Published online before print September 25, 2006, doi: 10.1161/01.HYP.0000244107.13957.2b
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(Hypertension. 2006;48:908.)
© 2006 American Heart Association, Inc.
Original Articles |
Genome-Wide Scan for Premature Hypertension Supports Linkage to Chromosome 2 in a Large Kyrgyz Family
From the Department of Experimental Medicine and Toxicology (B.K., L.M., M.R.W.), Imperial College London, London, United Kingdom; National Center of Cardiology and Internal Medicine (A.A., M.K., A.P., A.J.), Bishkek, Kyrgyz Republic; and the Genomic and Molecular Medicine (M.T.), Clinical Sciences Centre, Medical Research Council, London, United Kingdom.
Correspondence to Margaret Town, Genomic and Molecular Medicine, Room 205, Collier Bldg, Hammersmith Hospital, Du Cane Rd, London W12 0NN, United Kingdom. E-mail m.town{at}imperial.ac.uk
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Abstract |
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We report a genome-wide scan for susceptibility loci to hypertension in a single Kyrgyz family where 10 of the affected relatives developed hypertension before the age of 35 years, and some members have suffered stroke. The early onset of disease and the geographic isolation of the Kyrgyz population are both expected to select for an increased influence of genetic factors in hypertension. We genotyped 44 individuals from this Krygyz family with 374 microsatellite markers, covering a 10-centimorgan map. Nonparametric analysis suggests that affected status is linked to loci in the chromosome 2q23 to q37 genomic interval, whereas 2-point parametric analysis returned a logarithm of odds score of 2.67 for marker D2S2330 (2q24.3). Multipoint linkage analysis substantiated the evidence for a hypertension susceptibility allele in the chromosome 2q23 to q36 region. Fine mapping and haplotype analysis implicate that the genetic lesion resides between markers D2S2380 (166.5 cM) and D2S335 (175.9 cM). This finding supports other recent studies of early onset hypertension suggesting that the region 2q24.3 to q31.1 encompasses a novel locus for premature hypertension.
Key Words: hypertension • stroke • population • linkage • microsatellites • chromosome 2
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Introduction |
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Hypertension is a major risk factor for stroke and coronary vascular disease, and a recent study has drawn attention to the increasing prevalence of the condition in developing countries.1 Kyrgystan is a landlocked country in Central Asia, bordering China, Kazakhstan, Tajikistan, and Uzbekistan. The Kyrgyz population is descended, at least in part, from very ancient (201 AD) Central Asian inhabitants. The current stable Kyrgyz population was established
500 years ago, and since then has remained relatively isolated by geography. Experience with isolated populations shows that genetic heterogeneity in complex disorders may be lower than in Europeans or Africans because of founder effect and genetic drift, with fewer loci contributing greater effect,2–4 that is, although the disease is common, the number of "blood pressure (bp) alleles" within such a population and specifically within a single family is likely to be low. We have identified a 5-generation Krygyz family (Figure 1) susceptible to premature hypertension and stroke in which 10 of the affected relatives were diagnosed with hypertension before the age of 35 years.
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The contribution of genetic factors to bp regulation is well established,5 and the greatest advances toward our understanding of the pathophysiology of systemic hypertension in recent years have been through the study of families in which hypertension is inherited as a single gene disorder. Such an approach has revealed the genetic basis of glucocorticoid-remedial aldosteronism,6 Liddle’s syndrome,7 apparent mineralocorticoid excess,8 one form of pregnancy-associated hypertension,9 and Gordon’s syndrome.10 We report here the results of a genome-wide linkage scan for susceptibility loci to premature hypertension, genotyping microsatellite markers in 44 individuals from this large Krygyz family.
