Genetic susceptibility for human familial essential hypertension in a region of homology with blood pressure linkage on rat chromosome 10 (original) (raw)
Related papers
Genetics of hypertension: From experimental animals to humans
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2010
Essential hypertension affects 20 to 30% of the population worldwide and contributes significantly to cardiovascular mortality and morbidity. Heridability of blood pressure is around 15 to 40% but there are also substantial environmental factors affecting blood pressure variability. It is assumed that blood pressure is under the control of a large number of genes each of which has only relatively mild effects. It has therefore been difficult to discover the genes that contribute to blood pressure variation using traditional approaches including candidate gene studies and linkage studies. Animal models of hypertension, particularly in the rat, have led to the discovery of quantitative trait loci harbouring one or several hypertension related genes, but translation of these findings into human essential hypertension remains challenging. Recent development of genotyping technology made large scale genome-wide association studies possible. This approach and the study of monogenic forms of hypertension has led to the discovery of novel and robust candidate genes for human essential hypertension, many of which require functional analysis in experimental models.
A Genome-Wide Search For Susceptibility Loci to Human Essential Hypertension
Hypertension, 2000
We undertook a systematic search of the entire human genome with the affected sibling-pair model to identify major susceptibility loci to essential hypertension. Affected nuclear families (nϭ263) were recruited and divided according to definite or probable genetic contribution to hypertension depending on number of hypertensive siblings. The largest nuclear families were first screened with a set of microsatellite markers. Regions on the genome with PϽ0.05 were tested against the second set of smaller families. An exclusion map was generated to identify regions in which hypertension-causing genes are unlikely to reside. Sibling-pair linkage analysis identified a single locus on chromosome 11q (PϽ0.004) in the first pass. A second pass with nuclear families that had only affected sibling pairs was, as expected, insufficient to support linkage to 11q. Multipoint exclusion-linkage analysis showed that 3 genetic loci are necessary to explain familial aggregation of essential hypertension. Our preliminary findings suggest that no single region within the human genome contains genes with a major contribution to essential hypertension. We show that the disease is indeed polygenic, with each gene providing a relatively small risk. Our exclusion map will help future investigators to concentrate on areas likely to contain these genes. The region on chromosome 11 is the first to point to a new candidate gene for hypertension that has arisen out of a genome search, but replication of these results at a higher significance is necessary before positional cloning can be justified.
Genome-wide mapping of human loci for essential hypertension
The Lancet, 2003
Blood pressure may contribute to 50% of the global cardiovascular disease epidemic. By understanding the genes predisposing to common disorders such as human essential hypertension we may gain insights into novel pathophysiological mechanisms and potential therapeutic targets. In the Medical Research Council BRItish Genetics of HyperTension (BRIGHT) study, we aim to identify these genetic factors by scanning the human genome for susceptibility genes for essential hypertension. We describe the results of a genome scan for hypertension in a large white European population. We phenotyped 2010 affected sibling pairs drawn from 1599 severely hypertensive families, and completed a 10 centimorgan genome-wide scan. After rigorous quality control, we analysed the genotypic data by non-parametric linkage, which tests whether genes are shared in excess among the affected sibling pairs. Lod scores, calculated at regular points along each chromosome, were used to assess the support for linkage. Linkage analysis identified a principle locus on chromosome 6q, with a lod score of 3.21 that attained genome-wide significance (p=0.042). The inclusion of three further loci with lod scores higher than 1.57 (2q, 5q, and 9q) also show genome-wide significance (p=0.017) when assessed under a locus-counting analysis. These findings imply that human essential hypertension has an oligogenic element (a few genes may be involved in determination of the trait) possibly superimposed on more minor genetic effects, and that several genes may be tractable to a positional cloning strategy.
