Family Heart Study Research Articles

Metabolic syndrome traits exhibit genotype-by-environment interaction in relation to socioeconomic status in the Mexican American family heart study.

Background: Socioeconomic Status (SES) is a potent environmental determinant of health. To our knowledge, no assessment of genotype-environment interaction has been conducted to consider the joint effects of socioeconomic status and genetics on risk for metabolic disease. We analyzed data from the Mexican American Family Studies (MAFS) to evaluate the hypothesis that genotype-by-environment interaction (GxE) is an essential determinant of variation in risk factors for metabolic syndrome (MS). Methods: We employed a maximum likelihood estimation of the decomposition of variance components to detect GxE interaction. After excluding individuals with diabetes and individuals on medication for diabetes, hypertension, or dyslipidemia, we analyzed 12 MS risk factors: fasting glucose (FG), fasting insulin (FI), 2-h glucose (2G), 2-h insulin (2I), body mass index (BMI), waist circumference (WC), leptin (LP), high-density lipoprotein-cholesterol (HDL-C), triglycerides (TG), total serum cholesterol (TSC), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Our SES variable used a combined score of Duncan's socioeconomic index and education years. Heterogeneity in the additive genetic variance across the SES continuum and a departure from unity in the genetic correlation coefficient were taken as evidence of GxE interaction. Hypothesis tests were conducted using standard likelihood ratio tests. Results: We found evidence of GxE for fasting glucose, 2-h glucose, 2-h insulin, BMI, and triglycerides. The genetic effects underlying the insulin/glucose metabolism component of MS are upregulated at the lower end of the SES spectrum. We also determined that the household variance for systolic blood pressure decreased with increasing SES. Conclusion: These results show a significant change in the GxE interaction underlying the major components of MS in response to changes in socioeconomic status. Further mRNA sequencing studies will identify genes and canonical gene pathways to support our molecular-level hypotheses.

Association of potato consumption with calcified atherosclerotic plaques in the coronary arteries: The NHLBI Family Heart Study

Background and aimsWhile the association of potato consumption with risk factors for coronary artery disease has been inconsistent, no data are available in the literature on the influence of potato consumption on subclinical disease. Thus, we sought to examine whether baked/mashed potato consumption is associated with calcified atherosclerotic plaques in the coronary arteries. Methods and ResultsIn a cross-sectional design, we studied 2208 participants of the NHLBI Family Heart Study. These subjects were selected based on their elevated cardiovascular disease risk compared to the general population. Potato consumption was assessed by a semi-quantitative food frequency questionnaire. We defined prevalent CAC using an Agatston score of at least 100 and fitted generalized estimating equations to calculate prevalence odds ratios of CAC. Mean age at initial clinic visit was 58.2 years and 55% were female. Median consumption of potatoes was 2–4/week. There was no statistically significant association between frequency of potato consumption and prevalent CAC: odds ratios (95% CI) for CAC were 1.0 (reference), 0.85 (0.56–1.30), 0.85 (0.58–1.26), and 0.95 (0.60–1.53) among subjects reporting potato consumption of <1/week, 1/week, 2–4/week, and 5+/week, respectively (p for linear trend 0.83), adjusting for age, sex, BMI, smoking, exercise, diabetes, hypertension, total calories, prevalent coronary heart disease, income, education, and daily red meat intake. ConclusionsWe found no significant association between baked/mashed potato consumption and CAC in older adults. Study registration numberNCT00005136. Study registration date: 5/25/2000.

Lipidomic profiling in the Strong Heart Study identified American Indians at risk of chronic kidney disease

