Genomewide Association Study Using a High-Density Single Nucleotide Polymorphism Array and Case-Control Design Identifies a Novel Essential Hypertension Susceptibility Locus in the Promoter Region of Endothelial NO Synthase
Abstract
Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37–1.73]; combined P=2.58 · 10−13). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25–1.44; P=1.032 · 10−14). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16–3.66) for systolic and 1.40 (95% CI: 0.25–2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.
Introduction
Essential hypertension (EH) is a clinical condition affecting a large proportion (25% to 30%) of the adult population and is a major risk factor for cardiovascular and renal diseases.1,2 It is a complex trait influenced by multiple susceptibility genes, environmental, and lifestyle factors and their interactions.3 In the last years, huge efforts have been performed in recruiting and genotyping tens of thousands of individuals and meta-analyzing dozens of cross-sectional, population-based studies. In spite of this, the research on the genetics of EH has been frustrated by the small predictive value of the discovered genetic variants and by the fact that these variants explain a small proportion of the phenotypic variation.4–13 EH is a late-onset disease and, therefore, the small discovered effect sizes could in part be because of the effect of misclassification, sample selection bias, and inappropriate phenotyping of cases and controls.9,14,15 The selection of cases and controls may have important effects on the results, because misclassification bias can lead to loss of power. For common traits, such as EH, this bias can be remedied by defining more stringent selection criteria, by recruiting hypernormal controls and adopting a more stringent case definition.14,15
The HYPERGENES Project pursued a 2-stage study to investigate novel genetic determinants of EH. Cases and controls were recruited from extensively characterized cohorts over many years in different European regions using standardized clinical ascertainment. Particular care was devoted to control selection. A large proportion of the sample has been followed for 5 to 10 years after DNA collection, allowing for the exclusion of controls that developed hypertension at a later age, thereby defining the hypernormal controls.
Methods
Study Population
Cases and controls were recruited from extensively characterized cohorts using standardized clinical ascertainment, collected over many years in different European regions (balanced within North Europe, continental Italy, and Sardinia). The inclusion criteria are described in the Methods (S1) section of the online Data Supplement (available at http://hyper.ahajournals.org ). To perform a genetic association with continuous blood pressure (BP) phenotypes, we considered 2 additional cohorts (FLEMENGHO-EPOGH, n=1514, and Wandsworth Heart & Stroke Study, n=306, see Methods [S2] of the online Data Supplement) that provided population-based data. Description of the different samples is reported in the Methods S2 section.
Genotyping and Imputation
Genotyping details are shown in Methods S3 through S6 of the online Data Supplement. Briefly, in the discovery phase, the samples were genotyped using the Illumina 1M-Duo array, and the imputation was performed with MACH16 using as reference the 1000 Genomes haplotypes (release June 2010; Method S3). To validate and fine map the genes found associated with EH in discovery phase, an Illumina custom chip of 14 055 markers was created starting from the list of best-associated and of candidate single nucleotide polymorphisms (SNPs) based on a priori biological knowledge (Methods S4 and S5). For the replication stage, we used the in silico data of rs3918226 from Anglo-Scandinavian Cardiac Outcomes Trial/AIBIII/NBS, BRIGHT, EPIC Turin, HYPEST, and NORDIL/MDC studies (Methods S6).
Statistical Analysis
All of the quality controls and statistical analyses were performed in accordance with the protocols written by Anderson et al17 and Clarke et al18 (Methods S7 through S9). We tested each SNP for association with hypertension using a logistic regression under an additive model with adjustment for sex and for the first 10 principal components. Combined analysis for discovery, validation, and replication results was conducted using METAL.19 The quantitative effect of rs3918226 on systolic BP and diastolic BP was tested on 2 additional population-based cohorts (Methods S2). Moreover, we tested for multiplicative interaction between rs3918226 and the most plausible interactive partners of the endothelial NO synthase (eNOS) gene, actin genes and heat shock protein (HSP) 90 genes (Methods S9). The quantitative effect of rs3918226 on systolic BP and diastolic BP has been tested on 2 additional population-based cohorts (FLEMENGHO-EPOGH and Wandsworth Heart & Stroke Study, see Methods S2). The recognition sequences for transcription factors in the eNOS region were searched using TRANSFAC20,21 and the TFSEARCH database22 (Methods S10).
