Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness

Background

Genes implicated in common complex disorders such as obesity, type 2 diabetes mellitus (T2DM) or cardiovascular diseases are not disease specific, since clinically related disorders also share genetic components. Cysteine protease Calpain 10 (CAPN10) has been associated with T2DM, hypertension, hypercholesterolemia, increased body mass index (BMI) and polycystic ovary syndrome (PCOS), a reproductive disorder of women in which isunlin resistance seems to play a pathogenic role. The calpain 5 gene (CAPN5) encodes a protein homologue of CAPN10. CAPN5 has been previously associated with PCOS by our group. In this new study, we have analysed the association of four CAPN5 gene variants(rs948976A>G, rs4945140G>A, rs2233546C>T and rs2233549G>A) with several cardiovascular risk factors related to metabolic syndrome in general population.

Methods

Anthropometric measurements, blood pressure, insulin, glucose and lipid profiles were determined in 606 individuals randomly chosen from a cross-sectional population-based epidemiological survey in the province of Segovia in Central Spain (Castille), recruited to investigate the prevalence of anthropometric and physiological parameters related to obesity and other components of the metabolic syndrome. Genotypes at the four polymorphic loci in CAPN5 gene were detected by polymerase chain reaction (PCR).

Results

Genotype association analysis was significant for BMI (p ≤ 0.041), diastolic blood pressure (p = 0.015) and HDL-cholesterol levels (p = 0.025). Different CAPN5 haplotypes were also associated with diastolic blood pressure (DBP) (0.0005 ≤ p ≤ 0.006) and total cholesterol levels (0.001 ≤ p ≤ 0.029). In addition, the AACA haplotype, over-represented in obese individuals, is also more frequent in individuals with metabolic syndrome defined by ATPIII criteria (p = 0.029).

Conclusion

As its homologue CAPN10, CAPN5 seems to influence traits related to increased risk for cardiovascular diseases. Our results also may suggest CAPN5 as a candidate gene for metabolic syndrome.     

Genome-wide association of echocardiographic dimensions,brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study

Background:

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance due primarily to genetic defects in Fas (CD95/APO-1; TNFRSF6), a cell surface receptor that regulates apoptosis and its signaling apparatus.

Methods:

Fas ligand gene mutations from ALPS patients were identified through cDNA and genomic DNA sequencing. Molecular and biochemical assessment of these mutant Fas ligand proteins were carried out by expressing the mutant FasL cDNA in mammalian cells and analysis its effects on Fas-mediated programmed cell death.

Results:

We found an ALPS patient that harbored a heterozygous A530G mutation in the FasL gene that replaced Arg with Gly at position 156 in the protein's extracellular Fas-binding region. This produced a dominant-interfering FasL protein that bound to the wild-type FasL protein and prevented it from effectively inducing apoptosis.

Conclusion:

Our data explain how a naturally occurring heterozygous human FasL mutation can dominantly interfere with normal FasL apoptotic function and lead to an ALPS phenotype, designated Type Ib.     

Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study

Background

Heritable electrocardiographic (ECG) and heart rate variability (HRV) measures, reflecting pacemaking, conduction, repolarization and autonomic function in the heart have been associated with risks for cardiac arrhythmias. Whereas several rare monogenic conditions with extreme phenotypes have been noted, few common genetic factors contributing to interindividual variability in ECG and HRV measures have been identified. We report the results of a community-based genomewide association study of six ECG and HRV intermediate traits.

Methods

Genotyping using Affymetrix 100K GeneChip was conducted on 1345 related Framingham Heart Study Original and Offspring cohort participants. We analyzed 1175 Original and Offspring participants with ECG data (mean age 52 years, 52% women) and 548 Offspring participants with HRV data (mean age 48 years, 51% women), in relation to 70,987 SNPs with minor allele frequency ≥ 0.10, call rate ≥ 80%, Hardy-Weinberg p-value ≥ 0.001. We used generalized estimating equations to test association of SNP alleles with multivariable-adjusted residuals for QT, RR, and PR intervals, the ratio of low frequency to high frequency power (LF/HFP), total power (TP) and the standard deviation of normal RR intervals (SDNN).

Results

Associations at p < 10^-3 were found for 117 (QT), 105 (RR), 111 (PR), 102 (LF/HF), 121 (TP), and 102 (SDNN) SNPs. Several common variants in NOS1AP (4 SNPs with p-values < 10^-3; lowest p-value, rs6683968, p = 1 × 10^-4) were associated with adjusted QT residuals, consistent with our previously reported finding for NOS1AP in an unrelated sample of FHS Offspring and other cohorts. All results are publicly available at NCBI's dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.

Conclusion

In the community-based Framingham Heart Study none of the ECG and HRV results individually attained genomewide significance. However, the presence of bona fide QT-associated SNPs among the top 117 results for QT duration supports the importance of efforts to validate top results from the reported scans. Finding genetic variants associated with ECG and HRV quantitative traits may identify novel genes and pathways implicated in arrhythmogenesis and allow for improved recognition of individuals at high risk for arrhythmias in the general population.

