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1.  The Causal Effect of Vitamin D Binding Protein (DBP) Levels on Calcemic and Cardiometabolic Diseases: A Mendelian Randomization Study 
PLoS Medicine  2014;11(10):e1001751.
In this study, Richards and colleagues undertook a Mendelian randomization study to determine whether vitamin D binding protein (DBP) levels have a causal effect on common calcemic and cardiometabolic diseases. They concluded that DBP has no demonstrable causal effect on any of the diseases or traits investigated here, except Vit D levels.
Please see later in the article for the Editors' Summary
Observational studies have shown that vitamin D binding protein (DBP) levels, a key determinant of 25-hydroxy-vitamin D (25OHD) levels, and 25OHD levels themselves both associate with risk of disease. If 25OHD levels have a causal influence on disease, and DBP lies in this causal pathway, then DBP levels should likewise be causally associated with disease. We undertook a Mendelian randomization study to determine whether DBP levels have causal effects on common calcemic and cardiometabolic disease.
Methods and Findings
We measured DBP and 25OHD levels in 2,254 individuals, followed for up to 10 y, in the Canadian Multicentre Osteoporosis Study (CaMos). Using the single nucleotide polymorphism rs2282679 as an instrumental variable, we applied Mendelian randomization methods to determine the causal effect of DBP on calcemic (osteoporosis and hyperparathyroidism) and cardiometabolic diseases (hypertension, type 2 diabetes, coronary artery disease, and stroke) and related traits, first in CaMos and then in large-scale genome-wide association study consortia. The effect allele was associated with an age- and sex-adjusted decrease in DBP level of 27.4 mg/l (95% CI 24.7, 30.0; n = 2,254). DBP had a strong observational and causal association with 25OHD levels (p = 3.2×10−19). While DBP levels were observationally associated with calcium and body mass index (BMI), these associations were not supported by causal analyses. Despite well-powered sample sizes from consortia, there were no associations of rs2282679 with any other traits and diseases: fasting glucose (0.00 mmol/l [95% CI −0.01, 0.01]; p = 1.00; n = 46,186); fasting insulin (0.01 pmol/l [95% CI −0.00, 0.01,]; p = 0.22; n = 46,186); BMI (0.00 kg/m2 [95% CI −0.01, 0.01]; p = 0.80; n = 127,587); bone mineral density (0.01 g/cm2 [95% CI −0.01, 0.03]; p = 0.36; n = 32,961); mean arterial pressure (−0.06 mm Hg [95% CI −0.19, 0.07]); p = 0.36; n = 28,775); ischemic stroke (odds ratio [OR] = 1.00 [95% CI 0.97, 1.04]; p = 0.92; n = 12,389/62,004 cases/controls); coronary artery disease (OR = 1.02 [95% CI 0.99, 1.05]; p = 0.31; n = 22,233/64,762); or type 2 diabetes (OR = 1.01 [95% CI 0.97, 1.05]; p = 0.76; n = 9,580/53,810).
DBP has no demonstrable causal effect on any of the diseases or traits investigated here, except 25OHD levels. It remains to be determined whether 25OHD has a causal effect on these outcomes independent of DBP.
Please see later in the article for the Editors' Summary
Editors' Summary
Vitamin D deficiency is an increasingly common public health concern. According to some estimates, more than a billion people worldwide may be vitamin D deficient. Indeed, many people living in the US and Europe (in particular, elderly people, breastfed infants, people with dark skin, and obese individuals) have serum (circulating) 25-hydroxy-vitamin D (25OHD) levels below 50 nmol/l, the threshold for vitamin D deficiency. Vitamin D helps the body absorb calcium, a mineral that is essential for healthy bones. Consequently, vitamin D deficiency can lead to calcemic diseases such as rickets (a condition that affects bone development in children), osteomalacia (soft bones in adults), and osteoporosis (a condition in which the bones weaken and become susceptible to fracture). We get most of our vitamin D needs from our skin, which makes vitamin D after exposure to sunlight. Vitamin D is also found naturally in oily fish and eggs, and is added to some other foods, including cereals and milk, but some people need to take vitamin D supplements to avoid vitamin D deficiency.
Why Was This Study Done?