Dyslipidemia associates with and usually precedes the onset of chronic kidney disease (CKD), but a comprehensive assessment of molecular lipid species associated with risk of CKD is lacking. Here, we sought to identify fasting plasma lipids associated with risk of CKD among American Indians in the Strong Heart Family Study, a large-scale community-dwelling of individuals, followed by replication in Mexican Americans from the San Antonio Family Heart Study and Caucasians from the Australian Diabetes, Obesity and Lifestyle Study. We also performed repeated measurement analysis to examine the temporal relationship between the change in the lipidome and change in kidney function between baseline and follow-up of about five years apart. Network analysis was conducted to identify differential lipid classes associated with risk of CKD. In the discovery cohort, we found that higher baseline level of multiple lipid species, including glycerophospholipids, glycerolipids and sphingolipids, was significantly associated with increased risk of CKD, independent of age, sex, body mass index, diabetes and hypertension. Many lipid species were replicated in at least one external cohort at the individual lipid species and/or the class level. Longitudinal change in the plasma lipidome was significantly associated with change in the estimated glomerular filtration rate after adjusting for covariates, baseline lipids and the baseline rate. Network analysis identified distinct lipidomic signatures differentiating high from low-risk groups. Thus, our results demonstrated that disturbed lipid metabolism precedes the onset of CKD. These findings shed light on the mechanisms linking dyslipidemia to CKD and provide potential novel biomarkers for identifying individuals with early impaired kidney function at preclinical stages.

Dairy product consumption and calcified atherosclerotic plaques in the coronary arteries: The NHLBI Family Heart Study.

Diet modification is a major component of non-pharmacological coronary heart disease (CHD) prevention. Few studies have examined the association between consumption of different dairy products with subclinical coronary artery disease. We sought to examine whether milk, yogurt, or cheese consumption is associated with calcified atherosclerotic plaques in the coronary arteries. We cross-sectionally examined 2278 participants from the National Heart, Lung, and Blood Institute Family Heart Study. Dairy consumption was assessed by a semiquantitative food frequency questionnaire. Coronary artery calcium (CAC) was estimated by cardiac computed tomography. We used an Agatston score of ≥100 to indicate prevalent CAC and fitted multivariable logistic regression to calculate adjusted odds ratios. Mean age was 58±13 years and 45% were male. The frequency of milk (≤1/week, 2-4/week, and ≥5/week; 22%, 14%, and 64%, respectively), yogurt (almost never, <1/week, and ≥1/week; 54%, 20%, and 26%, respectively), and cheese consumption (<1/week, 1/week, 2-4/week, and ≥5/week; 15%, 17%, 41%, and 27%, respectively) varied in the cohort. We observed an inverse association of cheese consumption with prevalent CAC: odds ratio (95% CI) of 0.63 (0.42-0.94) when comparing cheese intake of ≥5 servings/week with <1/week, adjusting for sex, age, body mass index, cigarette pack years, presence of CHD, family income, and education (p for linear trend 0.007). In contrast, there was no association between yogurt or milk consumption and CAC (p for linear trend 0.51 and 0.87, respectively). Our data suggest that cheese consumption but not yogurt or milk is associated with a lower odds of CAC in men and women.

Relationship Between Psychosocial Stress and Blood Pressure: The National Heart, Lung, and Blood Institute Family Heart Study.

IntroductionVarious domains of psychosocial stress have been significantly related to blood pressure. However, ambiguity is present in how these relationships are defined in the literature.ObjectiveTo add to the existing literature and examine the relationship between psychosocial stress (financial strain and job strain) and other cofactors on blood pressure.MethodsThis secondary analysis is designed to analyze the relationship between levels of job and financial stress and blood pressure outcomes among participants in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study 2004–2008. The descriptive, cross-sectional design uses data from a subset of study participants, 350 White and 195 Black (n = 545), 338 female (62%), and all aged 18–56 years. Psychosocial stress was measured using the Singh Stress Scale. Resting systolic (SBP) and diastolic (DBP) blood pressure values obtained on a stress reactivity protocol day in the primary study, as well as calculated mean arterial pressure (MAP) were used for this analysis. Multivariate linear regression analyses were used to explore the relationship between psychosocial stress and blood pressure.ResultsIn this young cohort, self-report of either financial strain or job strain was associated with lower blood pressure levels than those of participants who reported neither stressor. Differential sex and race effects appear to contribute to these results. Blood pressure levels were not significantly associated with self-report of both stressors.ConclusionUnderstanding the effects of various forms of stress on blood pressure may inform more precise HTN risk-factor screening and interventions to improve BP management.

Tree nut consumption and prevalence of carotid artery plaques: The National Heart, Lung, and Blood Institute Family Heart Study.