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Methods |
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Phenotyping and DNA Extraction
Ethics approval for this study has been granted through the National Center for Cardiology Ethics Committee in Bishkek, Kyrgyzstan, and the Hammersmith Hospital, London. All of the participants gave informed consent, and all of the samples and personal/clinical data were collected in line with local guidelines. The index case was a woman (Figure 1, V-51) diagnosed with hypertension at 24 years of age. Family members >18 years of age were phenotyped by clinic and 24-hour ambulatory bp measurements, electrocardiography, echocardiography, and serum biochemistry. Clinic bp was taken in the nondominant arm using a mercury sphygmomanometer with the patient seated for 5 minutes. Twenty-four hour bp and heart rate monitoring were conducted using Tonoport-IV equipment (Marquette Hellige). Bp and heart rate were measured every 15 minutes during the day (6:00 AM to 12:00 AM) and every 30 minutes at night (12:00 AM to 6:00 AM). Hypertension was diagnosed on the basis of a mean daytime ambulatory bp >140/85 mm Hg. Recognized causes of secondary hypertension were excluded by physical examination, routine biochemistry, and abdominal ultrasound. All of the patients were normokaliemic at diagnosis. Blood samples were collected from 37 family members of generations IV and V and 7 of their marriage partners. DNA was extracted from whole blood with a BACC kit (Nucleon).
Simulation
Linkage simulation was carried out using SIMLINK,11 modeling for both autosomal dominant (AD) and autosomal recessive (AR) inheritance. A piecewise-linear penetrance function for an autosomal dichotomous trait was used. Because the disease phenotype is premature hypertension, full penetrance was assumed to occur at 35 years of age with minimal penetrance (0.05) <20 years of age. Given the frequency of the phenotype in the Kyrgyz population, modeling for both relatively rare (0.01) and more common (0.06) disease alleles was carried out, using equal marker allele frequencies for a multiallelic marker to simulate use of microsatellites. All of the calculations were based on 1000 replicates for a genetically homogeneous trait. Power was estimated for a single marker at recombination fractions 0.0, 0.05, 010, 0.2, and 0.5.
DNA Analyses
A primary screen was carried out, genotyping all of the DNA samples with a set of 374 microsatellite markers to ensure a 10 centimorgan (cM) map (ABI Prism Linkage Mapping Set MD10). The chromosome 2 candidate region was analyzed by genotyping 14 additional markers at increased (<5.0 cM) density. Primers for 6 of these markers were also from a commercially available source (ABI Prism Linkage Mapping Set MD05), whereas 4 (D2S284, D2S156, D2S2380, and D2S382) were selected by us from online sources (http://www.ensembl.org), and 4 (D2S2275, D2S306, D2S2345, and D2S294) were the kind gift of Prof Mark Caulfield and coworkers (William Harvey Research Institute, London). All of the genetic distances reported in this article are according to the Marshfield map (http://www2.marshfieldclinic.org/RESEARCH/GENETICS). PCR was performed according to the manufacturer’s protocols (ABI). Reactions were pooled and products separated by capillary electrophoresis (ABI Prism 3700 fragment analyser). Data output was analyzed using Genescan Analysis and Genotyper software (ABI). Raw data were checked manually and using the PedCheck facility incorporated into the MLINK program.12 Markers that failed to amplify or yielded genotyping errors were retyped once, and if the inconsistency was not resolved, these were replaced by the nearest high-heterozygosity microsatellites (http://www.ensembl.org).
Linkage Analyses
Genotype data were analyzed by several methods. Allele frequencies for each marker were determined from the whole family. Nonparametric analysis (excess allele sharing) was carried out using Genehunter-Plus,13 which generates nonparametric logarithm of odds ([LOD] NPL) scores. Because the original pedigree was too complex for this program, we split the consanguineous loop and dropped uninformative individuals from the analysis. LOD* scores were derived from Genehunter-Plus output files using the ASM program,14 the likelihood ratio test. Parametric 2-point and multipoint LOD scores were calculated using MLINK software of the LINKAGE package version 5.212 and SimWalk2,15 respectively, under the assumption of both AD and AR inheritance. A disease allele frequency of 0.01 was used and Hardy–Weinberg equilibrium assumed. To take in to account the age-related penetrance of hypertension in this kindred, we designated 2 liability classes for both AD and AR inheritance models. For AD class 1, D/D (homozygous for the disease-carrying allele) or D/d (heterozygous) individuals are assumed to be affected. In AD class 2, D/d or D/D individuals are assumed to have a 0.05 probability of displaying the phenotype. For AR class 1, only D/D individuals are assumed to be affected. In AR class 2, the D/D genotype assumes a 0.05 probability of displaying the phenotype. Liability class 1 includes all of the individuals >35 years of age, including all of the affected individuals (age independent). Liability class 2 includes the currently unaffected individuals <35 years of age. LOD scores were calculated at values of 
