Heritability of blood pressure traits and the genetic contribution to blood pressure variance explained by four blood-pressure-related genes

OBJECTIVE: To study the heritability of four blood pressure traits and the proportion of variance explained by four blood-pressure-related genes. METHODS: All participants are members of an extended pedigree from a Dutch genetically isolated population. Heritability and genetic correlations of systolic blood pressure, diastolic blood pressure, mean arterial pressure and pulse pressure were assessed using a variance components approach (SOLAR). Polymorphisms of the alpha-adducin (ADD1), angiotensinogen (AGT), angiotensin II type 1 receptor (AT1R) and G protein beta3 (GNB3) genes were typed. RESULTS: Heritability estimates were significant for all four blood pressure traits, ranging between 0.24 and 0.37. Genetic correlations between systolic blood pressure, diastolic blood pressure and mean arterial pressure were high (0.93-0.98), and those between pulse pressure and diastolic blood pressure were low (0.05). The ADD1 polymorphism explained 0.3% of the variance of pulse pressure (P = 0.07), and the polymorphism of GNB3 explained 0.4% of the variance of systolic blood pressure (P = 0.02), 0.2% of mean arterial pressure (P = 0.05) and 0.3% of pulse pressure (P = 0.06). CONCLUSION: Genetic factors contribute to a substantial proportion of blood pressure variance. In this study, the effect of polymorphisms of ADD1, AGT, AT1R and GNB3 explained a very small proportion of the heritability of blood pressure traits. As new genes associated with blood pressure are localized in the future, their effect on blood pressure variance should be calculated.     

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.     

Repeated blood pressure measurements in a sample of Swedish twins: heritabilities and associations with polymorphisms in the renin-angiotensin-aldosterone system

BACKGROUND : Twin and family studies have shown that genetic effects explain a relatively high amount of the phenotypic variation in blood pressure. However, many studies have not been able to replicate findings of association between specific polymorphisms and diastolic and systolic blood pressure. METHODS : In a structural equation-modelling framework the authors investigated longitudinal changes in repeated measures of blood pressures in a sample of 298 like-sexed twin pairs from the population-based Swedish Twin Registry. Also examined was the association between blood pressure and polymorphisms in the angiotensin-I converting enzyme and the angiotensin II receptor type 1 with the 'Fulker' test. Both linkage and association were tested simultaneously revealing whether the polymorphism is a Quantitative Trait Locus (QTL) or in linkage disequilibrium with the QTL. RESULTS : Genetic influences explained up to 46% of the phenotypic variance in diastolic and 63% of the phenotypic variance in systolic blood pressure. Genetic influences were stable over time and contributed up to 78% of the phenotypic correlation in both diastolic and systolic blood pressure. Non-shared environmental effects were characterised by time specific influences and little transmission from one time point to the next. There was no significant linkage and association between the polymorphisms and blood pressure. CONCLUSIONS : There is a considerable genetic stability in both diastolic and systolic blood pressure for a 6-year period of time in adult life. Non-shared environmental influences have a small long-term effect. Although associations with the polymorphisms could not be replicated, results should be interpreted with caution due to power considerations.     

Association of hypertension drug target genes with blood pressure and hypertension in 86,588 individuals

