative role in vivo remains speculative. By generating mice with cardiac-restricted knockout of connexin43 (Cx43), we have circumvented the perinatal lethal developmental defect associated with germline inactivation of this gap junction channel gene and uncovered an essential role for Cx43 in the maintenance of electrical stability. Mice with cardiac-specific loss of Cx43 have normal heart structure and contractile function, and yet they uniformly (28 of 28 conditional Cx43 knockout mice observed) develop sudden cardiac death from spontaneous ventricular arrhythmias by 2 months of age. Optical mapping of the epicardial electrical activation pattern in Cx43 conditional knockout mice revealed that ventricular conduction velocity was significantly slowed by up to 55% in the transverse direction and 42% in the longitudinal direction, resulting in an increase in anisotropic ratio compared with control littermates (2.1±0.13 versus 1.66±0.06; P<0.01). This novel genetic murine model of primary sudden cardiac death defines gap junctional abnormalities as a key molecular feature of the arrhythmogenic substrate.
PMCID: PMC3630465  PMID: 11179202
gap junction; connexin43; arrhythmia; conduction
Development (Cambridge, England)  2001;128(10):1785-1792.
The cardiac conduction system is a complex network of cells that together orchestrate the rhythmic and coordinated depolarization of the heart. The molecular mechanisms regulating the specification and patterning of cells that form this conductive network are largely unknown. Studies in avian models have suggested that components of the cardiac conduction system arise from progressive recruitment of cardiomyogenic progenitors, potentially influenced by inductive effects from the neighboring coronary vasculature. However, relatively little is known about the process of conduction system development in mammalian species, especially in the mouse, where even the histological identification of the conductive network remains problematic. We have identified a line of transgenic mice where lacZ reporter gene expression delineates the developing and mature murine cardiac conduction system, extending proximally from the sinoatrial node to the distal Purkinje fibers. Optical mapping of cardiac electrical activity using a voltage-sensitive dye confirms that cells identified by the lacZ reporter gene are indeed components of the specialized conduction system. Analysis of lacZ expression during sequential stages of cardiogenesis provides a detailed view of the maturation of the conductive network and demonstrates that patterning occurs surprisingly early in embryogenesis. Moreover, optical mapping studies of embryonic hearts demonstrate that a murine His-Purkinje system is functioning well before septation has completed. Thus, these studies describe a novel marker of the murine cardiac conduction system that identifies this specialized network of cells throughout cardiac development. Analysis of lacZ expression and optical mapping data highlight important differences between murine and avian conduction system development. Finally, this line of transgenic mice provides a novel tool for exploring the molecular circuitry controlling mammalian conduction system development and should be invaluable in studies of developmental mutants with potential structural or functional conduction system defects.
PMCID: PMC3630466  PMID: 11311159
Heart development; Conduction system; Purkinje fiber; Mouse; Optical mapping
Journal of Nuclear Cardiology  2011;19(1):28-36.
Although the severity of inducible ischemia provides incremental prognostic information in persons with known or suspected coronary artery disease (CAD), its significance for predicting long-term CAD outcomes in apparently healthy populations is unknown. This study was designed to evaluate the presence and degree of myocardial ischemia in asymptomatic siblings of persons with premature CAD <60 years of age and to determine its significance for predicting incident acute coronary syndromes (ACS) during follow-up of 5 to 25 years.
Siblings (n = 1,287, age 30-59 years, 55% female) were screened for traditional risk factors, underwent exercise treadmill testing with nuclear perfusion imaging, and were followed for the development of ACS (mean follow-up 11.6 ± 5.1 years). The severity of ischemia was assessed by semiquantitative methods using the standard 17-segment model and then categorized by the percent maximal summed stress score as none (0%), minimal (1% to <5%), mild (5% to 10%), moderate (10% to 15%), or severe (≥15%).
ACS occurred in 132 subjects (10.3%) and included sudden cardiac death (n = 13), acute MI (n = 62), and unstable angina with revascularization (n = 57). The presence of no (88%), minimal (6%), mild (5%), and moderate/severe (1%) ischemia was associated with an ACS incidence of 8.3%, 19.7%, 25.0%, and 38.9%, respectively (P < .0001 for trend). Kaplan-Meier event-free survival analyses by myocardial ischemia severity categories showed that even minimal and mild myocardial ischemia were associated with greater ACS incidence detectable as early as 2 years after baseline. A Cox proportional hazard model, adjusted for risk factors and follow-up time, showed that each 5% increment in the severity of ischemia resulted in a 77% increase in the hazard of incident ACS (P < .001).
