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1.  A novel ryanodine receptor mutation linked to sudden death increases sensitivity to cytosolic calcium 
Circulation research  2011;109(3):281-290.
Mutations in the cardiac type 2 ryanodine receptor (RyR2) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT-associated RyR2 mutations cause fatal ventricular arrhythmias in young individuals during beta-adrenergic stimulation.
This study sought to determine the effects of a novel identified RyR2-G230C mutation and whether this mutation and RyR2-P2328S alter the sensitivity of the channel to luminal calcium (Ca2+).
Functional characterizations of recombinant human RyR2-G230C channels were performed under conditions mimicking stress. Human RyR2 mutant channels were generated by site-directed mutagenesis and heterologously expressed in HEK293 cells together with calstabin2 (FKBP12.6). RyR2 channels were measured in order to examine the regulation of the channels by cytosolic vs. luminal SR Ca2+.
A 50 year-old Caucasian male with repeated syncopal episodes after exercise had a cardiac arrest and harbored the mutation RyR2-G230C. PKA-phosphorylated RyR2-G230C channels exhibited a significantly higher open probability (Po) at diastolic Ca2+ concentrations, associated with a depletion of calstabin2. The luminal Ca2+ sensitivities of RyR2-G230C and RyR2-P2328S channels were WT-like.
The RyR2-G230C mutant exhibits similar biophysical defects compared to previously characterized CPVT mutations: decreased binding of the stabilizing subunit calstabin2 and a leftward shift in the Ca2+-dependence for activation under conditions that simulate exercise, consistent with a “leaky” channel. Both RyR2-G230C and RyR2-P2328S channels exhibit normal luminal Ca2+ activation. Thus, diastolic SR Ca2+ leak caused by reduced calstabin2 binding and a leftward shift in the Ca2+-dependence for activation by diastolic levels of cytosolic Ca2+ is a common mechanism underlying CPVT.
PMCID: PMC3690513  PMID: 21659649
CPVT; sudden cardiac death; ryanodine receptor; calstabin
2.  Significant differences in global genomic DNA methylation by gender and race/ethnicity in peripheral blood 
Epigenetics  2011;6(5):623-629.
Reduced levels of global DNA methylation are associated with genomic instability and are independent predictors of cancer risk. Little is known about the environmental determinants of global DNA methylation in peripheral blood. We examined the association between demographic and lifestyle factors and levels of global leukocyte DNA methylation in 161 cancer-free subjects enrolled in the North Texas Healthy Heart Study aged 45–75 years in 2008. We used in-person interviews for demographics and lifestyle factors, a self-administrated Block food frequency questionnaire for diet, and bioelectrical impedance analysis and CT-scan for body composition. We measured genomic DNA methylation using bisulfite conversion of DNA and pyrosequencing for LINE-1. Body composition measures including body mass index, waist circumference, areas of subcutaneous fat and visceral fat, percent of fat mass and fat-free mass were not associated with global genomic DNA methylation after controlling the effect of age, gender and race/ethnicity. Instead, female gender was significantly associated with a reduced level of global methylation (β = −2.77, 95% CI: −4.33, −1.22). Compared to non-Hispanic whites, non-Hispanic blacks (β = −2.02, 95% CI: −3.55, −0.50) had significantly lower levels of global methylation. No association was found with age, cigarette smoking, alcohol drinking and dietary intake of nutrients in one-carbon metabolism. Global leukocyte DNA methylation differs by gender and race/ethnicity, suggesting these variables need to be taken into consideration in studies of global DNA methylation as an epigenetic marker for cancer.
PMCID: PMC3230547  PMID: 21739720
gender; race/ethnicity; DNA methylation
3.  Physical activity and global genomic DNA methylation in a cancer-free population 
Epigenetics  2011;6(3):293-299.
Changes in DNA methylation may represent an intermediate step between the environment and human diseases. Little is known on whether behavioral risk factors may modify gene expression through DNA methylation. To assess whether DNA methylation is associated with different levels of physical activity, we measured global genomic DNA methylation using bisulfite-converted DNA and real-time PCR (MethyLight) for LINE-1 in peripheral blood of 161 participants aged 45–75 years enrolled in the North Texas Healthy Heart Study and levels of physical activity using an accelerometer (Actigraph GT1M Monitor). We found that individuals with physical activity 26–30 min/day had a significantly higher level of global genomic DNA methylation compared to those with physical activity ≤10 min/day (β = 2.52, 95% CI: 0.70, 4.35). However, the association was attenuated and became statistically insignificant after multivariate adjustment (β = 1.24, 95% CI: −0.93, 3.40). There were some suggestions of a positive association between physical activity and global genomic DNA methylation in non-Hispanics (β = 1.50, 95% CI: −0.08, 3.08) that warrants further investigation.