While tree nut consumption has been shown to be cardioprotective, a few studies have examined the relationship between tree nut consumption and carotid atherosclerosis. We tested the hypothesis that tree nut consumption would be inversely related with carotid atherosclerosis in adults. We cross-sectionally analyzed data from 4536 participants of the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study conducted in the United States. Dietary patterns among participants were variable, tree nut consumption was self-reported using the Food Frequency Questionnaire (FFQ), and B-mode ultrasound of the carotid arteries was used to assess for the presence of carotid artery plaques (primary outcome) and carotid intima media thickness (cIMT). Multivariable logistic regression was used to estimate odds ratio (95% confidence interval) of prevalent carotid artery plaques and linear regression was used to estimate adjusted mean cIMT across categories of nut consumption. The mean age was 52.3years (SD = 13.6), 95.6% of the participants were white, and 54% were female. The median tree nut intake was 1-3 servings/month. Odds ratios (95% CI) for prevalent carotid artery plaques were 1.0 (reference), 1.03 [0.86, 1.4], 0.89 [0.70, 1.13], and 0.96 [0.73, 1.26] for tree nut consumption of almost never, 1-3 times/month, 1/week, and 2+/week, respectively, adjusting for age, sex, race, field center, BMI, smoking status, alcohol consumption, creatinine, energy intake, fruit and vegetable consumption, exercise, and education. In secondary analysis, there was a suggestive inverse association of tree nut consumption with cIMT in the internal carotid artery, but not the common carotid or bifurcation. Our data showed no association between tree nut consumption and prevalence of carotid artery plaques in adults.

Sugar-Sweetened Beverage Consumption and Calcified Atherosclerotic Plaques in the Coronary Arteries: The NHLBI Family Heart Study.

Background: Sugar-sweetened beverage (SSB) intake is associated with higher risk of weight gain, diabetes, hypertension, cardiovascular disease, and cardiovascular mortality. However, the association of SSB with subclinical atherosclerosis in the general population is unknown. Objective: Our primary objective was to investigate the association between SSB intake and prevalence of atherosclerotic plaque in the coronary arteries in The National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study. Methods: We studied 1991 participants of the NHLBI Family Heart Study without known coronary heart disease. Intake of SSB was assessed through a semi-quantitative food frequency questionnaire. Coronary artery calcium (CAC) was measured by cardiac Computed Tomography (CT) and prevalent CAC was defined as an Agatston score ≥100. We used generalized estimating equations to calculate adjusted prevalence ratios of CAC. A sensitivity analysis was also performed at different ranges of cut points for CAC. Results: Mean age and body mass index (BMI) were 55.0 years and 29.5 kg/m2, respectively, and 60% were female. In analysis adjusted for age, sex, BMI, smoking, alcohol use, physical activity, energy intake, and field center, higher SSB consumption was not associated with higher prevalence of CAC [prevalence ratio (95% confidence interval) of: 1.0 (reference), 1.36 (0.70–2.63), 1.69 (0.93–3.09), 1.21 (0.69–2.12), 1.05 (0.60–1.84), and 1.58 (0.85–2.94) for SSB consumption of almost never, 1–3/month, 1/week, 2–6/week, 1/day, and ≥2/day, respectively (p for linear trend 0.32)]. In a sensitivity analysis, there was no evidence of association between SSB and prevalent CAC when different CAC cut points of 0, 50, 150, 200, and 300 were used. Conclusions: These data do not provide evidence for an association between SSB consumption and prevalent CAC in adult men and women.

Long Life Family Study Shows Reduced Coronary Artery Disease Despite High Polygenic Hazard Scores

Polygenic hazard scores (PHS) for coronary artery disease (CAD) quantify individuals with age-specific genetic risk for CAD. We evaluated how well the PHS predict age at onset of CAD in the Long Life Family Study (LLFS; families selected for exceptional longevity), compared to the Family Heart Study (FamHS; random families and high CAD-risk families). LLFS contains 4572 European ancestry (EA) individuals from 581 families (age: 74.0 ± 14.3, range: 22-110 years). FamHS Random has 1806 EA individuals from 454 families (age: 56.2 ± 13.5, range: 22-91 years), while FamHS High CAD-risk has 2301 EA individuals from 553 families (age: 53.2 ± 12.8, range: 21-93 years). We generated the PHS from 176 published SNPs from GWAS for CAD (p< 5.0 x 10-8, r2< 0.2). In each of the extremes of the CAD PHS distributions (75%), Kaplan-Meier method showed that the LLFS presented significant delayed age at onset of CAD compared to FamHS (random and High CAD-risk: P<0.0001). A Cox proportional hazards regression model accounting for CAD age at onset, using family bootstrap (N= 1000) to correct for family relatedness, replicated these results. For example, in the top-25% CAD-PHS when comparing to FamHS high-risk, the LLFS CAD hazards ratio was 0.127 (95% CI: 0.099, 0.164). Our findings suggest that, while PHS captured some of the risk of CAD in LLFS, part of the predisposition remains to be determined. Other relevant factors, including additional genetic discoveries and lifestyle-environment influences are needed to fully determine CAD risk in extreme samples.