Inducible myocardial ischemia is prevalent in asymptomatic siblings of persons with early onset CAD. Most ischemia is minimal or mild in severity, and although the severity of ischemia is associated with the risk of ACS in a graded fashion, the presence of even minimal and mild perfusion defects predicts worse CAD outcomes in this population.
PMCID: PMC3266988  PMID: 22081304
SPECT; ischemia; myocardial; stress testing; acute coronary syndromes; outcomes research
The British journal of nutrition  2011;107(4):547-555.
Over the past 50 years, increases in dietary n-6 polyunsaturated fatty acids (PUFAs), such as linoleic acid, have been hypothesized to cause or exacerbate chronic inflammatory diseases. This study examines an individual’s innate capacity to synthesize n-6-long chain PUFAs (LC-PUFAs), with respect to the fatty acid desaturase (FADS) locus in Americans of African and European descent with diabetes/metabolic syndrome. Compared to European Americans (EAm), African Americans (AfAm) exhibited markedly higher serum levels of arachidonic acid (AA) (EAm 7.9±2.1; AfAm 9.8±1.9 % of total fatty acids, mean ± sd; p<2.29×10−9) and the AA to n-6-precursor fatty acid ratio, which estimates FADS1 activity (EAm 5.4±2.2, AfAm 6.9±2.2; p=1.44×10−5). Seven single nucleotide polymorphisms (SNP) mapping to the FADS locus revealed strong association with AA, eicosapentaenoic acid (EPA) and dihomogamma-linolenic acid (DGLA) in the EAm. Importantly, EAm homozygous for the minor allele (T) had significantly lower AA levels (TT: 6.3±1.0; GG: 8.5±2.1; p=3.0×10−5) and AA/DGLA ratios (TT: 3.4±0.8; GG: 6.5±2.3; p=2.2×10−7) but higher DGLA levels (TT: 1.9±0.4; GG: 1.4±0.4; p=3.3×10−7) compared to those homozygous for the major allele (GG). Allele frequency patterns suggest that the GG genotype at rs174537 (associated with higher circulating levels of AA) is much higher in AfAm (0.81) compared to EAm (0.46). Similarly, marked differences in rs174537 genotypic frequencies were observed in HapMap populations. These data suggest that there are likely important differences in the capacity of different populations to synthesize LC-PUFAs. These differences may provide a genetic mechanism contributing to health disparities between populations of African and European descent.
PMCID: PMC3494092  PMID: 21733300
SNP; FADS; arachidonic acid synthesis
European Heart Journal  2011;32(22):2766-2772.
A family history of premature coronary artery disease (CAD) in an apparently healthy individual conveys an increased risk of future CAD. The extent to which inducible myocardial ischaemia exists and is associated with long-term incident CAD in apparently healthy siblings of early-onset CAD patients is unknown.
Methods and results
Asymptomatic siblings (n = 1287, aged 30–59 years) of patients with onset of CAD <60 years of age underwent risk factor screening and maximal graded treadmill testing with nuclear perfusion imaging, and were followed for incident CAD events for up to 25 years. Incident CAD occurred in 15.2% of siblings (68% acute coronary syndromes); mean time to first CAD event was 8.2 ± 5.2 years. Inducible ischaemia was highly prevalent in male siblings (26.9%), and was independently associated with incident CAD. Male siblings ≥40 years of age who were low or intermediate risk by traditional risk assessment, had a prevalence of inducible ischaemia and a 10-year risk of incident CAD that were near or ≥20%. In female siblings ≥40 years of age, the presence of inducible ischaemia was also independently associated with incident CAD, but the prevalence of inducible ischaemia was markedly lower, as was the risk of incident CAD.
Inducible ischaemia is highly prevalent in male siblings, suggesting a previously unknown long quiescent period before the occurrence of a clinical event. While inducible ischaemia is associated with a worse prognosis, male siblings with negative tests still bear a high risk of incident disease, such that we propose that in male siblings over 40 years of age, aggressive primary prevention interventions be instituted without nuclear testing. For women, the prevalence of ischaemia was so low as to not warrant screening, but the incidence of CAD was high enough to at least warrant lifestyle interventions.
PMCID: PMC3214725  PMID: 21785111
Ischaemia; Coronary artery disease; Outcomes; Asymptomatic; Primary prevention; Risk assessment; Family; Sibling
American Journal of Epidemiology  2011;174(4):403-411.