Results
A classic 2-stage case-control strategy was used with a discovery phase of 1865 cases and 1750 controls (2294 males and 1321 females), all genotyped on the Illumina 1M Duo chip. The sample consisted of an ethnically diverse population (25.06% North Europeans, 38.70% Sardinians, and 36.24% continental Italy subjects). The discovery phase was followed by a validation phase of an additional 1385 cases and 1246 controls (1417 males and 1214 females). According to ethnicity, the validation sample was composed of 1262 North Europeans (47.97%), 788 Sardinians (29.95%), and 581 continental Italians (22.08%). Tables S1 and S2 (available in the online Data Supplement) show the demographic characteristics and baseline measures.
Principal component analysis of the genotype data were carried out to find the major axes of variation used as covariates to correct for population stratification.23 The discovery samples in the principal component map showed 3 (roughly) equal-sized distinct clusters corresponding with the 3 main ethnic groups, as expected from the study design (Figure S1). All of the association analyses were adjusted for the ancestry principal components and sex by including them as covariates in the logistic regression model. In addition, genomic control correction was applied (because genomic inflation factor was 1.04). In the discovery phase, 90 SNPs (57% intragenic) with P value <1 · 10−4 were identified after genomic control (Figure S2 and Table S4). The most promising SNPs were genotyped in the validation samples using an Illumina Infinium Custom chip. The meta-analysis of the discovery and validation data revealed SNP rs3918226 to be associated with EH in whites, reaching a Pcombined of 2.58 · 10−13 and odds ratio (OR) of 1.54 per T allele (95% CI: 1.37–1.73) under an additive model (Figure 1 and Table 1 and Figure S4). Estimated ORs in the discovery and validation samples were consistent across the different white populations of the HYPERGENES sample (Figure S5).
Marker Name | Chr | Position | Effect/Other Allele | Gene | OR Discovery | P Discovery | OR Validation | P Validation | OR Combined | CI Combined | Inverse Variance-Weighted P Combined | Z Score P Combined |
---|---|---|---|---|---|---|---|---|---|---|---|---|
rs3918226 | 7 | 150321109 | T/C | NOS3 | 1.425 | 4.81E-06 | 1.71 | 2.55E-09 | 1.538 | 1.372–1.726 | 1.98E-13 | 2.58E-13 |
rs341408 | 15 | 58928982 | G/A | RORA | 0.786 | 1.74E-06 | 0.956 | 4.29E-01 | 0.856 | 0.79–0.92 | 3.98E-05 | 2.79E-05 |
rs4976593 | 5 | 167710021 | G/A | WWC1 | 1.27 | 3.75E-06 | 1.045 | 4.60E-01 | 1.169 | 1.08–1.26 | 6.64E-05 | 5.29E-05 |
rs631208 | 16 | 9307225 | G/A | RP11-473I1.1 | 0.798 | 8.09E-06 | 0.951 | 3.84E-01 | 0.862 | 0.80–0.93 | 8.89E-05 | 6.36E-05 |
rs7907270 | 10 | 78550949 | G/A | KCNMA1 | 1.27 | 2.35E-06 | 0.989 | 8.53E-01 | 1.141 | 1.06–1.23 | 5.75E-04 | 4.25E-04 |
rs10519080 | 15 | 58925751 | G/A | RORA | 1.369 | 5.79E-06 | 0.979 | 7.95E-01 | 1.187 | 1.07–1.31 | 1.09E-03 | 8.49E-04 |
rs1406891 | 6 | 161107070 | G/A | PLG | 1.251 | 3.99E-06 | 0.949 | 3.50E-01 | 1.112 | 1.03–1.19 | 3.87E-03 | 2.97E-03 |
rs783182 | 6 | 161088538 | G/A | PLG | 0.797 | 2.95E-06 | 1.068 | 2.42E-01 | 0.902 | 0.84–0.97 | 5.31E-03 | 4.15E-03 |
rs1084656 | 6 | 161101282 | C/A | PLG | 1.243 | 6.67E-06 | 0.936 | 2.39E-01 | 1.103 | 1.03–1.18 | 7.66E-03 | 6.35E-03 |
rs783145 | 6 | 161072439 | G/A | PLG | 0.788 | 8.53E-07 | 1.102 | 8.45E-02 | 0.909 | 0.84–0.98 | 9.27E-03 | 6.85E-03 |
rs1247558 | 6 | 161110189 | G/A | PLG | 1.24 | 8.30E-06 | 0.932 | 2.14E-01 | 1.100 | 1.02–1.18 | 9.42E-03 | 7.93E-03 |
The table shows association results (OR and P values) for discovery and for validation samples and for the combined analysis (both inverse variance weighting and z score meta-analysis). P values and ORs with the associated 95% CIs have been calculated under an additive model using logistic regression adjusted for sex and principal components. To retrieve information about single nucleotide polymorphisms and their genomic context (the nearest gene) we used the hg18 (National Center for Biotechnology Information 36) assembly. OR indicates odds ratio; P, P values; CI, confidence interval; Chr, chromosome; SNP, single nucleotide polymorphism.