Hypertension, 2006
Human hypertension arises from a combination of genetic factors and lifestyle influences. With cardiovascular disease set to become the number 1 cause of death worldwide, it is important to understand the etiologic mechanisms for hypertension, because these might provide new routes to improved treatment. The British Genetics of Hypertension Study has recently published a primary genome screen that identified 4 chromosomal regions of interest. We have now genotyped additional markers to confirm the most promising regions for follow-up studies. Thirty-four additional microsatellites were genotyped in our severely hypertensive affected sibling pair resource (now 1635 families with 2142 affected sibling pairs), leading to a substantial increase in information content in the regions of interest. We found increased support for linkage of chromosome 5q13 to human hypertension (multipoint logarithm of oddsϭ2.50) with 3 adjacent markers yielding single point logarithm of odds scores of 3.22, 2.84, and 2.51. The placement of additional markers on 2q, 6q, and 9q diminished support for linkage in these regions. However, the addition of new data and families identified novel regions of interest on chromosomes 1q and 11q. The 3 positive markers in the chromosome 5 region were also genotyped in 712 distinct parent-offspring trios with the same severe phenotype to replicate linkage and association. Borderline support for replication was found (Pϭ0.07). We found increased evidence for linkage and borderline-significant evidence for association for a hypertension susceptibility locus on chromosome 5q13 that is worthy of detailed fine mapping and assessment of candidate genes. (Hypertension. 2006;48:105-111.)
Journal of Human Hypertension, 2004
Essential hypertension (EH) is thought to be a polygenic disease. Several candidate genes of this disease have been investigated in studies using polymorphic genetic markers, but some studies have failed to show any association of EH with these genes. In this experiment, we used microsatellite markers on chromosome 1, and performed an association study between EH and control subjects. Genomic DNA was amplified with fluorescently labelled primers from the Applied Biosystems PRISM linkage mapping set HD-5 comprising 63 highly polymorphic microsatellite markers with an average spacing of 4.5 cM. We isolated three loci showing significant differences: D1S507, D1S2713 and D1S2842. The P-values of the allele with the greatest post hoc contributions in D1S507, D1S2713 and D1S2842 were 0.0008, 0.0062 and 0.0084, respectively. All these values were significant after Bonferroni correction. Furthermore, we found that the three microsatellite alleles were associated with the levels of systolic blood pressure. These data suggest that there are at least the three susceptibility loci for EH on chromosome 1, and that a case-control study using microsatellite markers on genomewide basis is a useful method for isolating the susceptibility loci of multifactorial disorders.
The American Journal of Human Genetics, 2002
Essential hypertension (EH) is a complex disorder that results from the interaction of a number of susceptibility genes and environmental factors. We studied an isolated Sardinian village (Talana) in which the prevalence of hypertension is comparable to that in most Western populations. Talana exhibits features, such as slow demographic growth, high inbreeding, a low number of founders, stable lifestyle and culture, and accurate genealogical records, that make it suitable for the study of complex disorders. Clinical assessment of the entire adult population (N p ) identified ∼100 hypertensive subjects. For our study, we selected the individuals with the most-severe EH ∼ 1,000 (i.e., diastolic blood pressure 1100 mm Hg), belonging to a single deep-rooted pedigree (12 generations), whose common ancestors lived in the 17th century. We performed a three-stage genomewide search using 36 affected individuals, by means of parametric linkage and allele-sharing approaches. LOD scores 11 were observed on chromosomes 1, 2, 13, 15, 17, and 19 (stage I). The most striking result was found in a 7.57-cM region on chromosome 2p24-p25. All five nonparametric linkage statistics estimated by the SimWalk2 program lie above the significance threshold of for the whole region. Similar significance was obtained for 2p24-25 when para-P ! .008 metric linkage (LOD score 1.99) and linkage disequilibrium mapping ( ) were used, suggesting that a P p .00006 hypertension-susceptibility locus is located between D2S2278 and D2S168. This finding is strengthened by a recent report of linkage with marker D2S168 in a hypertensive sib-pair sample from China.