The association between physiologic levels of sex hormones and QT-interval duration in humans was evaluated using data from 727 men enrolled in the Third National Health and Nutrition Examination Survey and 2,942 men and 1,885 postmenopausal women enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). Testosterone, estradiol, and sex hormone-binding globulin levels were measured in serum and free testosterone was calculated from those values. QT interval was measured using a standard 12-lead electrocardiogram. In men from the Third National Health and Nutrition Survey, the multivariate adjusted differences in average QT-interval duration comparing the highest quartiles with the lowest quartiles of total testosterone and free testosterone were −8.5 ms (95% confidence interval (CI): −15.5, −1.4) and −8.0 ms (95% CI: −13.2, −2.8), respectively. The corresponding differences were −1.8 ms (95% CI: −3.8, −0.2), and −4.7 ms (95% CI: −6.7, −2.6), respectively, in men from MESA and −0.6 ms (95% CI: −3.0, 1.8) and 0.8 ms (95% CI: −1.6, 3.3), respectively, in postmenopausal women from MESA. Estradiol levels were not associated with QT-interval duration in men, but there was a marginally significant positive association in postmenopausal women. The findings suggest that testosterone levels may explain differences in QT-interval duration between men and women and could be a contributor to population variability in QT-interval duration among men.
PMCID: PMC3202165  PMID: 21768401
electrocardiography; estradiol; gonadal sex hormones; testosterone
Coviello, Andrea D. | Haring, Robin | Wellons, Melissa | Vaidya, Dhananjay | Lehtimäki, Terho | Keildson, Sarah | Lunetta, Kathryn L. | He, Chunyan | Fornage, Myriam | Lagou, Vasiliki | Mangino, Massimo | Onland-Moret, N. Charlotte | Chen, Brian | Eriksson, Joel | Garcia, Melissa | Liu, Yong Mei | Koster, Annemarie | Lohman, Kurt | Lyytikäinen, Leo-Pekka | Petersen, Ann-Kristin | Prescott, Jennifer | Stolk, Lisette | Vandenput, Liesbeth | Wood, Andrew R. | Zhuang, Wei Vivian | Ruokonen, Aimo | Hartikainen, Anna-Liisa | Pouta, Anneli | Bandinelli, Stefania | Biffar, Reiner | Brabant, Georg | Cox, David G. | Chen, Yuhui | Cummings, Steven | Ferrucci, Luigi | Gunter, Marc J. | Hankinson, Susan E. | Martikainen, Hannu | Hofman, Albert | Homuth, Georg | Illig, Thomas | Jansson, John-Olov | Johnson, Andrew D. | Karasik, David | Karlsson, Magnus | Kettunen, Johannes | Kiel, Douglas P. | Kraft, Peter | Liu, Jingmin | Ljunggren, Östen | Lorentzon, Mattias | Maggio, Marcello | Markus, Marcello R. P. | Mellström, Dan | Miljkovic, Iva | Mirel, Daniel | Nelson, Sarah | Morin Papunen, Laure | Peeters, Petra H. M. | Prokopenko, Inga | Raffel, Leslie | Reincke, Martin | Reiner, Alex P. | Rexrode, Kathryn | Rivadeneira, Fernando | Schwartz, Stephen M. | Siscovick, David | Soranzo, Nicole | Stöckl, Doris | Tworoger, Shelley | Uitterlinden, André G. | van Gils, Carla H. | Vasan, Ramachandran S. | Wichmann, H.-Erich | Zhai, Guangju | Bhasin, Shalender | Bidlingmaier, Martin | Chanock, Stephen J. | De Vivo, Immaculata | Harris, Tamara B. | Hunter, David J. | Kähönen, Mika | Liu, Simin | Ouyang, Pamela | Spector, Tim D. | van der Schouw, Yvonne T. | Viikari, Jorma | Wallaschofski, Henri | McCarthy, Mark I. | Frayling, Timothy M. | Murray, Anna | Franks, Steve | Järvelin, Marjo-Riitta | de Jong, Frank H. | Raitakari, Olli | Teumer, Alexander | Ohlsson, Claes | Murabito, Joanne M. | Perry, John R. B.
PLoS Genetics  2012;8(7):e1002805.
Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10−106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10−11), GCKR (rs780093, 2p23.3, p = 2.2×10−16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10−09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10−35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10−08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10−12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10−14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10−14), LHCGR (rs10454142, 2p16.3, p = 1.3×10−07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10−08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10−06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10−08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ∼15.6% and ∼8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
Author Summary
Sex hormone-binding globulin (SHBG) is the key protein responsible for binding and transporting the sex steroid hormones, testosterone and estradiol, in the circulatory system. SHBG regulates their bioavailability and therefore their effects in the body. SHBG has been linked to chronic diseases including type 2 diabetes and to hormone-sensitive cancers such as breast and prostate cancer. SHBG concentrations are approximately 50% heritable in family studies, suggesting SHBG concentrations are under significant genetic control; yet, little is known about the specific genes that influence SHBG. We conducted a large study of the association of SHBG concentrations with markers in the human genome in ∼22,000 white men and women to determine which loci influence SHBG concentrations. Genes near the identified genomic markers in addition to the SHBG protein coding gene included PRMT6, GCKR, ZBTB10, JMJD1C, SLCO1B1, NR2F2, ZNF652, TDGF3, LHCGR, BAIAP2L1, and UGT2B15. These genes represent a wide range of biologic pathways that may relate to SHBG function and sex steroid hormone biology, including liver function, lipid metabolism, carbohydrate metabolism and type 2 diabetes, and the development and progression of sex steroid hormone-responsive cancers.
PMCID: PMC3400553  PMID: 22829776
Fertility and Sterility  2008;91(4 Suppl):1316-1318.
Eleven patients underwent controlled ovarian hyperstimulation yielding seventy-two embryos for evaluation. Mean nitric oxide metabolite (NOx) levels in the insemination media (IM) were 2.6 times higher in embryos that progressed to blastocysts by culture day (CD) 5 than those that did not (p=0.009). A comparison of the ROC curves between morphologic predictors and NOx levels revealed a trend toward a stronger association of IM NOx with blastocyst formation.
PMCID: PMC3359095  PMID: 18377900
Diabetes  2011;60(4):1329-1339.
The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS.
Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected.
Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure.
Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.
PMCID: PMC3064107  PMID: 21386085
Background. The NCEP metabolic syndrome (MetS) is a combination of dichotomized interrelated risk factors from predominantly Caucasian populations. We propose a continuous MetS score based on principal component analysis (PCA) of the same risk factors in a multiethnic cohort and compare prediction of incident CVD events with NCEP MetS definition. Additionally, we replicated these analyses in the Health, Aging, and Body composition (Health ABC) study cohort. Methods and Results. We performed PCA of the MetS elements (waist circumference, HDL, TG, fasting blood glucose, SBP, and DBP) in 2610 Caucasian Americans, 801 Chinese Americans, 1875 African Americans, and 1494 Hispanic Americans in the multiethnic study of atherosclerosis (MESA) cohort. We selected the first principal component as a continuous MetS score (MetS-PC). Cox proportional hazards models were used to examine the association between MetS-PC and 5.5 years of CVD events (n = 377) adjusting for age, gender, race, smoking and LDL-C, overall and by ethnicity. To facilitate comparison of MetS-PC with the binary NCEP definition, a MetS-PC cut point was chosen to yield the same 37% prevalence of MetS as the NCEP definition (37%) in the MESA cohort. Hazard ratio (HR) for CVD events were estimated using the NCEP and Mets-PC-derived binary definitions. In Cox proportional models, the HR (95% CI) for CVD events for 1-SD (standard deviation) of MetS-PC was 1.71 (1.54–1.90) (P < 0.0001) overall after adjusting for potential confounders, and for each ethnicity, HRs were: Caucasian, 1.64 (1.39–1.94), Chinese, 1.39 (1.06–1.83), African, 1.67 (1.37–2.02), and Hispanic, 2.10 (1.66-2.65). Finally, when binary definitions were compared, HR for CVD events was 2.34 (1.91–2.87) for MetS-PC versus 1.79 (1.46–2.20) for NCEP MetS. In the Health ABC cohort, in a fully adjusted model, MetS-PC per 1-SD (Health ABC) remained associated with CVD events (HR = 1.21, 95%CI 1.12–1.32) overall, and for each ethnicity, Caucasian (HR = 1.24, 95%CI 1.12–1.39) and African Americans (HR = 1.16, 95%CI 1.01–1.32). Finally, when using a binary definition of MetS-PC (cut point 0.505) designed to match the NCEP definition in terms of prevalence in the Health ABC cohort (35%), the fully adjusted HR for CVD events was 1.39, 95%CI 1.17–1.64 compared with 1.46, 95%CI 1.23–1.72 using the NCEP definition. Conclusion. MetS-PC is a continuous measure of metabolic syndrome and was a better predictor of CVD events overall and in individual ethnicities. Additionally, a binary MetS-PC definition was better than the NCEP MetS definition in predicting incident CVD events in the MESA cohort, but this superiority was not evident in the Health ABC cohort.