from 0.00 to 0.45 in 0.05 increments. The high incidence of hypertension in this population may result in phenocopies among marriage partners and their offspring. Therefore, our penetrance data reflected a probability of 0.06 among affected subjects carrying the "normal genotype." All of the Genehunter and MLINK analyses were performed through the genetic linkage user environment through the Rosalind Franklin Centre for Genomics Research (now closed). Multipoint analysis was performed using SimWalk2 through the graphical interface MEGA2.16
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Identification of Candidate Loci
The full family structure for pedigree 01 is shown (Figure 1), and a summary of phenotypic data for all of the affected individuals of generation IV and V is shown in Table 1. Of note in generation V, all 9 of the affected members were aged <35 years at diagnosis, whereas 13 individuals aged >35 years are still healthy with mean ambulatory bp <140/85 mm Hg. The remaining 17 individuals of this generation are <35 years of age and have the potential to develop the phenotype. Hypertension in generation IV was diagnosed in 6 of 10 relatives, all aged <55 years. The pattern and incidence of the disease phenotype among blood relatives of pedigree 01 suggest that it may be a single gene disorder; however, the mode of inheritance is uncertain. Therefore, after genotyping of this family, we performed an initial model-free analysis (Genehunter-Plus and ASM) to estimate the significance of excess allele sharing of identical alleles by descent among affected individuals.13 The strongest evidence for excess allele sharing was indicated for chromosome 2q between 138 and 244 cM, with 2 peaks at 176 cM (LOD*=1.63) and at 213 cM (LOD*=1.89), close to markers D2S335 (2q31) and D2S2382 (2q35), respectively (Figure 2A).
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, AR model. The data indicate evidence to suggest linkage between hypertension and the 155 to 233 cM interval for the AD model. This finding supports previous studies of cohorts with early onset hypertension from 3 different populations. *1, data from British severely hypertensive families (BRIGHT study), LOD=1.76 at marker D2S142.
Supporting Evidence for Linkage to Chromosome 2
We also performed a genome-wide parametric analysis (MLINK, SimWalk2). Assuming autosomal dominance, the highest 2-point LOD score, 2.676 (at 0.00), was achieved with marker D2S2330 (169.4 cM) on chromosome 2q24.3 (Table 2). LOD scores close to 2.0 were also obtained for single markers D7S484 (LOD=1.968) and D11S1314 (LOD=2.048) on chromosomes 7p14.2 and 11q13.4, respectively (Figure I, available online at http://www.hypertensionaha.org). With the AR model, no scores >2.0 were observed. Simulations with pedigree 01 predicted mean 2-point LOD scores >2.0 (at 0.00) for a linked marker, and the estimated probability (in 1000 simulations) of obtaining an LOD >2.5 with an unlinked marker (ie, a false-positive) was 0 (Figure II). Therefore, the 2-point data provide supporting evidence for linkage of hypertension to a locus on chromosome 2q, with the possibility of further loci on chromosomes 7p and 11q.
Multipoint analysis was carried out across the 3 candidate regions of chromosomes 2, 7, and 11. Under the assumption of autosomal dominance, the data provided support for linkage to chromosome 2q23 to q36 (Figure 2B). The multipoint interval (155 to 233 cM) on chromosome 2 lies between markers D2S151 and D2S396 and is encompassed by the region of excess allele sharing indicated by nonparametric analysis (Figure 2A). The resulting broad interval might have been anticipated, because we have analyzed a single pedigree with an expected low number of recombination events across the chromosome. However, 2 peaks are apparent within the 78 cM interval, close to markers D2S2330 (169.4 cM; LOD=2.24) and D2S2382 (213.5 cM; LOD=2.26). This pattern is similar to that obtained with the nonparametric analysis and may suggest, for this family, genetic heterogeneity within a specific region of chromosome 2. The incidence of hypertension in this population is high, and it is possible that the affected marriage partners (Figure 1, individuals 20, 26, and 28) and, consequently, their affected offspring (Figure 1, individuals 49, 51, 53, and 81), may have a different underlying genetic cause for hypertension than blood relatives in pedigree 01. However, reanalysis after removal of the genotypes of these 3 family groups, in turn, did not significantly alter either the 2-peak pattern or the LOD scores (data not shown). Multipoint analysis gave a similar pattern when an AR model was used (Figure 2B), but overall LOD scores were lower for this model. Multipoint data (not shown) for chromosomes 7p and 11q were negative.