PMCID: PMC3092677  PMID: 21178401
DNA methylation; physical activity; peripheral blood
4.  The relationship between perceived sense of control and visceral adipose tissue - the North Texas Healthy Heart Study 
The purpose of this study was to assess the relationship between one's sense of control and visceral adipose tissue.
This cross-sectional study recruited 571 subjects (45 years and older) who were asymptomatic of CHD from Fort Worth, Texas from 2006 to 2008. Subjects completed a questionnaire, body measurements, a multi-slice computed tomography scan to assess for visceral adipose tissue (VAT) centered at the L4L5 spinal interspace, and serum chemistries. The natural log of L4L5 VAT (lnVAT) was used in all analyses to achieve normality of the data with final analyses including 506 participants. Linear regression was used to estimate unadjusted and adjusted beta-coefficients and standard errors for the association between sense of control and lnVAT.
A total of 506 participants were used in the data after adjusting for normality of the data. An increase in sense of control was associated with a decrease in lnVAT in the unadjusted (p < 0.001) and adjusted (p = 0.03) models. Other factors significantly associated with lnVAT in the adjusted model include age, BMI, male gender, non-Hispanic African American, and diet.
Sense of control remained as an independent factor associated with visceral adiposity despite adjusting for traditional cardiovascular risk factors, including BMI. Future studies should focus on establishing a causal relationship between sense of control and visceral adiposity.
PMCID: PMC3180246  PMID: 21914181
Sense of control; visceral adipose tissue; cardiovascular; psychosocial
5.  Self-reported racial discrimination, response to unfair treatment, and coronary calcification in asymptomatic adults - the North Texas Healthy Heart study 
BMC Public Health  2010;10:285.
Accruing evidence supports the hypothesis that psychosocial factors are related to cardiovascular disease. However, a limited number of studies have investigated the pathophysiologic pathways through which these associations occur. The purpose of this study was to assess whether experiences of self-reported racial discrimination and reactions to unfair treatment were associated with coronary artery calcification (CAC), an indicator of subclinical coronary heart disease (CHD).
This cross-sectional study recruited 571 subjects (45 years and older) who were asymptomatic of CHD from Fort Worth, Texas from 2006 to 2008. Subjects completed a questionnaire, a multi-slice computed tomography scan to assess for CAC presence (measured as Agatston score >0), and serum chemistries. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between self-reported discrimination and CAC. Results were stratified by response to unfair treatment as it was found to significantly modify the relationship between discrimination and CAC.
Among those who passively responded to unfair treatment, the odds of having CAC present were approximately 3 times higher for those experiencing discrimination (OR, 2.95; 95% CI, 1.19-7.32) after adjusting for age, gender, race/ethnicity, education, body mass index, hyperlipidemia, smoking status, hypertension, diabetes, and first degree relative with heart disease.
This is the first multi-racial/ethnic study to find racial discrimination associated with CAC, which differs based on how one responds to unfair treatment.
PMCID: PMC2887822  PMID: 20507602
6.  Acculturation and self-reported health among Hispanics using a socio-behavioral model: the North Texas Healthy Heart Study 
BMC Public Health  2010;10:53.
Acculturation is a continuous, firsthand contact with other cultures functioning at both group and individual levels and is reflected in our culturally diverse society, calling for a greater understanding of the environmental and cultural impact on health. Self-reported health (SRH), a robust and well validated predictor of future mortality for all racial/ethnic groups, has been differentially reported by Hispanics compared to whites, especially based on their acculturation status. This study investigated the relationship between acculturation and SRH among Hispanics. An adapted Andersen framework was used to develop logistic regression models to assess for an association between acculturation and general health status.
Hispanic participants (n = 135), as part of the North Texas Healthy Heart Study, were administered standardized questionnaires on acculturation, psychosocial measures which included sense of control, stress, depression and social support and a single item SRH measure. In addition, physiological measurements and demographic characteristics including age, gender, body mass index, medical history, and socioeconomic status were also obtained.
Bivariate analyses found Mexican-oriented participants 3.16 times more likely to report fair/poor SRH compared to Anglo-oriented Hispanics. Acculturation was also associated with SRH in multiple regression models controlling for enabling, need, and predisposing factors together (OR: 3.53, 95% CI: 1.04, 11.97).
Acculturation status was associated with SRH after accounting for other underlying factors. Medical and public health professionals should promote the use of acculturation measures in order to better understand its role in Hispanic behaviors, health outcomes and health care use. Such research findings will contribute to the design of culturally sensitive prevention and treatment strategies for diverse and immigrant populations.
PMCID: PMC2843663  PMID: 20122263

Results 1-6 (6)