PMCID: PMC3318892  PMID: 22536533
A cluster of metabolic abnormalities termed metabolic syndrome (MetS) is associated with vascular endothelial dysfunction and oxidative internal milieu. We examined whether the association of MetS with subclinical atherosclerosis is explained by biomarkers of endothelial damage and oxidative stress.
MESA is a population based study of 45-84 year old individuals of four US ethnicities without clinical cardiovascular disease. A random sample of 997 MESA participants had data on the following biomarkers: von Willebrand Factor, soluble intercellular adhesion molecule-1 (sICAM1), CD40 ligand, soluble thrombomodulin, E-selectin, and oxidized LDL (oxLDL). We examined whether the associations of MetS with B-mode ultrasound-defined common and internal carotid intimal medial thickness (IMT) and coronary artery calcium (CAC) measured using computerized tomography were explained by the biomarkers using multiple regression methods.
MetS was associated with higher levels of each of the biomarkers (p<0.001, CD40L suggestive association p=0.004), with greater IMT (p<0.001), and with greater extent of CAC in those in whom CAC was detectable (p=0.01). The association of MetS with measures of subclinical atherosclerosis remained unchanged after adjustment for the biomarkers. After adjusting for MetS, oxLDL was suggestively associated with greater prevalence of detectable CAC (p=0.005) and thicker internal carotid IMT (p=0.002), while sICAM-1was significantly associated with greater prevalence of detectable CAC (p=0.001).
The association of MetS with subclinical atherosclerosis was independent of its association with biomarkers of endothelial damage and oxidative stress, suggesting that metabolic abnormalities and oxidative endothelial damage may lead to atherosclerotic disease through distinct mechanisms.
PMCID: PMC3130805  PMID: 21505504
Metabolic syndrome; biomarkers; coronary artery atherosclerosis; carotid arteries
American journal of hematology  2010;85(12):971-973.
Von Willebrand Factor (vWF) is a plasma protein involved in thrombosis and hemostasis [1]. We examined whether common single nucleotide polymorphisms (SNPs) in the vWF gene were associated with vWF levels and platelet aggregation-related functional consequences in1230 Whites and 837 African Americans in a cross-sectional family based genetic study of platelet function. From a high-density scan, 28 SNPs with a minor allele frequency > 5% in both races were tested for association using age and sex adjusted variance components analysis in MERLIN. SNP rs216321, with the strongest association with vWF levels in biracial metaanalysis (p=9.5×10−6, Whites–p=8.1×10−4, African Americans–p=3.6×10−3), encoding a R852Q substitution in the D’D3 protein domain, demonstrated negative association with plasma vWF. The R852Q variant was recessively associated with 15.5% lower collagen-induced platelet aggregation adjusting for dose-response relationship (p=0.010, vWF-level adjusted p=0.003). Each copy of the R852Q variant was additively associated with 31% higher FVIII levels (p=0.039, vWF-adjusted p=0.033). In conclusion, this common missense polymorphism appears to have pleiotropic functional consequences.
