Low cardiorespiratory fitness is a powerful predictor of morbidity and cardiovascular mortality. In 473 sedentary adults, all whites, from 99 families of the Health, Risk Factors, Exercise Training, ...and Genetics (HERITAGE) Family Study, the heritability of gains in maximal O(2) uptake (VO(2max)) after exposure to a standardized 20-wk exercise program was estimated at 47%. A genome-wide association study based on 324,611 single-nucleotide polymorphisms (SNPs) was undertaken to identify SNPs associated with improvements in VO(2max) Based on single-SNP analysis, 39 SNPs were associated with the gains with P < 1.5 × 10(-4). Stepwise multiple regression analysis of the 39 SNPs identified a panel of 21 SNPs that accounted for 49% of the variance in VO(2max) trainability. Subjects who carried ≤9 favorable alleles at these 21 SNPs improved their VO(2max) by 221 ml/min, whereas those who carried ≥19 of these alleles gained, on average, 604 ml/min. The strongest association was with rs6552828, located in the acyl-CoA synthase long-chain member 1 (ACSL1) gene, which accounted by itself for ~6% of the training response of VO(2max). The genes nearest to the SNPs that were the strongest predictors were PR domain-containing 1 with ZNF domain (PRDM1); glutamate receptor, ionotropic, N-methyl-D-aspartate 3A (GRIN3A); K(+) channel, voltage gated, subfamily H, member 8 (KCNH8); and zinc finger protein of the cerebellum 4 (ZIC4). The association with the SNP nearest to ZIC4 was replicated in 40- to 65-yr-old, sedentary, overweight, and dyslipidemic subjects trained in Studies of a Targeted Risk Reduction Intervention Through Defined Exercise (STRRIDE; n = 183). Two SNPs were replicated in sedentary obese white women exercise trained in the Dose Response to Exercise (DREW) study (n = 112): rs1956197 near dishevelled associated activator of morphogenesis 1 (DAAM1) and rs17117533 in the vicinity of necdin (NDN). The association of SNPs rs884736 in the calmodulin-binding transcription activator 1 (CAMTA1) locus and rs17581162 ~68 kb upstream from regulator of G protein signaling 18 (RGS18) with the gains in VO(2max) in HERITAGE whites were replicated in HERITAGE blacks (n = 247). These genomic predictors of the response of Vo(2max) to regular exercise provide new targets for the study of the biology of fitness and its adaptation to regular exercise. Large-scale replication studies are warranted.
The aim of the HERITAGE Family Study was to investigate individual differences in response to a standardized endurance exercise program, the role of familial aggregation, and the genetics of response ...levels of cardiorespiratory fitness and cardiovascular disease and diabetes risk factors. Here we summarize the findings and their potential implications for cardiometabolic health and cardiorespiratory fitness. It begins with overviews of background and planning, recruitment, testing and exercise program protocol, quality control measures, and other relevant organizational issues. A summary of findings is then provided on cardiorespiratory fitness, exercise hemodynamics, insulin and glucose metabolism, lipid and lipoprotein profiles, adiposity and abdominal visceral fat, blood levels of steroids and other hormones, markers of oxidative stress, skeletal muscle morphology and metabolic indicators, and resting metabolic rate. These summaries document the extent of the individual differences in response to a standardized and fully monitored endurance exercise program and document the importance of familial aggregation and heritability level for exercise response traits. Findings from genomic markers, muscle gene expression studies, and proteomic and metabolomics explorations are reviewed, along with lessons learned from a bioinformatics-driven analysis pipeline. The new opportunities being pursued in integrative -omics and physiology have extended considerably the expected life of HERITAGE and are being discussed in relation to the original conceptual model of the study.
Endurance training-induced changes in hemodynamic traits are heritable. However, few genes associated with heart rate training responses have been identified. The purpose of our study was to perform ...a genome-wide association study to uncover DNA sequence variants associated with submaximal exercise heart rate training responses in the HERITAGE Family Study. Heart rate was measured during steady-state exercise at 50 W (HR50) on 2 separate days before and after a 20-wk endurance training program in 483 white subjects from 99 families. Illumina HumanCNV370-Quad v3.0 BeadChips were genotyped using the Illumina BeadStation 500GX platform. After quality control procedures, 320,000 single-nucleotide polymorphisms (SNPs) were available for the genome-wide association study analyses, which were performed using the MERLIN software package (single-SNP analyses and conditional heritability tests) and standard regression models (multivariate analyses). The strongest associations for HR50 training response adjusted for age, sex, body mass index, and baseline HR50 were detected with SNPs at the YWHAQ locus on chromosome 2p25 (P = 8.1 × 10(-7)), the RBPMS locus on chromosome 8p12 (P = 3.8 × 10(-6)), and the CREB1 locus on chromosome 2q34 (P = 1.6 × 10(-5)). In addition, 37 other SNPs showed P values <9.9 × 10(-5). After removal of redundant SNPs, the 10 most significant SNPs explained 35.9% of the ΔHR50 variance in a multivariate regression model. Conditional heritability tests showed that nine of these SNPs (all intragenic) accounted for 100% of the ΔHR50 heritability. Our results indicate that SNPs in nine genes related to cardiomyocyte and neuronal functions, as well as cardiac memory formation, fully account for the heritability of the submaximal heart rate training response.