We previously conducted genome-wide association meta-analysis of systolic blood pressure, diastolic blood pressure, and hypertension in 29,136 people from 6 cohort studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. Here we examine associations of these traits with 30 gene regions encoding known antihypertensive drug targets. We find nominal evidence of association of ADRB1, ADRB2, AGT, CACNA1A, CACNA1C, and SLC12A3 polymorphisms with 1 or more BP traits in the Cohorts for Heart and Aging Research in Genomic Epidemiology genome-wide association meta-analysis. We attempted replication of the top meta-analysis single nucleotide polymorphisms for these genes in the Global BPgen Consortium (n=34,433) and the Women's Genome Health Study (n=23,019) and found significant results for rs1801253 in ADRB1 (Arg389Gly), with the Gly allele associated with a lower mean systolic blood pressure (β: 0.57 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=4.7×10(-10)), diastolic blood pressure (β: 0.36 mm Hg; SE: 0.06 mm Hg; meta-analysis: P=9.5×10(-10)), and prevalence of hypertension (β: 0.06 mm Hg; SE: 0.02 mm Hg; meta-analysis: P=3.3×10(-4)). Variation in AGT (rs2004776) was associated with systolic blood pressure (β: 0.42 mm Hg; SE: 0.09 mm Hg; meta-analysis: P=3.8×10(-6)), as well as diastolic blood pressure (P=5.0×10(-8)) and hypertension (P=3.7×10(-7)). A polymorphism in ACE (rs4305) showed modest replication of association with increased hypertension (β: 0.06 mm Hg; SE: 0.01 mm Hg; meta-analysis: P=3.0×10(-5)). Two loci, ADRB1 and AGT, contain single nucleotide polymorphisms that reached a genome-wide significance threshold in meta-analysis for the first time. Our findings suggest that these genes warrant further studies of their genetic effects on blood pressure, including pharmacogenetic interactions.     

Genetic architecture of ambulatory blood pressure in the general population: insights from cardiovascular gene-centric array

Genetic determinants of blood pressure are poorly defined. We undertook a large-scale, gene-centric analysis to identify loci and pathways associated with ambulatory systolic and diastolic blood pressure. We measured 24-hour ambulatory blood pressure in 2020 individuals from 520 white European nuclear families (the Genetic Regulation of Arterial Pressure of Humans in the Community Study) and genotyped their DNA using the Illumina HumanCVD BeadChip array, which contains ≈ 50 000 single nucleotide polymorphisms in >2000 cardiovascular candidate loci. We found a strong association between rs13306560 polymorphism in the promoter region of MTHFR and CLCN6 and mean 24-hour diastolic blood pressure; each minor allele copy of rs13306560 was associated with 2.6 mm Hg lower mean 24-hour diastolic blood pressure (P = 1.2 × 10??). rs13306560 was also associated with clinic diastolic blood pressure in a combined analysis of 8129 subjects from the Genetic Regulation of Arterial Pressure of Humans in the Community Study, the CoLaus Study, and the Silesian Cardiovascular Study (P=5.4 × 10??). Additional analysis of associations between variants in gene ontology-defined pathways and mean 24-hour blood pressure in the Genetic Regulation of Arterial Pressure of Humans in the Community Study showed that cell survival control signaling cascades could play a role in blood pressure regulation. There was also a significant overrepresentation of rare variants (minor allele frequency: < 0.05) among polymorphisms showing at least nominal association with mean 24-hour blood pressure indicating that a considerable proportion of its heritability may be explained by uncommon alleles. Through a large-scale gene-centric analysis of ambulatory blood pressure, we identified an association of a novel variant at the MTHFR/CLNC6 locus with diastolic blood pressure and provided new insights into the genetic architecture of blood pressure.     

Familial and genomic analyses of postural changes in systolic and diastolic blood pressure

The physiological adaptation to the erect posture involves integrated neural and cardiovascular responses that might be determined by genetic factors. We examined the familial- and individual-specific components of variance for postural changes in systolic and diastolic blood pressure in 767 volunteer nuclear adult families from the Victorian Family Heart Study. In 274 adult sibling pairs, we made a genome-wide scan using 400 markers for quantitative trait loci linked with the postural changes in systolic and diastolic pressures. Overall, systolic pressure did not change on standing, but there was considerable variation in this phenotype (SD=8.1 mm Hg). Familial analyses revealed that 25% of the variance of change in systolic pressure was attributable to genetic factors. In contrast, diastolic pressure increased by 6.3 mm Hg (SD=7.0 mm Hg) on standing and there was no evidence of contributory genetic factors. Multipoint quantitative genome linkage mapping suggested evidence (Z=3.2) of linkage of the postural change in systolic pressure to chromosome 12 but found no genome-wide evidence of linkage for the change in diastolic pressure. These findings suggest that genetic factors determine whether systolic pressure decreases or increases when one stands, possibly as the result of unidentified alleles on chromosome 12. The genetics of postural changes in systolic blood pressure might reflect the general buffering function of the baroreflex; thereby, the predisposition to sudden decreases or increases in systolic pressure might cause postural hypotension or vessel wall disruption, respectively.     

