Hypertension-related Phenotypes Research Articles

A Review of the Genetics of Hypertension with a Focus on Gene-Environment Interactions.

Here, we discuss the interpretation and modeling of gene-environment interactions in hypertension-related phenotypes, with a focus on the necessary assumptions and possible challenges. Recently, small cohort studies have discovered several novel genetic variants associated with hypertension-related phenotypes through modeling gene-environment interactions. Several consortia-based meta-analytic efforts have uncovered many novel genetic variants in hypertension without modeling interaction terms, giving promise to future meta-analytic efforts that incorporate gene-environment interactions. Heritability studies and genome-wide association studies have established that hypertension, a prevalent cardiovascular disease, has a genetic component that may be modulated by the environment (such as lifestyle factors). This review includes a discussion of known genetic associations for hypertension/blood pressure, including those resulting from the incorporation of gene-environmental interaction modeling.

Phenome-wide association study (PheWAS) for detection of pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network.

Using a phenome-wide association study (PheWAS) approach, we comprehensively tested genetic variants for association with phenotypes available for 70,061 study participants in the Population Architecture using Genomics and Epidemiology (PAGE) network. Our aim was to better characterize the genetic architecture of complex traits and identify novel pleiotropic relationships. This PheWAS drew on five population-based studies representing four major racial/ethnic groups (European Americans (EA), African Americans (AA), Hispanics/Mexican-Americans, and Asian/Pacific Islanders) in PAGE, each site with measurements for multiple traits, associated laboratory measures, and intermediate biomarkers. A total of 83 single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) were genotyped across two or more PAGE study sites. Comprehensive tests of association, stratified by race/ethnicity, were performed, encompassing 4,706 phenotypes mapped to 105 phenotype-classes, and association results were compared across study sites. A total of 111 PheWAS results had significant associations for two or more PAGE study sites with consistent direction of effect with a significance threshold of p<0.01 for the same racial/ethnic group, SNP, and phenotype-class. Among results identified for SNPs previously associated with phenotypes such as lipid traits, type 2 diabetes, and body mass index, 52 replicated previously published genotype–phenotype associations, 26 represented phenotypes closely related to previously known genotype–phenotype associations, and 33 represented potentially novel genotype–phenotype associations with pleiotropic effects. The majority of the potentially novel results were for single PheWAS phenotype-classes, for example, for CDKN2A/B rs1333049 (previously associated with type 2 diabetes in EA) a PheWAS association was identified for hemoglobin levels in AA. Of note, however, GALNT2 rs2144300 (previously associated with high-density lipoprotein cholesterol levels in EA) had multiple potentially novel PheWAS associations, with hypertension related phenotypes in AA and with serum calcium levels and coronary artery disease phenotypes in EA. PheWAS identifies associations for hypothesis generation and exploration of the genetic architecture of complex traits.

EFFECT OF NEDD4L GENE FIVE COMMON POLYMORPHISMS ON HYPERTENSION-RELATED PHENOTYPES IN HAN CHINESE HYPERTENSION PATIENTS

ObjectivesHypertension is a complex disorder; part is due to genetic determinants. Mounting evidence has suggested that NEDD4L plays a pivotal role in maintaining Na+ balance, extracellular fluid volume and long...

A Genome-Wide Association Study of Hypertension-Related Phenotypes in a Japanese Population