Because the most suggestive evidence for linkage is to chromosome 2q23 to q36, we investigated this region in greater detail. We genotyped pedigree 01 with an additional 14 markers (>65% heterozygosity), increasing the mean density to 4.6 cM (range: 3 to 5 cM). Pairwise analysis at this increased marker density gave positive 2-point LOD scores for several markers (Table 2). Under the AD model, positive LOD scores were obtained for sequential markers D2S382 to D2S294 with a peak LOD of 2.676 at D2S2330 (169.4 cM), providing further support for linkage of the smaller 2q24 to q31 interval with hypertension in this Kyrgyz pedigree.
Defining Candidate Haplotypes
Haplotype assignment for the whole family was carried out (SimWalk2) with all 43 markers on chromosome 2 and without regard to the trait locus. Informative affected and unaffected individuals in generations IV and V demonstrated almost complete AD penetrance of alleles between markers D2S142 and D2S206 (161.3 to 240.8 cM), which is coincident with the positive region indicated by multipoint analysis. Within this region, we observed (Figure 3) that alleles for only 4 markers, between D2S2380 and D2S335 (166.5 to 175.9 cM), are shared by related affected individuals. This suggests that a gene contributing to hypertension may lie in the 2q24.3 to q31.1 interval. Affected individuals 51 and 53 do not have any alleles in common with other related affected persons (Figure 3). Because these are the offspring of an affected marriage partner, the lack of shared alleles may be explained by a different underlying genetic cause for hypertension, as suggested previously by the result of multipoint analysis. Affected individual 64 (Figure 3), whose parents are related (Figure 1), shares alleles with all of the other affected relatives at just 2 markers: D2S2330 (169.4 cM) and D2S2345 (171.04 cM). In this case, haplotype assignment suggests segregation with the disease of a substantially smaller (<6.0 cM) interval than that indicated by the linkage data alone.
Comparative Linkage Analysis of Chromosome 2q
Data from this study support previous genome-wide linkage screens in identifying a genomic region that may influence bp regulation on chromosome 2. We have made a comparison of data from the Kyrgyz pedigree 01 with 4 studies that also specified the phenotype as early onset hypertension. The 155 to 233 cM region of chromosome 2q, identified by multipoint analysis in our Kyrgyz pedigree, overlaps with peaks of linkage identified in 3 of these studies (Figure 2B). Zhu et al17 found linkage to chromosome 2q with a cohort of Chinese hypertensive sibling pairs, where disease onset was between 20 and 60 years of age. The authors confirmed a peak of linkage around marker D2S142 at 161 cM. Likewise, this marker was also 1 of 4 loci attaining genome-wide significance in the Medical Research Council BRItish Genetics of HyperTension (BRIGHT) study, which selected for early onset (<60 years) hypertension in 1599 severely hypertensive British families.18 In addition, Perola et al19 found suggestive evidence for linkage of hypertension to a 17-cM region on chromosome 2q at 169.4 to 186.8 cM in Finnish sibling pairs with an age of disease onset <50 years. The fourth study was also a scan for early onset hypertension in an independent Scandinavian sibling-pair collection.20 Two main susceptibility loci were suggested, including a region on chromosome 2q, which covered a broad, weakly positive region with a peak (LOD=1.8) between markers D2S2216 (111.2 cM) and D2S347 (131.5 cM), adjacent to our Krygyz candidate region.
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Discussion |
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Hypertension is a major health problem in the Kyrgyz Republic in Central Asia.1 We have identified a Kyrgyz family in which hypertension appears at an early age and where several family members have suffered stroke. The genome-wide linkage screen of this large pedigree with premature hypertension has generated a candidate localization for a gene conferring susceptibility to this disorder on chromosome 2q24.3 to q31.1. Although we intend to investigate the possibility of other loci contributing to the phenotype in pedigree 01, we believe that the linkage evidence and critical recombination events observed with this family suggest that a causative locus that influences premature hypertension may lie within a single <10-cM area of chromosome 2q24.3 to q31.1 between markers D2S2380 and D2S335.