Sex-dependent association of blood pressure with oestrogen receptor genes ERalpha and ERbeta

BACKGROUND: There is mounting physiological evidence for an important role of the oestrogen receptors, ERalpha and ERbeta, in vasodilatation and the response to vascular injury. In addition, genetic studies have suggested that the genes encoding these receptors may be involved in the genetic regulation of blood pressure. The existence of such sex steroid-related genes may help to explain the observed sex differences in blood pressure. OBJECTIVE: To investigate the role of the oestrogen receptor genes (ERalpha and ERbeta) in blood pressure variation in women and in men. DESIGN: We performed a genetic association study of the oestrogen receptor genes in 718 unrelated healthy white individuals (386 men and 332 women) from the parental generation of the Victorian Family Heart Study, a general population survey of cardiovascular risk. METHODS: Participants were genotyped for single nucleotide polymorphisms (SNPs) in ERalpha and ERbeta, and blood pressure phenotypes were compared between genotype groups by analysis of variance. RESULTS: When genotype groups were compared, men inheriting the 'a' allele of the ERalpha SNP had significantly higher systolic blood pressure than men with other genotypes [127.7 +/-14.3 mmHg (mean +/- SD) compared with 132.4 +/- 16.1 mmHg; P = 0.014)]. In addition, men inheriting the 'b' allele of the ERbeta SNP had significantly higher diastolic blood pressure than men with other genotypes (81.4 +/-8.1 mmHg compared with 84.4 +/- 9.6 mmHg; P = 0.004). No significant associations between the oestrogen receptor genes and blood pressure were detected in women. DISCUSSION: These results suggest that ERalpha and ERbeta may be involved in the genetic regulation of blood pressure in men, that the two genes may have different roles, and that these genes may contribute to the differences in blood pressures between the sexes.     

Isolated diastolic hypotension and incident heart failure in older adults

Aging is often associated with increased systolic blood pressure and decreased diastolic blood pressure. Isolated systolic hypertension or an elevated systolic blood pressure without an elevated diastolic blood pressure is a known risk factor for incident heart failure in older adults. In the current study, we examined whether isolated diastolic hypotension, defined as a diastolic blood pressure <60 mm Hg and a systolic blood pressure ≥100 mm Hg, is associated with incident heart failure. Of the 5795 Medicare-eligible community-dwelling adults age ≥65 years in the Cardiovascular Health Study, 5521 were free of prevalent heart failure at baseline. After excluding 145 individuals with baseline systolic blood pressure <100 mm Hg, the final sample included 5376 participants, of whom 751 (14%) had isolated diastolic hypotension. Propensity scores for isolated diastolic hypotension were calculated for each of the 5376 participants and used to match 545 and 2348 participants with and without isolated diastolic hypotension, respectively, who were balanced on 58 baseline characteristics. During >12 years of median follow-up, centrally adjudicated incident heart failure developed in 25% and 20% of matched participants with and without isolated diastolic hypotension, respectively (hazard ratio associated with isolated diastolic hypotension: 1.33 [95% CI: 1.10-1.61]; P=0.004). Among the 5376 prematch individuals, multivariable-adjusted hazard ratio for incident heart failure associated with isolated diastolic hypotension was 1.29 (95% CI: 1.09-1.53; P=0.003). As in isolated systolic hypertension, among community-dwelling older adults without prevalent heart failure, isolated diastolic hypotension is also a significant independent risk factor for incident heart failure.     