The polymorphism rs3918226 maps to the promoter region of the eNOS gene (−665 C>T, NOS3).24,25 The T-allele frequencies in the present study are 13.8% in cases and 8.9% in controls. SNP rs3918226 is monomorphic in the nonwhite HYPERGENES samples (Wandsworth Heart & Stroke Study cohort) and African and Asian HapMap samples. The second best hit chr7:150,314,954 (G/A SNP, minor allele frequency of A allele=3%) with P value 2.46 · 10−6 and OR 2.25 was imputed based on the 1000 Genomes haplotypes (release June 2010); its imputation quality was very high (r2-hat=0.94). Unfortunately we could not replicate the observation in validation because of low imputation quality. An additional 7 SNPs within eNOS gene showed significant P values (1 · 10−3<P<1 · 10−5): rs2853792 (intronic, Pcombined=7.76 · 10−5), rs1549758 (coding, Pcombined=3.32 · 10−4), rs1800779 (intronic, Pcombined=1.16 · 10−3), rs6951150 (intergenic, Pcombined=1.64 · 10−3), rs743507 (intronic, Pcombined=1.76 · 10−3), rs1800780 (intronic, Pcombined=1.96 · 10−3), and rs1800783 (intronic, Pcombined=2.89 · 10−3; Figure 1).
Table 1 shows also other significant SNPs with P values between 1 · 10−3 and 1 · 10−5 mapping different genes as calcium-activated potassium channel subunit α-1 (KCNMA1), plasminogen (PLG), retinoid-related orphan receptor-α (RORA), and WW domain-containing protein 1 (WWC1). Moreover, the signals of SNPs presented previously in literature are in our study in the same direction as the original studies,5,6,8 showing evidence of a marginally significant association in HYPERGENES (Table S5).
We meta-analyzed rs3918226 using in silico data from Anglo-Scandinavian Cardiac Outcomes Trial/AIBIII/NBS, BRIGHT, EPIC-Turin, HYPEST, and NORDIL/MDC samples (Methods S2 and S6), resulting in an overall OR of 1.34 per T allele (95% CI: 1.25–1.44; Pcombined=1.032 · 10−14; Table 2 and Figure 2) for a total of 21 714 subjects. Because case and control definitions differed between HYPERGENES and the in silico replication samples, the ORs are not directly comparable. In our study, the P value of heterogeneity calculated for HYPERGENES samples is 0.13. It decreased slightly but remained nonsignificant, as expected, when EPIC-Turin was also considered together in the meta-analysis (P=0.092), because the recruitment criteria for cases and controls were identical. Conversely, the heterogeneity increased significantly (P=0.005) when HYPERGENES samples were meta-analyzed with all of the other samples (Anglo-Scandinavian Cardiac Outcomes Trial/AIBIII/NBS, BRIGHT, HYPEST, and NORDIL/MDC).
Variable | Study | Sample Size | OR | SE | 95% CI | P |
---|---|---|---|---|---|---|
HYPERGENES samples | HYPERGENES discovery | 3596 | 1.43 | 0.11 | 1.224–1.657 | 4.81E–06 |
HYPERGENES validation | 2610 | 1.71 | 0.155 | 1.440–2.049 | 2.55E–09 | |
Combined analysis HYPERGENES | 6206 | 1.54 | 0.038 | 1.372–1.726 | 2.58E–13 | |
Replication samples | ASCOT/AIBIII/NBS | 4049 | 1.06 | 0.092 | 0.895–1.256 | 4.97E–01 |
BRIGHT | 3641 | 1.39 | 0.126 | 1.168–1.663 | 2.32E–04 | |
EPIC Turin | 2714 | 1.28 | 0.126 | 1.050–1.551 | 1.44E–02 | |
HYPEST | 1204 | 1.13 | 0.236 | 0.754–1.705 | 5.45E–01 | |
NORDIL/MDC | 3900 | 1.25 | 0.124 | 1.030–1.519 | 2.40E–02 | |
Combined Analysis of Replication Samples | 15 508 | 1.23 | 0.056 | 1.125–1.344 | 6.50E–06 | |
Meta-analysis | 21 714 | 1.34* | 1.248–1.437† | 1.032E–14‡ | 6.198E–16§ |
Top section shows association results (odds ratios, SEs, CIs, and P values) for discovery, validation, and combined analysis of the HYPERGENES samples. Middle section shows results for ASCOT/AIBIII/NBS, BRIGHT, Epic Turin, HYPEST, and NORDIL/MDC studies and combined analysis of replication in silico samples. Bottom section shows meta-analysis results for all of the samples using both the z score and inverse variance-weighted P value methods.