Exome Sequencing Analysis Identifies Rare Variants in ATM and RPL8 That Are Associated With Shorter Telomere Length.

Telomeres are important for maintaining genomic stability. Telomere length has been associated with aging, disease, and mortality and is highly heritable (∼82%). In this study, we aimed to identify rare genetic variants associated with telomere length using whole-exome sequence data. We studied 1,303 participants of the Erasmus Rucphen Family (ERF) study, 1,259 of the Rotterdam Study (RS), and 674 of the British Heart Foundation Family Heart Study (BHF-FHS). We conducted two analyses, first we analyzed the family-based ERF study and used the RS and BHF-FHS for replication. Second, we combined the summary data of the three studies in a meta-analysis. Telomere length was measured by quantitative polymerase chain reaction in blood. We identified nine rare variants significantly associated with telomere length (p-value < 1.42 × 10–7, minor allele frequency of 0.2–0.5%) in the ERF study. Eight of these variants (in C11orf65, ACAT1, NPAT, ATM, KDELC2, and EXPH5) were located on chromosome 11q22.3 that contains ATM, a gene involved in telomere maintenance. Although we were unable to replicate the variants in the RS and BHF-FHS (p-value ≥ 0.21), segregation analysis showed that all variants segregate with shorter telomere length in a family. In the meta-analysis of all studies, a nominally significant association with LTL was observed with a rare variant in RPL8 (p-value = 1.48 × 10−6), which has previously been associated with age. Additionally, a novel rare variant in the known RTEL1 locus showed suggestive evidence for association (p-value = 1.18 × 10–4) with LTL. To conclude, we identified novel rare variants associated with telomere length. Larger samples size are needed to confirm these findings and to identify additional variants.

Heritability of 596 lipid species and genetic correlation with cardiovascular traits in the Busselton Family Heart Study

CVD is the leading cause of death worldwide, and genetic investigations into the human lipidome may provide insight into CVD risk. The aim of this study was to estimate the heritability of circulating lipid species and their genetic correlation with CVD traits. Targeted lipidomic profiling was performed on 4,492 participants from the Busselton Family Heart Study to quantify the major fatty acids of 596 lipid species from 33 classes. We estimated narrow-sense heritabilities of lipid species/classes and their genetic correlations with eight CVD traits: BMI, HDL-C, LDL-C, triglycerides, total cholesterol, waist-hip ratio, systolic blood pressure, and diastolic blood pressure. We report heritabilities and genetic correlations of new lipid species/subclasses, including acylcarnitine (AC), ubiquinone, sulfatide, and oxidized cholesteryl esters. Over 99% of lipid species were significantly heritable (h2: 0.06-0.50) and all lipid classes were significantly heritable (h2: 0.14-0.50). The monohexosylceramide and AC classes had the highest median heritabilities (h2 = 0.43). The largest genetic correlation was between clinical triglycerides and total diacylglycerol (rg = 0.88). We observed novel positive genetic correlations between clinical triglycerides and phosphatidylglycerol species (rg: 0.64-0.82), and HDL-C and alkenylphosphatidylcholine species (rg: 0.45-0.74). Overall, 51% of the 4,768 lipid species-CVD trait genetic correlations were statistically significant after correction for multiple comparisons. This is the largest lipidomic study to address the heritability of lipids and their genetic correlation with CVD traits. Future work includes identifying putative causal genetic variants for lipid species and CVD using genome-wide SNP and whole-genome sequencing data.