Ambulatory blood pressure is associated with polymorphic variation in P2X receptor genes

The P2X receptor gene family encodes a series of proteins that function as ATP-gated nonselective ion channels. P2X receptor channels are involved in transducing aldosterone-mediated signaling in the distal renal tubule and are potential candidate genes for blood pressure regulation. We performed a family based quantitative genetic association study in 248 families ascertained through a proband with hypertension to investigate the relationship between common genetic variation in the P2X4, P2X6, and P2X7 genes and ambulatory blood pressure. We genotyped 28 single nucleotide polymorphisms, which together captured the common genetic variability in the 3 genes. We corrected our results for multiple comparisons specifying a false discovery rate of 5%. We found significant evidence of association between the single nucleotide polymorphism rs591874 in the first intron of the P2X7 gene and blood pressure. The strongest association was found for nighttime diastolic blood pressure (P=0.0032), although association was present for both systolic and diastolic blood pressures measured by an observer during the day and at night. Genotypes were associated with a 0.2 SD ( approximately 2.5 mm Hg) difference in night diastolic blood pressure per allele and accounted for approximately 1% of the total variability in this measurement. Other suggestive associations were found, but these were nonsignificant after correction for multiple testing. These genetic data suggest that drugs affecting P2X receptor signaling may have promise as clinical antihypertensive agents.     

Insulin sensitivity and blood pressure in black and white children

Although insulin sensitivity is correlated with high blood pressure in adults, it is unclear whether such a relationship exists in children across ethnic groups. Therefore, the aims of the study were to establish (1) if body composition and insulin sensitivity were related to blood pressure in children, and (2) if any differences in blood pressure between white and black children were explained by body composition and/or insulin sensitivity. Insulin sensitivity and the acute insulin response were established by the minimal model and body composition by dual-energy X-ray absorptiometry. Blood pressure was recorded in the supine position. Body composition, fasting insulin (P<0.01), and the acute insulin response (P<0.05) were positively related to systolic blood pressure but not to diastolic blood pressure, and insulin sensitivity (P<0.001) was negatively related to systolic blood pressure but not to diastolic blood pressure. Insulin sensitivity was negatively associated with systolic and diastolic blood pressure after adjustment for body composition (P<0.01). Black children had higher systolic (110+/-9.2 versus 105+/-8.5 mm Hg, P=0.01) and diastolic (59+/-7.0 versus 54+/-8.0 mm Hg, P<0.01) blood pressure than did white children. The ethnic difference in blood pressure was not explained by body composition, fasting insulin, acute insulin response, or insulin sensitivity. In conclusion, the relationship between insulin sensitivity and systolic blood pressure is evident early in life. Black ethnicity and low insulin sensitivity contribute independently to higher blood pressure in children.     

Y2 receptor gene variants reduce the risk of hypertension in obese children and adolescents

OBJECTIVE: To verify whether peptide YY (PYY) and its Y2 receptor (Y2R) gene variants can be associated with obesity or hypertension or both in a cohort of obese children and adolescents. PATIENTS AND METHODS: Two hundred and twenty-nine obese children (105 girls, mean z-score BMI 5.1 +/- 2.4; mean age 10.5 +/- 2.9 years) and 250 age and sex-matched lean controls (130 women, mean z-score BMI 0.5 +/- 1.1; mean age 10.3 +/- 2.8) were enrolled in the study. Height, weight, BMI, waist circumference and 24-h systolic and diastolic blood pressure were measured. Night-time, day-time and 24-h systolic and diastolic blood pressures were evaluated by 24 h ambulatory blood pressure measurement, and appropriate standard deviation scores according to sex, age and height were calculated. Molecular screening of the PYY and Y2R genes was performed. RESULTS: No new mutations were found. We observed three previously described polymorphisms: G767C on PYY and T585C and T936C on Y2R. An association study was carried out in obese patients. No associations were found between the PYY genotypes and the studied phenotypes. The Y2R gene variants, T585C and T936C, which are in almost complete linkage disequilibrium, were found to be associated with night-time, day-time and 24-h systolic and diastolic blood pressures. In particular, subject homozygotes for the T allele showed lower systolic and diastolic blood pressure values compared with the other genotypes. Moreover, obese children homozygous for the T585 allele showed a lower risk of developing hypertension than patients carrying the CC and CT genotypes (chi 6.9; df = 1, P = 0.03; odds ratio = 0.5, 95% confidence interval: 0.27-0.88). CONCLUSION: Our results suggest that Y2R gene variants are involved in blood pressure regulation in obese children and adolescents.     