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,
Novel Quantitative Trait Loci for Blood Pressure and Related Traits on Rat Chromosomes 1, 10, and 18
Biochemical and Biophysical Research Communications, 1997
understood. However, considering that more than 30% Hypertension and diabetes mellitus are known to of all diabetics do not develop hypertension despite long be frequently associated. The genetic dissection of diabetes duration, obesity and insulin resistance, gediseases such as hypertension or diabetes mellitus is netic factors must play a crucial role. This phenomenon possible by using experimental crosses, which allow is also seen in animal models used in diabetes research. identification of loci influencing phenotypic traits Most of these models develop hyperglycemia or im-(quantitative trait loci-QTLs). In this study the sponpaired glucose tolerance with obesity, hyperinsulintaneously hypertensive rat (SHR) and spontaneously emia and/or hyperlipidemia, but animals developing diabetic, but normotensive rat (BB/OK) were crossed diabetic hypertension are not available. Also the sponand the F2 population was analysed in order to search taneously diabetic BB rat which is a well-established for QTLs on selected chromosomes (1, 10, 18) for blood animal model of insulin-dependent diabetes does not pressure and some metabolic traits related to diabedevelop hypertension, despite the long diabetes durates, renal function and hypertension. There were 3 tion(2). One supposes that the BB rat is genetically not regions found on chromosome 1 which showed linksusceptible for hypertension. The transfer of chromoage to blood pressure. The strongest evidence for linksomal regions carrying blood pressure quantitative age was observed between loci Igf2 and D1Mgh12. On chromosome 10 there was a QTL for blood pressure trait loci (QTLs) from hypertensive rats onto the gefound between Ppy and Abp and on chromosome 18 netic background of the diabetes-prone BB rat could there were three regions (Ttr-Grl, Tilp-Gja1, Olfprovide an diabetic and hypertensive animal model for D18Mit9) with linkage to blood pressure. Since the 24 the study of diabetic hypertension. Advances in molechr albumin and phosphate excretion correlated with ular biology have allowed to dissect genetically phenoblood pressure in F2 hybrids, the same regions were types such as blood pressure and there were several linked to both parameters. Region with linkage to seblood pressure QTLs detected by a genome wide search rum concentrations of cholesterol (probably located with microsatellite markers in the rat (3-12). However, beyond the terminal marker Ttr of the linkage group) an important point in QTL mapping is the fact that were also found. The results of this study with a new mapping results need not be consistent among different F2(BB 1 SHR) population confirm the existence of crosses (13). Linkage analysis reveals only those trait previously described blood pressure loci (Sa and Bp2) affecting loci that differ between two animal models and showed novel QTLs on chromosomes 1, 10 and 18. used for crossing. It means that a QTL may be detected
Identification of Hypertension Susceptibility Loci on Rat Chromosome 12 * Novelty and Significance
Hypertension, 2012
Previous studies have identified multiple blood pressure and renal disease quantitative trait loci located on rat chromosome 12. In the present study, we narrowed blood pressure loci using a series of overlapping Dahl saltsensitive/Mcwi (SS)-12 Brown Norway (BN) congenic lines. We found that transferring 6.1 Mb of SS chromosome 12 (13.4-19.5 Mb) onto the consomic SS-12 BN background significantly elevated blood pressure on 1% NaCl (146±6 versus 127±1 mm Hg; P<0.001) and 8% NaCl diets (178±7 versus 144±2 mm Hg; P<0.001). Compared with the SS-12 BN consomic, these animals also had significantly elevated albumin (218±31 versus 104±8 mg/d; P<0.001) and protein excretion (347±41 versus 195±12 mg/d; P<0.001) on a 1% NaCl diet. Elevated blood pressure, albuminuria, and proteinuria coincided with greater renal and cardiac damage, demonstrating that SS allele(s) within the 6.1 Mb congenic interval are associated with strong cardiovascular disease phenotypes. Sequence analysis of the 6.1 Mb congenic region revealed 12 673 single nucleotide polymorphisms between SS and BN rats. Of these polymorphisms, 293 lie within coding regions, and 18 resulted in nonsynonymous changes in conserved genes, of which 5 were predicted to be potentially damaging to protein function. Syntenic regions in human chromosome 7 have also been identified in multiple linkage and association studies of cardiovascular disease, suggesting that genetic variants underlying cardiovascular phenotypes in this congenic strain can likely be translated to a better understanding of human hypertension. (Hypertension. 2012;60:942-948.) • Online Data Supplement