     

Clinical and genetic correlates of aldosterone-to-renin ratio and relations to blood pressure in a community sample

Aldosterone:renin ratio (ARR) is used to screen for hyperaldosteronism. Data regarding correlates of ambulatory ARR in the community and its relation to hypertension incidence are limited. We defined clinical correlates of ARR, determined its heritability, tested for association and linkage, and related ARR to blood pressure (BP) progression in nonhypertensive individuals among 3326 individuals from the Framingham Heart Study (53% women; mean age: 59 years). Ambulatory morning ARR (serum aldosterone and plasma renin concentrations) were related to clinical covariates, genetic variation across the REN locus, a 10-cM linkage map, and among nonhypertensive participants (n=1773) to progression of >or=1 Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure BP category (optimal: <120/80 mm Hg, normal: 120 to 129/80 to 84 mm Hg, high normal: 130 to 139/85 to 89 mm Hg, hypertension: >or=140/90 mm Hg), or incident hypertension (systolic BP: >or=140 mm Hg, diastolic BP: >or=90 mm Hg, or use of antihypertensive treatment). ARR was positively associated with age, female sex, untreated hypertension, total/high-density lipoprotein cholesterol ratio, hormone replacement therapy, and beta-blocker use, but negatively associated with angiotensin-converting enzyme inhibitor and diuretic use. ARR was heritable (h(2)=0.40), had modest linkage to chromosome 11p (logarithm of the odds: 1.89), but was not associated with 17 common variants in REN (n=1729). On follow-up (mean: 3 years), 607 nonhypertensive individuals (34.2%) developed BP progression, and 283 (16.0%) developed hypertension. Higher baseline logARR was associated with increased risk of BP progression (odds ratio per SD increment: 1.23; 95% CI: 1.11 to 1.37) and hypertension incidence (odds ratio per SD increment: 1.16; 95% CI: 1.00 to 1.33). ARR is a heritable trait influenced by clinical and genetic factors. There is a continuous gradient of increasing risk of BP progression across ARR levels in nonhypertensive individuals.     

Association of genetic variation in the natriuretic peptide system with cardiovascular outcomes

Polymorphisms within individual natriuretic peptide genes have been associated with risk factors for cardiovascular disease, but their association with clinical outcomes was previously unknown. This study aimed to investigate the association between genetic variants in key genes of the natriuretic peptide system with cardiovascular outcomes in patients with coronary artery disease. Coronary disease patients (n = 1810) were genotyped for polymorphisms within NPPA, NPPB, NPPC, NPR1 and NPR2. Clinical history, natriuretic peptide concentrations, echocardiography, all-cause mortality and cardiovascular hospital readmissions were recorded over a median 2.8 years. Minor alleles of NPPA rs5068, rs5065 and rs198358 were associated with less history of hypertension; minor alleles of NPPA rs5068 and rs198358 was also associated with higher circulating natriuretic peptide levels (p = 0.003 to p = 0.04). Minor alleles of NPPB rs198388, rs198389, and rs632793 were associated with higher circulating BNP and NT-proBNP (p = 0.001 to p = 0.03), and reduced E/E¹ (p = 0.011), or LVESVI (p = 0.001) and LVEDVI (p = 0.004). Within NPPC, both rs11079028 and rs479651 were associated with higher NT-proBNP and CNP (p = 0.01 to p = 0.03), and rs479651 was associated with lower LVESVI (p = 0.008) and LVEDVI (p = 0.018). NPR2 rs10758325 was associated with smaller LVMI (p < 0.02). A reduced rate of cardiovascular readmission was observed for minor alleles of NPPA rs5065 (p < 0.0001), NPPB rs632793 (p < 0.0001), rs198388 (p < 0.0001), rs198389 (p < 0.0001), and NPR2 rs10758325 (p < 0.0001). There were no associations with all-cause mortality. In established cardiovascular disease, natriuretic peptide system polymorphisms were associated with natriuretic peptide levels, hypertension, echocardiographic indices and the incidence of hospital readmission for cardiovascular events.     

Genetic variants and blood pressure in a population-based cohort: the Cardiovascular Risk in Young Finns study

Clinical relevance of a genetic predisposition to elevated blood pressure was quantified during the transition from childhood to adulthood in a population-based Finnish cohort (N=2357). Blood pressure was measured at baseline in 1980 (age 3-18 years) and in follow-ups in 1983, 1986, 2001, and 2007. Thirteen single nucleotide polymorphisms associated with blood pressure were genotyped, and 3 genetic risk scores associated with systolic and diastolic blood pressures and their combination were derived for all of the participants. Effects of the genetic risk score were 0.47 mm Hg for systolic and 0.53 mm Hg for diastolic blood pressures (both P<0.01). The combination genetic risk score was associated with diastolic blood pressure from age 9 years onward (β=0.68 mm Hg; P=0.015). Replications in 1194 participants of the Bogalusa Heart Study showed essentially similar results. The participants in the highest quintile of the combination genetic risk score had a 1.82-fold risk of hypertension in adulthood (P<0.0001) compared with the lowest quintile, independent of a family history of premature hypertension. These findings show that genetic variants are associated with preclinical blood pressure traits in childhood; individuals with several susceptibility alleles have, on average, a 0.5-mm Hg higher blood pressure, and this trajectory continues from childhood to adulthood.