Possible locus on chromosome 18q influencing postural systolic blood pressure changes

We conducted a genome-wide scan for quantitative trait loci influencing the systolic blood pressure, diastolic blood pressure, and pulse responses to a postural challenge in 498 white sibling-pairs from the Hypertension Genetic Epidemiology Network, a multicenter study of the genetic susceptibility to hypertension. All participants were hypertensive (systolic blood pressure >/=140 mm Hg, diastolic blood pressure >/=90 mm Hg, or on antihypertensive medications) with diagnosis before age 60. Blood pressure and pulse were measured by an oscillometric method after a 5-minute rest in a supine position and again immediately on standing. The genome scan included a total of 387 autosomal short-tandem-repeat polymorphisms typed by the National Heart, Lung, and Blood Institute Mammalian Genotyping Service at Marshfield. We used multipoint variance-components linkage analysis to identify possible quantitative trait loci influencing postural change phenotypes after adjusting for sex, age, and use of antihypertensive medications. There was suggestive evidence for linkage on chromosome 18q for the postural systolic blood pressure response (maximum logarithm of the odds score=2.6 at 80 centiMorgans). We also observed a maximum logarithm of the odds score of 1.9 for the systolic blood pressure response and 1.7 for the diastolic blood pressure response on chromosome 6p. The marker that demonstrated the strongest evidence for linkage for the systolic blood pressure response (D18S858) lies within 20 centiMorgans of a marker previously linked to rare familial orthostatic hypotensive syndrome. Our findings indicate that there may be 1 or more genes on chromosome 18q that regulate systolic blood pressure during the physiological recovery period after a postural stressor.     

Common variation in the WNK1 gene and blood pressure in childhood: the Avon Longitudinal Study of Parents and Children

WNK1 gene variants have been associated with adult blood pressure. We aimed to investigate relationships between WNK1 variants and blood pressure, as well as blood pressure change with age, in a longitudinal childhood study. Associations between single nucleotide polymorphisms in WNK1 and blood pressure and the rate of blood pressure change between 7 and 11 years were examined in the Avon Longitudinal Study of Parent and Children Study (n=5326 for systolic blood pressure at 11 years). We observed associations (P<0.05) with diastolic blood pressure gradient with age for 33 of 82 typed and imputed polymorphisms, including polymorphisms in exons 4, 10, and 11 (rs10774466, rs1012729, and rs9804992). The minor allele (G) of rs1012729 (frequency: 25.6%) was associated with a gender-adjusted change in a diastolic blood pressure gradient of -0.11 mm Hg/y (95% CI: -0.20 to -0.03 mm Hg/y; P=0.0054). No associations were shown with the systolic blood pressure gradient. At age 11 years, 30 polymorphisms showed association (P<0.05) with systolic blood pressure, including variants in exons 4 and 10 (rs10774466 and rs1012729). Only 3 polymorphisms were associated with diastolic blood pressure at 11 years. In exploration of polymorphism-dietary cation interactions on systolic blood pressure at 11 years, 59 reached significance (P<0.05; 12.3 expected by chance), mostly (n=33) related to dietary calcium. The findings show that common intronic and exonic WNK1 variants are associated with diastolic blood pressure gradient from 7 to 11 years and with systolic blood pressure at 11 years. Our study suggests that previously reported effects of WNK1 variants on blood pressure are mediated via effects on the gradient of blood pressure change with age.     