PMCID: PMC2992080  PMID: 20941784
Assimes, Themistocles L | Hólm, Hilma | Kathiresan, Sekar | Reilly, Muredach P | Thorleifsson, Gudmar | Voight, Benjamin F | Erdmann, Jeanette | Willenborg, Christina | Vaidya, Dhananjay | Xie, Changchun | Patterson, Chris C | Morgan, Thomas M | Burnett, Mary Susan | Li, Mingyao | Hlatky, Mark A | Knowles, Joshua W | Thompson, John R | Absher, Devin | Iribarren, Carlos | Go, Alan | Fortmann, Stephen P | Sidney, Stephen | Risch, Neil | Tang, Hua | Myers, Richard M | Berger, Klaus | Stoll, Monika | Shah, Svati H. | Thorgeirsson, Gudmundur | Andersen, Karl | Havulinna, Aki S | Herrera, J. Enrique | Faraday, Nauder | Kim, Yoonhee | Kral, Brian G. | Mathias, Rasika | Ruczinski, Ingo | Suktitipat, Bhoom | Wilson, Alexander F | Yanek, Lisa R. | Becker, Lewis C | Linsel-Nitschke, Patrick | Lieb, Wolfgang | König, Inke R | Hengstenberg, Christian | Fischer, Marcus | Stark, Klaus | Reinhard, Wibke | Winogradow, Janina | Grassl, Martina | Grosshennig, Anika | Preuss, Michael | Eifert, Sandra | Schreiber, Stefan | Wichmann, H-Erich | Meisinger, Christa | Yee, Jean | Friedlander, Yechiel | Do, Ron | Meigs, James B | Williams, Gordon | Nathan, David M | MacRae, Calum A | Qu, Liming | Wilensky, Robert L | Matthai, William H. | Qasim, Atif N | Hakonarson, Hakon | Pichard, Augusto D | Kent, Kenneth M | Satler, Lowell | Lindsay, Joseph M | Waksman, Ron | Knouff, Christopher W | Waterworth, Dawn M | Walker, Max C | Mooser, Vincent | Marrugat, Jaume | Lucas, Gavin | Subirana, Isaac | Sala, Joan | Ramos, Rafael | Martinelli, Nicola | Olivieri, Oliviero | Trabetti, Elisabetta | Malerba, Giovanni | Pignatti, Pier Franco | Guiducci, Candace | Mirel, Daniel | Parkin, Melissa | Hirschhorn, Joel N | Asselta, Rosanna | Duga, Stefano | Musunuru, Kiran | Daly, Mark J | Purcell, Shaun | Braund, Peter S | Wright, Benjamin J | Balmforth, Anthony J | Ball, Stephen G | Ouwehand, Willem H | Deloukas, Panos | Scholz, Michael | Cambien, Francois | Huge, Andreas | Scheffold, Thomas | Salomaa, Veikko | Girelli, Domenico | Granger, Christopher B. | Peltonen, Leena | McKeown, Pascal P | Altshuler, David | Melander, Olle | Devaney, Joseph M | Epstein, Stephen E | Rader, Daniel J | Elosua, Roberto | Engert, James C | Anand, Sonia S | Hall, Alistair S | Ziegler, Andreas | O’Donnell, Christopher J | Spertus, John A | Siscovick, David | Schwartz, Stephen M | Becker, Diane | Thorsteinsdottir, Unnur | Stefansson, Kari | Schunkert, Heribert | Samani, Nilesh J | Quertermous, Thomas
We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455) and clinical coronary artery disease (CAD).
Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with non-carriers.
The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in nineteen case-control studies of non-fatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports.
Over 17 000 cases and 39 000 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the nineteen studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with non-carriers. Regression analyses and fixed effect meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early onset disease (<50 years of age for males and <60 years for females) compared with similarly aged controls as well as all non-European subgroups.
The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.
PMCID: PMC3084526  PMID: 20933357
kinesin-like protein 6; KIF6; coronary artery disease; myocardial infarction; polymorphism
Objectives To use changes in heart disease mortality rates with age to investigate the plausibility of attributing women’s lower heart disease mortality than men to the protective effects of premenopausal sex hormones.
Design Modelling study of longitudinal mortality data with models assuming (i) a linear association between mortality rates and age (absolute mortality) or (ii) a logarithmic association (proportional mortality). We fitted models to age and sex specific mortality rates in the census years 1950 to 2000 for three birth cohorts (1916-25, 1926-35, and 1936-45).
Data sources UK Office for National Statistics and the US National Center for Health Statistics.
Main outcome measure(s) Fit of models to data for England and Wales and for the US.
Results For England-Wales data, proportional increases in ischaemic heart disease mortality fitted the data better than absolute increases (improvement in deviance statistics: women, 58 logarithmic units; men, 37). We identified a deceleration in male mortality after age 45 years (decreasing from 30.3% to 5.2% per age-year, P=0.042), although the corresponding difference in women was non-significant (P=0.43, overall trend 7.9% per age-year, P<0.001). By contrast, female breast cancer mortality decelerated significantly after age 45 years (decreasing from 19.3% to 2.6% per age-year, P<0.001). We found similar results in US data.
Conclusions Proportional age related changes in ischaemic heart disease mortality, suggesting a loss of reparative reserve, fit longitudinal mortality data from England, Wales, and the United States better than absolute age related changes in mortality. Acceleration in male heart disease mortality at younger ages could explain sex differences rather than any menopausal changes in women.
PMCID: PMC3167164  PMID: 21896608

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