Genome-wide mapping of human loci for essential hypertension (original) (raw)
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Scanning the Genome for Essential Hypertension Loci
Clinical and Experimental Pharmacology and Physiology, 1998
1. Essential hypertension occurs in people with an underlying genetic predisposition \rho subject thernselves to adverse en. vironmental influences, The number of genes involved is unknown, as is the extent to which each contributes to final blood pressure and the severity of the disease. 2. In the past, studies of potential candidate genes have been performed by association (case-control) analysis of unrelated individuals or linkage (pedigree or sibpair) analysis of families. Th€se studies have r'€sulted in several positive findings but as one may expect, also an enormous number of negatiye r€sults. 3. In ord€r to uncover the major genetic loci for essential hypertension, it is proposed that scanning the genome systematically in 100-200 alTected sibships should prove successful. 4. This involves genotyping sets of hypertensive sibships to determine their complement of several hundred microsatellite polymorphisms, Those that are highly informative, by having a high heterozygosity, are most suitable. Also, the markers need to be spaced sumciendy evenly across the geDome so as to ensure adequate coverage. 5. Tests are performed to determine increased segregation of alleles of each marker llith hypertension. The analytical tools involve specialized statistical prograrns that can detectsuch differences. Non-parametric multipoint analysis is an appropriate approach. 6, In this way, loci for essential hlpertension are beginning to emerge,
Hypertension Research, 2008
A multiple candidate-gene approach was used to investigate not only candidate genes, but also candidate pathways involved in the regulation of blood pressure. We evaluated 307 single nucleotide polymorphisms (SNPs) in 307 genes and performed an association study between 758 cases and 726 controls. Genes were selected from among those encoding components of signal transduction pathways, including receptors, soluble carrier proteins, binding proteins, channels, enzymes, and G-proteins, that are potentially related to blood pressure regulation. In total, 38 SNPs were positively (p <0.05) associated with hypertension. Replication of the findings and possible polygenic interaction was evaluated in five G-protein-related positive genes (GNI2, GNA14, RGS2, RGS19, RGS20) in a large cohort population (total n =9,700, 3,305 hypertensives and 3,827 normotensive controls). In RGS20 and GNA14, dominant models for the minor allele were significantly associated with hypertension. Multiple dimension reduction (MDR) analysis revealed the presence of gene-gene interaction between GNA14 and RGS20. The MDR-proved combination of two genotypes showed a significant association with hypertension ( 2 = 9.93, p = 0.0016) with an odds ratio of the high-risk genotype of 1.168 (95% confidence interval [CI] [1.061-1.287]). After correction for all possible confounding parameters, the MDR-proved high-risk genotype was still a risk for hypertension ( p = 0.0052). Furthermore, the highrisk genotype was associated with a significantly higher systolic blood pressure (133.not only hypertension-susceptibility genes but also hypertension-susceptibility pathways in which related genes may synergistically collaborate through gene-gene interactions to predispose to hypertension.
A genome wide scan for early onset primary hypertension in Scandinavians
Human Molecular Genetics, 2003
With the aim of identifying hypertension susceptibility loci, we performed a genome wide scan in Scandinavian sib-pairs with early onset primary hypertension. To be classified as affected, a diagnosis of primary hypertension at age 50 years was required. Two hundred and forty three patients with onset of primary hypertension at 40.0 AE 7.7 (mean AE SD) years from 91 families (91 sib-ships with a mean of 2.7 and a range of 2-6 affected members per sib-ship) were genotyped with 362 microsatellite markers with a density of $10 cM. Loci obtaining nominal P 0.016 (LOD score !1.0) were fine mapped with additional markers. Multipoint non-parametric linkage analysis was performed using GENEHUNTER v 2.0. Using simulations, a nominal P 0.0002 was determined to be a genome wide significant evidence of linkage. In the 10 cM genome wide scan, nominal P 0.016 were found on chromosomes 1 at 81 cM (P ¼ 0.007), 2 at 115 cM (P ¼ 0.006), 3 at 108 cM (P ¼ 0.006), 14 at 45 cM (P ¼ 0.0002) and at 99 cM (P ¼ 0.001), 17 at 42 cM (P ¼ 0.015) and 19 at 89 cM (P ¼ 0.007). After fine mapping of these loci, one of the chromosome 14 loci just obtained the level of genome wide significance (P ¼ 0.0002 at 41 cM) and the chromosome 2 locus reached suggestive evidence of linkage (P ¼ 0.002 at 118 cM). Our data suggest a hypertension susceptibility locus on chromosome 14 around 41 cM. The locus on chromosome 2 is also promising as it has been implicated in hypertension and blood pressure regulation in earlier genome scans.