Body-mass index and cardiometabolic disease: a Mendelian randomisation study of UK Biobank participants

BackgroundHigher body-mass index (BMI) is a risk factor for cardiometabolic disease, although the underlying causal associations remain unclear. The conflicting evidence with respect to the magnitude of association between BMI and cardiometabolic diseases lends support to adopting a Mendelian randomisation approach: we aimed to contribute a fairly large amount of data with detailed covariate information to this question.MethodsThe UK Biobank is a prospective general cohort study of adults aged 40–70 years at baseline (between 2006 and 2010). We examined 119 859 UK Biobank participants with complete cross-sectional phenotypic and genetic data, using a polygenic risk score consisting of 93 single nucleotide polymorphisms associated with BMI from previous genome-wide association studies. We used the polygenic risk score to derive causal estimates using a Mendelian randomisation approach. Cardiometabolic outcomes were based on self-report of clinical diagnosis for each of hypertension, coronary heart disease, type 2 diabetes, and blood pressure. This study was conducted under generic approval from the NHS National Research Ethics Service (ref 11/NW/0382).FindingsMendelian randomisation analysis showed significant positive associations (all p values <0·0001) between genetically instrumented higher BMI and risk of hypertension (odds ratio per 1 SD increase in BMI 1·64, 95% CI 1·48–1·83), coronary heart disease (1·35, 1·09–1·69), type 2 diabetes (2·53, 2·04–3·13), diastolic blood pressure (difference per 1 SD increase in BMI [β] 1·65 mmHg, 0·78–2·52) and systolic blood pressure (1·37, 0·88–1·85). These associations were independent of age, sex, Townsend deprivation scores, alcohol intake, and smoking history.InterpretationThe results of this study add to the evidence of a causal association between higher BMI and increased risk of cardiometabolic diseases. This finding has relevance for public health policies in countries struggling with increasing obesity levels. BMI is a modifiable risk factor for ameliorating risk of cardiometabolic disease. This report advances the field by including a fairly large sample size including detailed covariates; by using a 93-locus polygenic risk score; and by conducting Mendelian randomisation of BMI on a range of cardiometabolic disease outcomes.FundingNone.     

Serum- and glucocorticoid-regulated kinase (SGK1) gene and blood pressure

The serum- and glucose-regulated kinase (SGK1) gene has recently been identified as an important aldosterone-induced protein kinase that mediates trafficking of the renal epithelial Na(+) channel (ENaC) to the cell membrane. Thus, SGK1 is an appealing candidate for blood pressure regulation and possibly essential hypertension. To test this hypothesis, we recruited monozygotic (126 pairs) and dizygotic (70 pairs) normotensive twin subjects and parents of dizygotic twins. Blood pressure was measured in a controlled fashion: recumbent, sitting, and upright. We documented genetic variance on blood pressure in all positions. We then relied on microsatellite markers at the SGK1 gene locus (D6S472, D6S1038, and D6S270) and 2 single nucleotide polymorphisms within the SGK1 gene. We found significant linkage of the SGK1 gene locus to diastolic blood pressure (P<0.0002) and suggestive evidence for linkage for systolic blood pressure (P<0.04), documenting the locus as a quantitative trait locus for blood pressure. We next performed association, using all dizygotic twins and a monozygotic member from each pair. We found significant associations between both single nucleotide polymorphism variants and blood pressure, as well as a significant interaction between the single nucleotide polymorphisms enhancing the effect. This combined effect of the polymorphisms was confirmed in an independent sample of 260 young normotensive men. We conclude that the SGK1 gene is relevant to blood pressure regulation and probably to hypertension in man.     