*
Data are OR combined.
†
Data are 95% CI combined.
‡
Data are combined P (z score).
§
Data are combined P (inverse variance weighted).
Moreover, we tested for epistatic multiplicative interactions between eNOS rs3918226 and all of the available polymorphisms in genes known to be involved in targeting and regulating the overall availability of eNOS at the cell membrane26–28: actin genes (ACTA1, ACTA2, ACTB, ACTG1, and ACTG2)29,30 and HSP90 genes (HSP90AA1, HSP90AA2, and HSP90AB1).26 Nominally significant interactions were observed between rs3918226 and rs13447427 (P=1.34 · 10−3) in actin-β gene (ACTB), rs7503750 (P=1.57 · 10−3) in actin-γ1 (ACTG1), and rs4922796 and rs17309979 (P=3.47 · 10−3, P=4.88 · 10−3) in HSP-α2 (HSP90AA2; Table S6). When controlling for multiple testing, these interactions remained significant at a false discovery rate of 20%.
The quantitative analysis confirmed the qualitative observation. In fact, the β coefficient of the regression between systolic BP or diastolic BP with rs3918226 is, respectively, 1.91 (95% CI: 0.16–3.66) and 1.40 (95% CI: 0.25–2.55) per T allele. The coefficient is the effect size on BP in millimeter of mercury per coded allele based on an additive genetic model. The BP distribution according to rs3918226 genotype is shown in Table S7.
Because rs3918226 maps to the promoter region of eNOS, we tested whether it may fall into a regulatory binding site. Using the PATCH algorithm of TRANSFAC database,21 we characterized a putative binding site for transcription factors of the ETS family directly next to rs3918226. The ETS family members are present in endothelial cells and participated in activation of the eNOS promoter.31 Using the TFSEARCH tool,22 we confirmed this finding with a score of 87.3.
We also tested the degree of evolutionary conservation of rs3918226 locus in primates and placental mammals using the conservation track of the University of California, Santa Cruz genome browser. Figure S6 shows that the region in which rs3918226 lies is conserved from placental mammals to primates.
Discussion
EH is a complex clinical condition representing the main risk factor responsible for renal and cardiovascular complications. The HYPERGENES Project investigated undiscovered associations between genetic variants and EH pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited in different European regions.
We discovered rs3918226 in the promoter region of the eNOS gene to be significantly associated with hypertension (OR: 1.54 [95% CI: 1.37–1.73]; P=2.58 · 10−13). The result was confirmed by meta-analyzing in silico data for a total of 21714 subjects (OR: 1.34 [95% CI: 1.25–1.44]; P=1.032 · 10−14). We observed heterogeneity in the findings of meta-analysis (P=0.005 for Q test of heterogeneity) that could be attributed to both different sample sizes and recruitment criteria not directly comparable between HYPERGENES and the in silico replication samples (Figure 2).
The quantitative effect of rs3918226 was also estimated in continuous BP phenotypes, resulting in a β-coefficient of 1.91 for systolic BP and 1.40 for diastolic BP, despite the low P values of the regression probably because of the low sample size. This finding reinforces the observation on the qualitative phenotype.
We identified a potential transcription factor binding site for the ETS family domain directly next to rs3918226. The members of ETS family, as ETS-1 and ELF-1, are essential factors for the activation of the eNOS promoter.31 This suggests that, by affecting transcription factor–binding affinity, rs3918226 might modulate the transcription of the eNOS gene.
It is also worth noting that the region in which rs3918226 lies is conserved from placental mammals to primates. We propose rs3918226 as a novel susceptibility SNP, because among the genomewide association studies so far published, this is the first that points to eNOS: the novelty of the rs39118226 finding is that the association between eNOS and hypertension has been found in whites using a genomewide association study approach.
The use of the Illumina 1M array and Human CVD BeadArray was crucial in detecting the association, because rs3918226 is not present on other commercial arrays.32 Other than being poorly covered by other genotyping platforms, the region has a relatively high recombination rate toward the coding region (Figure 1). This has resulted in low linkage disequilibrium with markers present on older platforms (eg, rsq-hat <0.2 for Affy500K platform). These facts largely limited the potential to replicate our finding using data from other genomewide association studies samples, almost all of which relied on older platforms.