The potential importance of other loci on chromosome 2 in the control of bp is supported by previous genome-wide scans and association studies in human populations. Specifically, a recent study showed significant linkage of unresponsiveness to antihypertensive drugs to chromosome 2p,21 and a meta-analysis of 9 genome-wide scans for bp variation and hypertension in whites showed evidence of linkage to a 27-cM interval at 2p12 to q22.1.22 The Bogalusa Heart Study showed significant evidence of linkage to 2p13 at 73 cM for long-term (child to young adult) levels of diastolic bp.23 Additionally, a 140 to 170 cM interval has been linked to pre-eclampsia in Finnish24 and Australasian25 populations, whereas linkage peaks at 40 to 140 cM and at 230 cM, obtained with 2 independent Family Blood Pressure Program (FBPP) Studies,26,27 immediately flank that of the candidate interval (155 to 233 cM) suggested by analysis of the Kyrgyz pedigree in this study.
The 4 studies highlighted in this article, covering Scandinavians, Finnish, Chinese, and British populations, were specified as collected on the basis of early onset hypertension in an attempt to include families with an expected strong genetic influence on bp level. Interestingly, each of these demonstrate some evidence for linkage in the region overlapping that found for our prematurely hypertensive Kyrgyz family.17–19
With the accumulated evidence for the implication of 2q23 to q36 in harboring loci, which may influence control of bp, the focus is now on taking such studies forward into candidate gene analysis.28 Haplotype analysis of our Kyrgyz pedigree has suggested a small interval that may be responsible for the premature hypertensive phenotype. The current release of the human genome assembly, available through Ensembl (www.ensembl.org), indicates that the 2q24.3 to q31.1 region between markers D2S2380 and D2S335 (166.5 to 175.9 cM) spans <9 megabase pairs and encompasses 36 genes of known or predicted function. None of the genes responsible for the monogenic forms of hypertension are found within this region. However, we have identified 4 well-characterized genes that could be considered biologically plausible candidates. SCN7A codes for the 
-subunit of a cardiac and skeletal muscle sodium channel protein. Recently, a polymorphism in exon 18 of this gene was associated with essential hypertension of the Chinese Han population in Shanghai, China.29 Also CMYA3, which codes for a human hypothetical protein very highly expressed in heart and skeletal muscle, is homologous to the mouse cardiomyopathy-associated 1 (Xin) gene30 and porcine CMYA3,31 which are implicated in cardiac morphogenesis. In addition, the NO synthase trafficker (NOSTRIN) gene product binds and contributes to the trafficking and targeting of endothelial NO synthase.32 Endothelial NO synthase is responsible for NO production, which is a potent mediator in biologic processes, such as neurotransmission, inflammatory response, and vascular homeostasis. Investigating the potential influence of these candidates will form the basis of a resequencing project in this family and others from the Kyrgyz region.
Perspectives
Recently, a study of individuals from 2 Kyrgyz villages recorded an age-adjusted prevalence of hypertension at 39%.1 The authors suggested that the rapid rise in hypertension in this former Soviet state may be the herald of a coming epidemic of cardiovascular disease. The linkage reported for this Kyrgyz family, in concert with previous studies, strongly supports a region on chromosome 2 as a candidate for contributing to the worldwide susceptibility to essential hypertension.
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Acknowledgments |
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We thank the study subjects for their continued participation and staff at the Institute of Molecular Biology and Medicine, National Center of Cardiology and Internal Medicine, Bishkek, Kyrgyz Republic. We are also grateful to Professor Mark Caulfield and coworkers (William Harvey Research Institute) for helpful discussion and the gift of primers, Stuart Horswell (Medical Research Council Clinical Sciences Centre, United Kingdom) for invaluable support with linkage analysis, and Dr Carol Shoulders (Medical Research Council Clinical Sciences Centre) for constructive ideas and critical reading of the article.
Source of Funding
The Wellcome Trust has provided support for B.K. to come to the United Kingdom from Kyrgyzstan and complete this research.
Disclosures
None.
Received June 23, 2006; first decision July 11, 2006; accepted August 20, 2006.
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