Blood pressure variability in children with essential hypertension

The aim of this study was to assess blood pressure variability (BPV) and its determinants in untreated hypertensive children. The study group consisted of 124 children, 91 boys and 33 girls, aged 14.9+/-2.5 with essential hypertension and no use of antihypertensive drugs. The subjects underwent routine examination, blood tests and ambulatory blood pressure (BP) monitoring. BPV was defined as the value of the standard deviation of BP for day- and night time periods. Daytime BPV was higher than night time BPV, and systolic BPV was higher than diastolic BPV. Significant positive correlations between 24-h, day- and night time systolic blood pressure (SBP), but not for diastolic blood pressure (DBP), and BPV were observed. In univariate analysis, day- and night time systolic BPVs were correlated with fasting glucose (r=0.609, P=0.02 and r=0.439, P=0.04); daytime systolic BPV, daytime diastolic BPV and night time systolic BPV were correlated with birth length (r=0.428, P=0.04; r=0.426, P=0.04 and r=0.439, P=0.04, respectively), and night time systolic BPV and night time diastolic BPV were correlated with age (r=0.604, P=0.02 and r=0.833, P=0.0001). However, in multiple linear regression analysis, daytime diastolic BPV was determined only by gender and systolic 24-h BP; night time systolic BPV depended on age, daytime SBP and DBP values, and daytime SBP and DBPs were determinants of night time diastolic BPV. The results highlighted the complex nature of BPV, with favourable role of host factors in its aetiology. The determinants of BPV in children are consistent with those in adults. Relationships between BPV and its determinants in untreated hypertensive subjects ought to be investigated in further researches.     

Genome-wide scan for blood pressure suggests linkage to chromosome 11, and replication of loci on 16, 17, and 22

Hypertension was one of the first complex traits to be studied and is thought to be influenced by polygenic and multiple environmental risk factors. Several genomic studies have found suggestive logarithm of odds (LOD) scores for either blood pressure or essential hypertension, but few loci have been replicated. In this study, we performed a genome-wide linkage analysis for systolic blood pressure (SBP) and diastolic blood pressure (DBP) on 1109 white female dizygotic twin pairs from the TwinsUK registry in London. Multipoint linkage analysis replicated the locations of 3 previously reported linkage peaks: on chromosome 16 at 65 cM (LOD 0.8 for SBP and 1.8 for DBP); on chromosome 17 at 70 cM (LOD 1.8 SBP); and at 35 cM on chromosome 22 (LOD 0.97 SBP and 0.99 DBP). Results from multipoint analysis showed 1 novel suggestive linkage for SBP (multipoint LOD 2.28; 2-point P=0.0007) at 35 cM on chromosome 11. Results were similar when those on blood pressure medication were excluded. These are encouraging results for hypertensive research and demonstrate that despite past disappointments, linkage studies can be used to replicate regions from other studies and potentially discover new genetic risk factors of moderate to large effect size. Considering the differences in selection and ascertainment of the previous linkage studies, these results also suggest that some quantitative trait loci are likely to influence the normal range of blood pressure and clinical hypertension, whereas others will be specific to each trait. Future studies should focus on the fine mapping of these replicated regions, which include potential candidate genes.     

Association of alpha-adducin Gly460Trp polymorphism with coronary artery disease in a Korean population

OBJECTIVE: Coronary artery disease is caused by multiple genetic and environmental factors. The disease is also closely associated with cardiovascular conditions such as hypertension. In order to investigate any possible role of hypertension candidate genes in the disease development and progression, we examined the association of the polymorphisms of 31 hypertension candidate genes with coronary artery disease. METHODS: Genetic polymorphisms of 31 hypertension candidate genes were initially screened by resequencing DNA samples from 24 unrelated individuals in a Korean population. Association analysis was performed using 1284 unrelated Korean men, including 749 coronary artery disease subjects and 535 normal healthy controls. RESULTS: We identified a total of 409 single nucleotide polymorphisms including 40 nonsynonymous single nucleotide polymorphisms, 32 insertions/deletions and four microsatellites. Among 40 nonsynonymous single nucleotide polymorphisms, 29 were examined for an association with coronary artery disease. A significant association with coronary artery disease was observed in a polymorphism of the ADD1 gene (Gly460Trp; +29017G/T) (odds ratio 0.71-0.81; P = 0.01-0.04). The same polymorphism was also associated with the number of arteries with significant coronary artery stenosis in the coronary artery disease patients (P = 0.01) as well as the increase in systolic blood pressure (P = 0.02). CONCLUSIONS: The ADD1 Gly460Trp polymorphism is significantly associated with an increased risk of coronary artery disease as well as blood pressure, indicating that ADD1 plays a role in the pathogenesis of coronary artery disease as well as hypertension.     