Indeed, eNOS has been found inconsistently associated with hypertension with several underpowered candidate gene studies, many of which only focused on a few variants with relatively small numbers of cases and controls compared with the large sample sizes of genomewide association studies. Positive studies were substantially on Asian cohorts,33–35 whereas the majority were negative in whites, as summarized in a recent meta-analysis.36 The polymorphisms studied in our white sample G894T (rs1799983) and T-786C (rs2070744) did not reach genomewide significant association with hypertension. If looked with candidate gene threshold, the P value and the sample size of the present study by far outnumber all of the other published so far. rs1799983 was associated with EH with a P value of 2.63×10−3 (OR=1.038) and rs2070744 with a P value of 6.42×10−4 (OR=1.04), as shown in Table S8. To summarize, the ORs are clinically irrelevant. We underline the low linkage disequilibrium between rs3918226 and rs1799983 (R2=0.16) and rs2070744 (R2=0.17), suggesting that these 2 SNPs are independent from rs3918226 and do not have any additional effect on the phenotype.
There is considerable biological evidence linking eNOS with hypertension and hypertension-associated cardiovascular target organ damage.37 eNOS, which catalyzes the synthesis of NO by vascular endothelium, is responsible for the vasodilator tone that is fundamental for the regulation of BP. Furthermore, eNOS is a critical mediator of cardiovascular homeostasis through regulation of blood vessels diameter and of the maintenance of an antiproliferative and antiapoptotic environment.
Because NO is highly active, it cannot be stored inside producing cells. Indeed, eNOS signaling capacity must be controlled, at least in part, by regulating its targeting from Golgi apparatus to plasma membrane by its compartmentalization within the plasma membrane and by its later internalization from the plasma membrane to the cytoplasm. eNOS is a dually acylated peripheral membrane protein that is targeted to endothelial plasmalemmal caveolae through an interaction with the caveolae structural protein, caveolin 1 (Cav1).26,27 Cav1 inhibition of eNOS is lessened by calmodulin (Calm) causing dissociation of eNOS from caveolin. This regulatory mechanism is further altered by HSP90,27 which binds to eNOS and facilitates displacement of Cav1 by Calm. Moreover, eNOS directly interacts with actin cytoskeleton.29 Recently, Kondrikov et al30 added that β-actin is associated with the eNOS oxygenase domain increasing eNOS activity and NO production. To explore such a pathway, we tested the interaction between the discovered eNOS SNP and its most plausible interactive partners. We observed nominally significant interactions between rs3918226 and rs13447427 in ACTB, rs7503750 in ACTG1, and rs4922796 and rs17309979 in the HSP90AA2 gene.
In conclusion, with a stringent case-control design and a population-based study, we identified a novel hypertension susceptibility locus in the promoter region of eNOS with a relatively high effect size. Our finding could provide new insights into the mechanism of vascular regulation and could help in better understanding the genetics of EH. Furthermore, we believe that this indication can be useful to guide fine mapping or sequencing efforts to single out causal variants.
Perspectives
Further investigations and high-throughput sequencing of region of interest will help to identify the real causal variant and to clarify the functional role of eNOS in EH.
Acknowledgments
The complete list is reported in supplemental material.
Supplemental Material
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Sources of Funding
This work was supported by the HYPERGENES project (European Network for Genetic-Epidemiological Studies: building a method to dissect complex genetic traits, using essential hypertension as a disease model), grant HEALTH-2007-201550, funded by the European Union within the FP7. T.J. was supported by the Wellcome Trust (grant 093078/Z/10/Z). J.C. has received research grants from Servier International and from the National Health and Medical Research Council (Australia), administered through the University of Sydney, for the Perindopril Protection Against Recurrent Stroke Study and ADVANCE Trials and for the ADVANCE posttrial follow-up study. M.J.C. has received British Heart Foundation grant support for developing CVD bead array and KASPAr genotyping.
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© 2011 American Heart Association, Inc.
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Received: 15 September 2011
Revision received: 6 October 2011
Accepted: 21 November 2011
Published online: 19 December 2011
Published in print: February 2012
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T.J. received honoraria for speaking about these studies at scientific meetings. M.J.C. was supported by British Heart Foundation grant for developing CVD BeadArray and KASPAr assay. J.C. received honoraria for speaking about the PROGRESS and ADVANCE Trials and for the ADVANCE-Post Trial follow-up study.
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