Multiple Genes for Essential-Hypertension Susceptibility on Chromosome 1q
The American Journal of Human Genetics, 2007
Essential hypertension, defined as elevated levels of blood pressure (BP) without any obvious cause, is a major risk factor for coronary heart disease, stroke, and renal disease. BP levels and susceptibility to development of essential hypertension are partially determined by genetic factors that are poorly understood. Similar to other efforts to understand complex, non-Mendelian phenotypes, genetic dissection of hypertension-related traits employs genomewide linkage analyses of families and association studies of patient cohorts, to uncover rare and common disease alleles, respectively. Familybased mapping studies of elevated BP cover the large intermediate ground for identification of genes with common variants of significant effect. Our genomewide linkage and candidate-gene-based association studies demonstrate that a replicated linkage peak for BP regulation on human chromosome 1q, homologous to mouse and rat quantitative trait loci for BP, contains at least three genes associated with BP levels in multiple samples: ATP1B1, RGS5, and SELE. Individual variants in these three genes account for 2-5-mm Hg differences in mean systolic BP levels, and the cumulative effect reaches 8-10 mm Hg. Because the associated alleles in these genes are relatively common (frequency 15%), these three genes are important contributors to elevated BP in the population at large.
Genome-wide linkage reveals a locus for human essential (primary) hypertension on chromosome 12p
Human Molecular Genetics, 2003
Essential (primary) hypertension is an important risk factor for cardiovascular morbidity and mortality. Blood pressure is largely heritable; however, the genetic factors contributing to essential hypertension are mostly unknown. We examined a large Chinese kindred (n ¼ 387) and selected a subset of 94 individuals for genotyping. An additional 32 Chinese nuclear families with essential hypertension were also recruited. Genome-wide parametric linkage analysis identified a new locus for primary hypertension on chromosome 12p (parametric LOD score 3.44). This locus overlaps with the assigned locus that causes severe autosomaldominant hypertension and brachydactyly, the only form of monogenic hypertension known to date that resembles primary hypertension. We suggest that this genomic region, spanning 18 annotated genes, will be of great relevance in elucidating new mechanisms for primary hypertension.
American journal of hypertension, 2003
Four multicenter Networks (GenNet, GENOA, HyperGEN, SAPPHIRe) form the National Heart, Lung and Blood Institute Family Blood Pressure Program (FBPP), to search for hypertension/blood pressure (BP) genes. The networks used different family designs and targeted multiple ethnic groups, using standardized protocols and definitions. Linkage genome scans were done on samples within each network (N = 6245 relatives). The evidence was synthesized using meta-analysis. Combining ethnic groups, no region reached LOD >2, but several small peaks were identified, including chromosome 2p where two other recent reports find hypertension linkage. No regions show uniformly large effects on BP/hypertension in all populations.
Nature …, 2009
Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5m genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N≤71,225 European ancestry, N=12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N=29,136). We identified association between systolic or diastolic blood pressure and common variants in 8 regions near the CYP17A1 (P=7×10−24), CYP1A2 (P=1×10−23), FGF5 (P=1×10−21), SH2B3 (P=3×10−18), MTHFR (P=2×10−13), c10orf107 (P=1×10−9), ZNF652 (P=5×10−9) and PLCD3 (P=1×10−8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
Current Hypertension Reports, 2011
Blood pressure (BP), hypertension (HT) and cardiovascular disease (CVD) are common complex phenotypes, which are affected by multiple genetic and environmental factors. This article describes recent genome-wide association studies (GWAS) that have reported causative variants for BP/HT and CVD/heart traits and analyzes the overlapping associated gene polymorphisms. It also examines potential replication of findings from the HyperGEN data on African Americans and whites. Several genes involved in BP/HT regulation also appear to be involved in CVD. A better picture is emerging, with overlapping hot-spot regions and with interconnected pathways between BP/HT and CVD. A systemic approach to full understanding of BP/HT and CVD development and their progression to disease may lead to the identification of gene targets and pathways for the development of novel therapeutic interventions.