Orthostatic hypotension and novel blood pressure-associated gene variants: Genetics of Postural Hemodynamics (GPH) Consortium

Aims Orthostatic hypotension (OH), an independent predictor of mortality and cardiovascular events, strongly correlates with hypertension. Recent genome-wide studies have identified new loci influencing blood pressure (BP) in populations, but their impact on OH remains unknown. Methods and results A total of 38 970 men and women of European ancestry from five population-based cohorts were included, of whom 2656 (6.8%) met the diagnostic criteria for OH (systolic/diastolic BP drop ≥20/10 mmHg within 3 min of standing). Thirty-one recently discovered BP-associated single nucleotide polymorphisms (SNPs) were examined using an additive genetic model and the major allele as referent. Relations between OH, orthostatic systolic BP response, and genetic variants were assessed by inverse variance-weighted meta-analysis. We found Bonferroni adjusted (P < 0.0016) significant evidence for association between OH and the EBF1 locus (rs11953630, per-minor-allele odds ratio, 95% confidence interval: 0.90, 0.85-0.96; P = 0.001), and nominal evidence (P < 0.05) for CYP17A1 (rs11191548: 0.85, 0.75-0.95; P = 0.005), and NPR3-C5orf23 (rs1173771: 0.92, 0.87-0.98; P= 0.009) loci. Among subjects not taking BP-lowering drugs, three SNPs within the NPPA/NPPB locus were nominally associated with increased risk of OH (rs17367504: 1.13, 1.02-1.24; P = 0.02, rs198358: 1.10, 1.01-1.20; P = 0.04, and rs5068: 1.22, 1.04-1.43; P = 0.01). Moreover, an ADM variant was nominally associated with continuous orthostatic systolic BP response in the adjusted model (P= 0.04). Conclusion The overall association between common gene variants in BP loci and OH was generally weak and the direction of effect inconsistent with resting BP findings. These results suggest that OH and resting BP share few genetic components.     

Association of estrogen receptor beta gene polymorphisms with left ventricular mass and wall thickness in women

BACKGROUND: Left ventricular (LV) hypertrophy is a significant risk factor for cardiovascular disease. Given sex-based differences in cardiac structure and remodeling, we hypothesized that variation in estrogen pathway genes might be associated with alteration of LV structure. METHODS: We studied 1249 unrelated individuals, 547 men and 702 women (mean age 59 years) from the Framingham Heart Study. Eight single nucleotide polymorphisms in the genes for estrogen receptor alpha and estrogen receptor beta (ESR2) were tested for association with 5 LV measures: LV mass (LVM), LV wall thickness (LVWT), LV internal diameter at end-diastole and end-systole, and fractional shortening. Sex-specific multiple regression analyses were performed adjusting for age, weight, height, systolic and diastolic blood pressure, hypertension treatment, diabetes, and in women, menopausal status. RESULTS: In men, there was no evidence of association between the estrogen pathway polymorphisms tested and LV structure or function. In women, however, two polymorphisms, ESR2 rs1256031 and ESR2 rs1256059, in linkage disequilibrium with one another, were associated with LVM and LVWT (P = .0007 to .03); the association was most pronounced in those women with hypertension (P = .0006 to .01). The association did not appear to be explained by variation in blood pressure, plasma lipoprotein levels, or hyperglycemia. CONCLUSIONS: The ESR2 polymorphisms are associated with LV structural differences in women with hypertension in a community-based population. These data are consistent with the hypothesis that genetic factors may mediate part of the observed sex-based differences in LV structure and remodeling.