The availability of high-throughput genotyping technologies and massive amounts of marker data for testing genetic associations is a dual-edged sword. On one side is the possibility that the ...causative gene (or a closely linked one) will be found from among those tested for association, but on the other testing, many loci for association creates potential false positive results and the need to accommodate the multiple testing problem. Traditional solutions involve correcting each test using adjustments such as a Bonferroni correction. This worked well in settings involving a few tests (e.g., 10-20, as is typical for candidate gene studies) and even when the number of tests was somewhat larger (e.g., a few hundred as in genome-wide microsatellite scans). However, the current dense single nucleotide polymorphism (SNP) and/or whole-genome association (WGA) studies often consider several thousand to upwards of 500,000 and 1 million SNPs. In these settings, a Bonferroni correction is not practical as it does not take into account correlations between the tests due to linkage disequilibrium and hence can be too conservative. The effect sizes of susceptibility alleles will rarely (if ever) reach the required level of significance in WGA studies if a Bonferroni correction is used, and the number of false negatives is likely to be large. Thus, one of the burning methodological issues in contemporary genetic epidemiology and statistical genetics is how to balance false positives and false negatives in large-scale association studies. This chapter reviews developments in this area from both historical and current perspectives.
The rates of cardiovascular disease (CVD) and its risk factors are increasing in low-income groups worldwide and capable, highly motivated, and well-trained underrepresented individuals are needed ...because underrepresented research professionals are more likely to work in areas related to underserved minorities and low-income populations (1,2)....medical researchers of underrepresented backgrounds tend to have a cultural understanding of minority communities, facilitating their potential to implement effective interventions (3)....research productivity measured by number of publications more than tripled (3.7-fold increase) after mentees completed the training (from 125 to 467 publications)....mentees have gained career development tools, an understanding of research methods, and confidence in their ability to pursue grant opportunities at NIH and elsewhere, and have become knowledgeable about health disparities–focused research, especially in CVDs.
The percentage of biomedical, behavioral, and clinical under-represented minority (URM) junior faculty is lower than their respective populations in the United States; whereas racial and ethnic ...minorities (African Americans, Hispanic Americans/Latinos, American Indians, Alaska Natives, Native Hawaiian, Pacific Islanders) comprise 32% of U.S. residents, they represent only 8% of medical school faculty (1,2). African Americans (n = 107; 79%), Hispanic Americans (n = 26; 19%), or Native Americans (n = 3; 2%); of these, 90 (66%) were women; 96 (70%) PhDs (or equivalent doctoral degree), 36 (26%) MDs, and 4 (3%) MD/PhDs.Primary outcomes Grants submitted/awarded during and after 2 years post-training After excluding data from 19 individuals from the 2017 to 2018 cohort who were still in training, 187 peer-reviewed grant applications were submitted by 117 mentees (during or after training), and 123 grants were awarded (success rate: 66%). ...of SIPID/PRIDE training, the number of scientific publications also increased significantly (3.3 times the number of publications prior to program participation). ...equally importantly, the number of applicants (n = 297) far exceeded the number who matriculated in the program (n = 136), suggesting that there is an unmet need for additional opportunities for mentored-research training programs such as SIPID/PRIDE.
We performed genome-wide and transcriptome-wide profiling to identify genes and single nucleotide polymorphisms (SNPs) associated with the response of triglycerides (TG) to exercise training.
Plasma ...TG levels were measured before and after a 20-week endurance training programme in 478 white participants from the HERITAGE Family Study. Illumina HumanCNV370-Quad v3.0 BeadChips were genotyped using the Illumina BeadStation 500GX platform. Affymetrix HG-U133+2 arrays were used to quantitate gene expression levels from baseline muscle biopsies of a subset of participants (N=52). Genome-wide association study (GWAS) analysis was performed using MERLIN, while transcriptomic predictor models were developed using the R-package GALGO.
The GWAS results showed that eight SNPs were associated with TG training-response (ΔTG) at p<9.9×10(-6), while another 31 SNPs showed p values <1×10(-4). In multivariate regression models, the top 10 SNPs explained 32.0% of the variance in ΔTG, while conditional heritability analysis showed that four SNPs statistically accounted for all of the heritability of ΔTG. A molecular signature based on the baseline expression of 11 genes predicted 27% of ΔTG in HERITAGE, which was validated in an independent study. A composite SNP score based on the top four SNPs, each from the genomic and transcriptomic analyses, was the strongest predictor of ΔTG (R(2)=0.14, p=3.0×10(-68)).