Large-scale genome-wide association studies (GWAS) have been successful in identifying genes that contribute to common diseases and phenotypes. A GWAS of hypertension-related phenotypes in a Japanese population was conducted in the current study. A total of 936 participants were recruited from the Suita Study and a GWAS with 538,732 single nucleotide polymorphisms (SNP) was performed. The phenotypes included were systolic and diastolic blood pressure (SBP and DBP), body mass index (BMI), waist-to-hip ratio (WHR), plasma renin activity (PRA), plasma aldosterone concentration (PAC), plasma brain natriuretic peptide (BNP) concentration and alcohol consumption (AC). The SNP exceeding the genome-wide significance level were subjected to subsequent association studies using samples available from the Suita Study and Nomura Study. There is no master gene in the Japanese population that profoundly affects SBP, DBP, BMI, WHR, PRA and PAC. AC was influenced by the functional polymorphism in ALDH2, which affected BP levels in men. The BNP concentration was influenced by a polymorphism in the 3' region of the gene encoding for BNP. However, this polymorphism did not influence blood pressure (BP). Six SNP were identified to be associated with hypertension in both the Suita and Nomura studies. Although several candidate SNP relevant to hypertension and those influencing AC and BNP were identified, our middle-sized GWAS indicated that there is no master gene in Japanese people that profoundly affects BP-related phenotypes.

Lipoprotein lipase variants associated with an endophenotype of hypertension: hypertension combined with elevated triglycerides

Previously, we observed that young-onset hypertension was independently associated with elevated plasma triglyceride(s) (TG) levels to a greater extent than other metabolic risk factors. Thus, focusing on the endophenotype--hypertension combined with elevated TG--we designed a family-based haplotype association study to explore its genetic connection with novel genetic variants of lipoprotein lipase gene (LPL), which encodes a major lipid metabolizing enzyme. Young-onset hypertension probands and their families were recruited, numbering 1,002 individuals from 345 families. Single-nucleotide polymorphism discovery for LPL, linkage disequilibrium (LD) analysis, transmission disequilibrium tests (TDT), bin construction, haplotype TDT association and logistic regression analysis were performed. We found that the CC- haplotype (i) spanning from intron 2 to intron 4 and the ACATT haplotype (ii) spanning from intron 5 to intron 6 were significantly associated with hypertension-related phenotypes: hypertension (ii, P=0.05), elevated TG (i, P=0.01), and hypertension combined with elevated TG (i, P=0.001; ii, P<0.0001), according to TDT. The risk of this hypertension subtype increased with the number of risk haplotypes in the two loci, using logistic regression model after adjusting within-family correlation. The relationships between LPL variants and hypertension-related disorders were also confirmed by an independent association study. Finally, we showed a trend that individuals with homozygous risk haplotypes had decreased LPL expression after a fatty meal, as opposed to those with protective haplotypes. In conclusion, this study strongly suggests that two LPL intronic variants may be associated with development of the hypertension endophenotype with elevated TG.

SAH gene variants revisited in the European Project On Genes in Hypertension

Previous studies found significant association of hypertension and hypertension-related phenotypes with genetic variation in SAH (Spontaneously hypertensive rat-clone A-Hypertension-associated). We sought independent confirmation of these findings in the European Project On Genes in Hypertension. We randomly recruited 2603 relatives from 560 families and 31 unrelated subjects from six European populations (mean age 38.8 +/- 15.7 years; 52.1% women). We measured systolic/diastolic blood pressure (mean, 122.4/76.6 mmHg), body mass index (24.9 kg/m2), triceps skinfold (1.7 cm), waist-to-hip ratio (0.83 units), serum total and high-density lipoprotein (HDL) cholesterol (5.14 and 1.33 mmol/l), serum triglycerides (1.95 mmol/l) and blood glucose (4.90 mmol/l). We genotyped the G-1606A and -962del/ins polymorphisms. In all subjects, the allele frequencies were 11.8 and 29.5% for -1606A and -962del, respectively. Lewontin's D' was 0.97 (P < 0.0001). Haplotype frequencies were 58.8% for -1606G plus -962ins, 29.5% for -1606G plus -962del, and 11.7% for -1606A plus -962ins. Both before and after adjustment for covariates, none of the phenotype-genotype associations approached statistical significance. Our study had 80% power to detect on two-sided tests (P = 0.05), effect sizes of 1.8/1.3 mmHg for systolic/diastolic blood pressure, 0.52 kg/m2 for body mass index, 0.01 units for the waist-to-hip ratio, 0.96 mm for the triceps skinfold, 0.13 and 0.05 mmol/l for total and HDL cholesterol, 0.18 mmol/l for serum triglycerides, and 0.11 mmol/l for blood glucose. The family-based analyses did not reveal population stratification (P > or = 0.67). The evidence supporting an association of hypertension or hypertension-related phenotypes with the SAH gene remains equivocal in human studies.