Gene discovery for high-density lipoprotein cholesterol level change over time in prospective family studies

Backgrounds and aimsSeveral genes are known to contribute to the levels and metabolism of HDL-C, however, their protective effects in cardiovascular disease (CVD), healthy aging, and longevity are complex and poorly understood. It is also unclear if these genes predict longitudinal HDL-C change. We aimed to identify loci influencing HDL-C change. MethodsWe performed a genome-wide association study (GWAS) with harmonized HDL-C and imputed genotype in three family-based studies recruited for exceptional survival (Long Life Family Study), from community-based (Framingham Heart Study) and enriched for CVD (Family Heart Study). In 7738 individuals with at least 2 visits, we employed a growth curve model to estimate the random linear trajectory parameter of age-sex-adjusted HDL-C for each person. GWAS was performed using a linear regression model on HDL-C change accounting for kinship correlations, population structure, and differences among studies. ResultsWe identified a novel association for HDL-C with GRID1 (p = 5.43 × 10−10), which encodes a glutamate receptor channel subunit involved in synaptic plasticity. Seven suggestive novel loci (p < 1.0 × 10−6; MBOAT2, LINC01876-NR4A2, NTNG2, CYSLTR2, SYNE2, CTXND1-LINC01314, and CYYR1) and a known lipid gene (ABCA10) showed associations with HDL-C change. Two additional sex-specific suggestive loci were identified in women (DCLK2 and KCNJ2). Several of these genetic variants are associated with lipid-related conditions influencing cardiovascular and metabolic health, have predictive regulatory function, and are involved in lipid-related pathways. ConclusionsModeling longitudinal HDL-C in prospective studies, with differences in healthy aging, longevity and CVD risk, contributed to gene discovery and provided insights into mechanisms of HDL-C regulation.

Family Based Prevention of Cardiovascular Disease Risk Factors in Children by Lifestyle Change: The PEP Family Heart Study.

The 14years' Prevention Education Program PEP was started 1994 among first graders, their siblings and parents living in the half million city Nuremberg (Germany). The aim of prospective family-based observational study was early detection and lifestyle intervention of traditional cardiovascular risk factors. Out of 3370 families 24,927 adults and 23,740 children participated in the PEP Family Heart study. Anthropometric parameters including blood pressure and fasting lipids were measured. Because these variables change specifically because of natural growth and development in 3-18years old children we had to calculate age-and gender-specific growth curves using the LMS method. Non-overweight (normal weight) is defined as BMI < 85th percentile (pctl), overweight as BMI 85th to <95th percentile, obesity as BMI ≥ 95th percentile and severe obesity as ≥ 120% of the 95th pctl. Prehypertension is categorized as the ≥90th to <95th pctl or ≥120/80 mm Hg and hypertension as ≥95th pctl on ≥3 occasions. 1. Cardiovascular risk (CVD) factor screening in school children predicted CVD risk in parents. 2. The growths curves for auscultatory systolic (SBP) and diastolic (DBP) blood pressure of non-overweight 8713 boys and 8138 girls nearly identical with the percentile curves of all 11,328 boys and 10,723 girls. 3. The shapes of the 10 lipid percentile curves between the 3rd and 97th pctl differ considerably by age and gender. 4. The wais-to-height ratio (WHtR) percentiles as a measure for abdominal adiposity vary substantially by age and gender 5. Among overweight and obese ≥85th pctl the percentile curves of body fat increase steeply until age 10years and then decrease slowly in boys whereas the BF% percentile curves in girls increase continuously until age 18years 6. The prevalence of hypertension increased strongly in severe obesity at the 99th pctl, more steeply beyond 120% of the 95th pctl to 59.1% in boys and 56% in girls. 7. The association between hypertension and normal weight, overweight and obesity increased in boys from 0,5, via 2,7 to 4,3 and in girls from 0,4 via 2,1 to 5,9. 8. Between 2000 and 2007 mean blood pressure decreased from 138.3±18.5 mm Hg to 124.0±13.8 mm Hg in fathers and from 119.1±2.8 mm Hg to 110.4±11.2 mm Hg in mothers. 9. After 1year weighed dietary protocols demonstrate in 166 fathers a decrease of all six nutrional components like daily energy consumption from 2423 to 2307Kcal, from 98g to 91g fat, from 260g to 252g carbohydrates, from 88g to 84g protein, cholesterol from 362 mg to 339 mg and alcohol from 19g to 17g per day and in 237 mothers from 1915Kcal to 1830Kcal, from 79g to 73g total fat, from 216g to 212g carbohydrates, from 66g to 64g protein, from 299g to 244 mg cholesterol. 10. Sustained intensive individual and family-based lifestyle counseling in daily life in terms of healthy diet, less sedentary behavior and more leisure time physical activity slightly improved the CVD risk factor profiles in parents and their children already after 1year.