Our results indicate that skeletal muscle transcript abundance at 11 genes and SNPs at a number of loci contribute to TG response to exercise training. Combining data from genomics and transcriptomics analyses identified a SNP-based gene signature that should be further tested in independent samples.
Abstract
BACKGROUND
A resequencing study of renal epithelial sodium channel (ENaC) genes was conducted to identify rare variants associated with blood pressure (BP) salt-sensitivity.
METHODS
The ...Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study was conducted among 1,906 participants who underwent a 7-day low-sodium followed by a 7-day high-sodium feeding-study. The 300 most salt-sensitive and 300 most salt-resistant GenSalt participants were selected for the resequencing study. Three ENaC genes (SCNN1A, SCNN1B, and SCNN1G) were resequenced using capillary-based sequencing methods. Traditional burden tests were utilized to examine association between rare variants and BP salt-sensitivity. Associations of low-frequency and common variants were tested using single-marker analyses.
RESULTS
Carriers of SCNN1A rare variants had a 0.52 95% confidence interval (CI): 0.32–0.85 decreased odds of BP salt-sensitivity compared with noncarriers. Neither SCNN1B nor SCNN1G associated with salt-sensitivity of BP in rare variant analyses (P = 0.65 and 0.48, respectively). In single-marker analyses, 3 independent common variants in SCNN1A, rs11614164, rs4764586, and rs3741914, associated with salt-sensitivity after Bonferroni correction (P = 4.4 × 10–4, 1.1 × 10–8, and 1.3 × 10–3). Each copy of the minor allele of rs4764586 was associated with a 1.36-fold (95% CI: 1.23–1.52) increased odds of salt-sensitivity, whereas each copy of the minor allele of rs11614164 and rs3741914 was associated with 0.68-fold (95% CI: 0.55–0.84) and 0.69-fold (95% CI: 0.54–0.86) decreased odds of salt-sensitivity, respectively.
CONCLUSIONS
This study demonstrated for the first time a relationship between rare variants in the ENaC pathway and BP salt-sensitivity. Future replication and functional studies are needed to confirm the findings in this study.
CLINICAL TRIAL REGISTRY
Trial Number NCT00721721
African Americans have been understudied in genome wide association studies of diabetes and related traits. In the current study, we examined the joint association of single nucleotide polymorphisms ...(SNPs) and copy number variants (CNVs) with fasting insulin and an index of insulin resistance (HOMA-IR) in the HyperGEN study, a family based study with proband ascertainment for hypertension. This analysis is restricted to 1,040 African Americans without diabetes. We generated allele specific CNV genotypes at 872,243 autosomal loci using Birdsuite, a freely available multi-stage program. Joint tests of association for SNPs and CNVs were performed using linear mixed models adjusting for covariates and familial relationships. Our results highlight SNPs associated with fasting insulin and HOMA-IR (rs6576507 and rs8026527, 3.7*10(-7)≤P≤1.1*10(-5)) near ATPase, class V, type 10A (ATP10A), and the L Type voltage dependent calcium channel (CACNA1D, rs1401492, P≤5.2*10(-6)). ATP10A belongs to a family of aminophospholipid-transporting ATPases and has been associated with type 2 diabetes in mice. CACNA1D has been linked to pancreatic beta cell generation in mice. The two most significant copy variable markers (rs10277702 and rs361367; P<2.0*10(-4)) were in the beta variable region of the T-cell receptor gene (TCRVB). Human and mouse TCR has been shown to mimic insulin and its receptor and could contribute to insulin resistance. Our findings differ from genome wide association studies of fasting insulin and other diabetes related traits in European populations, highlighting the continued need to investigate unique genetic influences for understudied populations such as African Americans.
Chronic kidney disease (CKD) can be a consequence of diabetes, hypertension, immunologic disorders, and other exposures, as well as genetic factors that are still largely unknown. Glomerular ...filtration rate (GFR), which is widely used to measure kidney function, has a heritability ranging from 25% to 75%, but only 1.5% of this heritability is explained by genetic loci that have been identified to date. In this study we tested for associations between GFR and 234 SNPs in 26 genes from pathways of blood pressure regulation in 3,025 rural Chinese participants of the "Genetic Epidemiology Network of Salt Sensitivity" (GenSalt) study. We estimated GFR (eGFR) using baseline serum creatinine measurements obtained prior to dietary intervention. We identified significant associations between eGFR and 12 SNPs in 6 genes (ACE, ADD1, AGT, GRK4, HSD11B1, and SCNN1G). The cumulative effect of the protective alleles was an increase in mean eGFR of 4 mL/min per 1.73 m2, while the cumulative effect of the risk alleles was a decrease in mean eGFR of 3 mL/min per 1.73 m2. In addition, we identified a significant interaction between SNPs in CYP11B1 and ADRB2. We have identified common variants in genes from pathways that regulate blood pressure and influence kidney function as measured by eGFR, providing new insights into the genetic determinants of kidney function. Complex genetic effects on kidney function likely involve interactions among genes as we observed for CYP11B1 and ADRB2.
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