Positional identification of hypertension susceptibility genes on chromosome 2.

Chromosome 2 has been consistently identified as a genomic region with genetic linkage evidence suggesting that one or more loci contributes to blood pressure and hypertension status. As with all complex disease traits, following-up linkage evidence to identify the underlying susceptibility gene(s) is an arduous yet biologically and clinically important task. Using combined positional candidate gene methods, the Family Blood Pressure Program (FBPP) has concentrated efforts in narrowing a large region of chromosome 2, demonstrating evidence for linkage in several populations, and identifying underlying candidate hypertension susceptibility gene(s). Initial informatics efforts identified the boundaries of the region and the known genes within it. A total of 82 polymorphic sites in 8 genes were genotyped in a large hypothesis-generating sample consisting of 1640 African Americans, 1339 whites, and 1616 Mexican Americans. After resampling-based false discovery adjustment, SLC4A5, a sodium bicarbonate transporter, was identified as a primary candidate gene for hypertension. Polymorphisms in SLC4A5 were subsequently genotyped and analyzed for validation in two other subcomponents of the FBPP, each contributing African Americans (N=461; N=778) and whites (N=550; N=967). Again, single nucleotide polymorphisms within this gene were significantly associated with blood pressure levels and hypertension status. Although not identifying a single causal gene variant that is significantly associated with blood pressure levels and hypertension status across all samples, the results further implicate SLC4A5 as a candidate hypertension susceptibility gene. Moreover, the present study validates previous evidence for one or more genes on chromosome 2 that influence hypertension-related phenotypes in the population-at-large.

Gender-specific correlates of leptin with hypertension-related phenotypes in African Americans

Leptin may be a link in the relationship of obesity with hypertension. We evaluated associations of leptin with blood pressure (BP) in 54 normotensive and 114 hypertensive African American individuals. Plasma leptin was higher ( P < .03) in hypertensive women than in normotensive women, although body mass index did not differ (30.5 ± 0.5 v 30.2 ± 0.8 kg/m 2). After adjusting for obesity and insulin resistance, there were no significant relationships between leptin and BP; however, leptin independently predicted 28% of the variability of heart rate in hypertensive men ( P < .01) and 18% of the variability of lithium clearance in hypertensive women ( P < .01). Thus, in these obese hypertensive African American women, there is no direct or independent association of leptin with BP. However, leptin may contribute to hypertension in these women by increasing renal tubular sodium reabsorption.

Identification of hypertension-related QTLs in African American sib pairs.

To link hypertension-related phenotypes with chromosomal loci, genome scans were performed in 150 African American sib pairs concordant for essential hypertension. Phenotypes included blood pressure, anthropomorphic measurements, and estimates of body fluid compartments as determined by impedance plethysmography. These phenotypes were also measured in 335 normotensive African Americans. Phenotypes with LOD scores >3.3 were further evaluated for significance by use of permutation procedures. Significant linkage was detected for body mass index (BMI) on chromosomes 1 and 8 and for the ratio of extracellular water to total body water (ECF/TBW) on chromosomes 3, 5, 6, and 7. Both BMI and ECF/TBW were greater in hypertensive sibs than in normotensive subjects (P<0.001). In a subset of hypertensive sibs and normotensive subjects, average 24-hour blood pressures were correlated with ECF/TBW (P<0.01). A region linked to BMI in the hypertensive sibs corresponds to a region of conserved synteny containing blood pressure-related QTLs in an F2 cross of Brown NorwayxDahl salt-sensitive rats. Focusing on hypertension-related phenotypes is a promising approach for identifying the genetic determinants of hypertension.