P4387Cardiometabolic risk factors in hypertensive children and adolescents: the PEP Family Heart Study

P4387Cardiometabolic risk factors in hypertensive children and adolescents: the PEP Family Heart Study

P1543Associations of skinfold thickness with cardiovascular risk factors in 7076 children and adolescents participating in the PEP Family Heart Study

P1543Associations of skinfold thickness with cardiovascular risk factors in 7076 children and adolescents participating in the PEP Family Heart Study

Gestational Age and the Cord Blood Lipidomic Profile in Late Preterm and Term Infants

Background: Lipid metabolism is vital to fetal development and cardiometabolic health and the final weeks of gestation are known to be a time of intense metabolic activity. New techniques such as lipidomics allow investigation of a complex lipidomic profile in infants. Objectives: This research aimed to (1) describe variations in lipidomic profile in late preterm and term infants and (2) compare variations to an adult lipidomic profile with known clinical implications. Methods: The Barwon Infant Study (n = 1,074) is a population-derived pre-birth cohort study. The lipidomic profile of cord blood was measured by liquid chromatography-mass spectrometry in 225 participants and the association between gestational age and lipidomic profile was investigated using multiple linear regression adjusting for birth weight, exposure to labour, and infant sex. Patterns of association with gestational age across the lipidomic profile were compared with associations between body mass index (BMI) and lipidomic profile observed among adults in the San Antonia Family Heart Study (n = 994). Results: Gestational age was independently associated with the abundances of 39% of lipid species. Variations in the lipidomic profile with increasing gestational age were comparable to some variations observed in association with increasing BMI among adults. Conclusion: There is a strong relationship between gestational age and the cord blood lipid profile at birth, providing further evidence for the importance of metabolic changes of late gestation. A number of the variations in the lipid profile with increasing gestational age are analogous to differences observed in the adult lipid profile with an increasing BMI.

What do we Learn from the Prevention Education Program Family Heart Study about Lifestyle change, Blood Pressure, and Lipids in Children and Parents?

Objectives:The PEP Family Heart Study is a perspective community-based long-term project for the whole family to improve cardiovascular health aiming to assess and to amend risk factors in children and their parents by lifestyle change.Methods:A total of 48,667 subjects (24,927 adults and 23,740 children) from 3,370 families living in 94% of the elementary school districts of Nuremberg (Germany) participated in this observational study from 1993/1994 -2007/2008. The yearly surveys consisting of personal and family histories, structured interviews on leisure time physical activity and tobacco smoke exposition, physical examinations and nutritional intake as documented by seven days weighed dietary protocols and sustained healthy lifestyle counselling were mainly performed at home. Fasting blood collections for biochemical analyses in the study laboratories, cooking courses and seminars on healthy lifestyle were performed on weekends in central school buildings.Results:Here we report some of the main results demonstrating e.g., that at least one CVD risk factor in a child conferred a 2–4 fold higher risk among their parents, that obese children and adolescents had a nearly five times higher prevalence of hypertension than non-overweight youths.Conclusions:Sustained healthy lifestyle behavior can be implemented in daily life of family members which results in amended nutritional intake and improved cardiometabolic risk factors.

Age- and gender-specific silent cardiovascular risk factors in children and adolescents: The PEP family heart study

Age- and gender-specific silent cardiovascular risk factors in children and adolescents: The PEP family heart study

TRAK2, a novel regulator of ABCA1 expression, cholesterol efflux and HDL biogenesis.