Genetic determinants of hypertension: identification of candidate phenotypes.

Our long-term objective is to identify genes whose expression results in hypertension and in phenotypic changes that may contribute to hypertension. The purpose of the present study was to describe evidence for the heritability of hypertension-related phenotypes in hypertensive, hyperlipidemic black sib pairs. Outpatient anthropomorphic measurements were obtained in >200 affected sib pairs. In addition, 68 of these sib pairs were studied under controlled, standardized conditions at an inpatient clinical research center while off both antihypertensive and lipid-lowering medications. Heritability was estimated on the basis of sib-sib correlations and with an association model. Higher heritability estimates for blood pressure were observed with multiple measurements averaged over 24 hours than with measurements at a single time point, and heritability estimates for nighttime blood pressures were higher than those for daytime blood pressures. Heritability estimates for several of the phenotypes were augmented by obtaining measurements in response to a standardized stimulus, including (1) blood pressure responses to the assumption of upright posture, standardized psychological stress, and norepinephrine infusion; (2) plasma renin, aldosterone, epinephrine, and cAMP and cGMP responses to the assumption of upright posture; (3) para-aminohippurate and inulin clearances in response to norepinephrine infusion; and (4) plasma arginine vasopressin in response to NaCl infusion. High heritability estimates were also observed for various measures of body size and body fat, left ventricular size, cardiac index, stroke volume, total peripheral resistance, and serum concentrations of LDL and HDL cholesterol and leptin. These heritability estimates identify the hypertension-related phenotypes that may facilitate the identification of specific genetic determinants of hypertension in blacks with hyperlipidemia.

Candidate hypertension-related phenotypes

Candidate hypertension-related phenotypes

Newborn and adult recombinant inbred strains: A tool to search for genetic determinants of target organ damage in hypertension

It has been proposed that one of the primary events in the development of essential hypertension is a growth-related process initiated as early as during fetal development. Differences in kidney size have been observed between most rat models of hypertension and their respective controls. In this study, we analyzed relative kidney size (kidney weight/body wt) in a set of rat recombinant inbred strains (RIS) (N = 27) and their progenitors, the spontaneously hypertensive rat strain (SHR/Ola) and Brown Norway congenic strain (BN.1x), at two different ages, at birth and at 15 weeks. In the progenitors, the relative kidney weight was higher in the hypertensive than in the normotensive strain of both the newborn (P < 0.001) and adult (P < 0.001) animals. In the RIS, a significant correlation was found between the newborn and adult relative kidney weight (r = 0.49, P = 0.01), indicating that the two phenotypes share some of their genetic determinants. A total genome search of newborn and adult relative kidney weight was performed with a total of 453 genetic markers. These analyses revealed several suggestive quantitative trait loci (QTL), some of which were, indeed, significant for both newborn and adult relative kidney weight (such as, D3Mit9 on rat chromosome 3; r = -0.50, P < 0.01; r = -0.47, P < 0.01; respectively). Others, such as the locus on rat chromosome 1 (Rt6; r = -0.43, P < 0.05), were significant only for the adult relative kidney size. This QTL was found in close proximity to a region previously related to susceptibility to hypertensive renal disease in the fawn-hooded rat and, similarly to that study, its effect was found to be independent of blood pressure. Furthermore, a growth pattern of the kidneys after birth, evaluated as the difference between the newborn and adult relative kidney weight, was also subjected to total genome scan. Several suggestive QTL were identified. One of the most significant loci was found at the D1a marker on rat chromosome 17 (r = -0.51, P < 0.01), which was previously related to the determination of adult heart weight in the RIS. In conclusion, the current study demonstrates the usefulness of RIS in studies of hypertension-related phenotypes, some of which are abnormal before the development of high blood pressure. To better understand their role in the pathogenesis of hypertension, studies at different ages are needed, which are uniquely feasible in RIS.