The recent failures of HDL-raising therapies have underscored our incomplete understanding of HDL biology. Therefore there is an urgent need to comprehensively investigate HDL metabolism to enable the development of effective HDL-centric therapies. To identify novel regulators of HDL metabolism, we performed a joint analysis of human genetic, transcriptomic, and plasma HDL-cholesterol (HDL-C) concentration data and identified a novel association between trafficking protein, kinesin binding 2 (TRAK2) and HDL-C concentration. Here we characterize the molecular basis of the novel association between TRAK2 and HDL-cholesterol concentration. Analysis of lymphocyte transcriptomic data together with plasma HDL from the San Antonio Family Heart Study (n = 1240) revealed a significant negative correlation between TRAK2 mRNA levels and HDL-C concentration, HDL particle diameter and HDL subspecies heterogeneity. TRAK2 siRNA-mediated knockdown significantly increased cholesterol efflux to apolipoprotein A-I and isolated HDL from human macrophage (THP-1) and liver (HepG2) cells by increasing the mRNA and protein expression of the cholesterol transporter ATP-binding cassette, sub-family A member 1 (ABCA1). The effect of TRAK2 knockdown on cholesterol efflux was abolished in the absence of ABCA1, indicating that TRAK2 functions in an ABCA1-dependent efflux pathway. TRAK2 knockdown significantly increased liver X receptor (LXR) binding at the ABCA1 promoter, establishing TRAK2 as a regulator of LXR-mediated transcription of ABCA1. We show, for the first time, that TRAK2 is a novel regulator of LXR-mediated ABCA1 expression, cholesterol efflux, and HDL biogenesis. TRAK2 may therefore be an important target in the development of anti-atherosclerotic therapies.

Genetic correlation of the plasma lipidome with type 2 diabetes, prediabetes and insulin resistance in Mexican American families

BackgroundDifferential plasma concentrations of circulating lipid species are associated with pathogenesis of type 2 diabetes (T2D). Whether the wide inter-individual variability in the plasma lipidome contributes to the genetic basis of T2D is unknown. Here, we investigated the potential overlap in the genetic basis of the plasma lipidome and T2D-related traits.ResultsWe used plasma lipidomic data (1202 pedigreed individuals, 319 lipid species representing 23 lipid classes) from San Antonio Family Heart Study in Mexican Americans. Bivariate trait analyses were used to estimate the genetic and environmental correlation of all lipid species with three T2D-related traits: risk of T2D, presence of prediabetes and homeostatic model of assessment – insulin resistance. We found that 44 lipid species were significantly genetically correlated with one or more of the three T2D-related traits. Majority of these lipid species belonged to the diacylglycerol (DAG, 17 species) and triacylglycerol (TAG, 17 species) classes. Six lipid species (all belonging to the triacylglycerol class and containing palmitate at the first position) were significantly genetically correlated with all the T2D-related traits.ConclusionsOur results imply that: a) not all plasma lipid species are genetically informative for T2D pathogenesis; b) the DAG and TAG lipid classes partially share genetic basis of T2D; and c) 1-palmitate containing TAGs may provide additional insights into the genetic basis of T2D.

Familial Analysis of Epistatic and Sex-Dependent Association of Genes of the Renin-Angiotensin-Aldosterone System and Blood Pressure.

Renin-angiotensin-aldosterone system genes have been inconsistently associated with blood pressure, possibly because of unrecognized influences of sex-dependent genetic effects or gene-gene interactions (epistasis). We tested association of systolic blood pressure with single-nucleotide polymorphisms (SNPs) at renin (REN), angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AGTR1), and aldosterone synthase (CYP11B2), including sex-SNP or SNP-SNP interactions. Eighty-eight tagSNPs were tested in 2872 white individuals in 809 pedigrees from the Victorian Family Heart Study using variance components models. Three SNPs (rs8075924 and rs4277404 at ACE and rs12721297 at AGTR1) were individually associated with lower systolic blood pressure with significant (P<0.00076) effect sizes ≈1.7 to 2.5 mm Hg. Sex-specific associations were seen for 3 SNPs in men (rs2468523 and rs2478544 at AGT and rs11658531 at ACE) and 1 SNP in women (rs12451328 at ACE). SNP-SNP interaction was suggested (P<0.005) for 14 SNP pairs, none of which had shown individual association with systolic blood pressure. Four SNP pairs were at the same gene (2 for REN, 1 for AGT, and 1 for AGTR1). The SNP rs3097 at CYP11B2 was represented in 5 separate pairs. SNPs at key renin-angiotensin-aldosterone system genes associate with systolic blood pressure individually in both sexes, individually in one sex only and only when combined with another SNP. Analyses that incorporate sex-dependent and epistatic effects could reconcile past inconsistencies and account for some of the missing heritability of blood pressure and are generally relevant to SNP association studies for any phenotype.