Observational studies have reported that the low levels of serum 25OHD and serum vitamin D binding protein (DBP, a key determinant of serum 25OHD level) are both associated with the risk of several common diseases and traits. Such studies have implicated vitamin D deficiency in cardiometabolic disease (cardiovascular diseases that affect the heart and/or blood vessels and metabolic diseases that affect the cellular chemical reactions needed to sustain life), in some cancers, and in Alzheimer disease. But observational studies cannot prove that vitamin D deficiency or DBP levels actually cause any of these diseases. So, for example, an observational study might report an association between vitamin D deficiency and type 2 diabetes (a metabolic disease), but the individuals who develop type 2 diabetes might share another unknown characteristic that is actually responsible for disease development (a confounding factor). Alternatively, type 2 diabetes might reduce circulating vitamin D levels (reverse causation). Here, the researchers undertake a Mendelian randomization study to determine whether circulating DBP levels have causal effects on calcemic and cardiometabolic diseases. In Mendelian randomization, causality is inferred from associations between genetic variants that mimic the influence of a modifiable environmental exposure and the outcome of interest. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. So, if low DBP levels lead to low serum 25OHD levels, and vitamin D levels have a causal effect on common diseases, genetic variants associated with low DBP levels should be associated with the development of common diseases.
What Did the Researchers Do and Find?
The researchers analyzed the association between a genetic variant called single nucleotide polymorphism (SNP) rs2282679, which is known to alter DBP levels, and calcemic and cardiometabolic diseases and related traits in 2,254 participants in the Canadian Multicentre Osteoporosis Study (CaMos). The researchers report that there was a strong association between SNP rs2282679 and both serum DBP and 25OHD levels among the CaMos participants. However, there were no significant associations (associations unlikely to have occurred by chance) between SNP rs2282679 and calcium level, osteoporosis, or several cardiometabolic diseases, including heart attacks and diabetes. Moreover, when the researchers examined publically available genome-wide association study data collected by several international consortia investigating genetic influences on disease, they found no significant associations between rs2282679 and a wide range of calcemic and cardiometabolic diseases.
What Do These Findings Mean?
In this Mendelian randomization study, DBP level had no demonstrable causal effect on any of the calcemic or cardiometabolic diseases or traits investigated, except 25OHD level. Because most of the participants in CaMos and the international consortia were of European descent, these findings are applicable only to people of European ancestry. Moreover, like all Mendelian randomization studies, the reliability of these findings depends on several assumptions made by the researchers. Notably, although this study strongly suggests that DBP level does not have a causal influence on several common diseases, it remains to be determined whether 25OHD has a causal effect on any calcemic or cardiometabolic outcomes independent of DBP level.
Additional Information
Please access these websites via the online version of this summary at
The UK National Health Service Choices website provides information about vitamin D and about how to get vitamin D from sunshine; “Behind the Headlines” articles describe a recent observational study that reported an association between vitamin D deficiency and Alzheimer disease and the media coverage of this study, other health claims made for vitamin D, and a randomized control trial that questioned the role of vitamin D in disease
The US National Institutes of Health Office of Dietary Supplements provides information about vitamin D (in English and Spanish)
The US Centers for Disease Control and Prevention provides information about the vitamin D status of the US population
MedlinePlus has links to further information about vitamin D (in English and Spanish)
Information about the Canadian Multicentre Osteoporosis Study is available
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
PMCID: PMC4211663  PMID: 25350643
2.  Variants in CXADR and F2RL1 are associated with blood pressure and obesity in African-Americans in regions identified through admixture mapping 
Journal of hypertension  2012;30(10):1970-1976.
Genetic variants in 296 genes in regions identified through admixture mapping of hypertension, BMI, and lipids were assessed for association with hypertension, blood pressure, BMI, and HDL-C.
This study identified coding SNPs identified from HapMap2 data that were located in genes on chromosomes 5, 6, 8, and 21, where ancestry association evidence for hypertension, BMI or HDL-C was identified in previous admixture mapping studies. Genotyping was performed in 1,733 unrelated African-Americans from the National Heart, Lung and Blood Institute’s (NHLBI) Family Blood Pressure Project, and gene-based association analyses were conducted for hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), BMI, and HDL-C. A gene score based on the number of minor alleles of each SNP in a gene was created and used for gene-based regression analyses, adjusting for age, age2, sex, local marker ancestry, and BMI, as applicable. An individual’s African ancestry estimated from 2,507 ancestry-informative markers was also adjusted for to eliminate any confounding due to population stratification.
CXADR (rs437470) on chromosome 21 was associated with SBP and DBP with or without adjusting for local ancestry (p < 0.0006). F2RL1 (rs631465) on chromosome 5 was associated with BMI (p = 0.0005). Local ancestry in these regions was associated with the respective traits as well.
This study suggests that CXADR and F2RL1 likely play important roles in blood pressure and obesity variation, respectively; and these findings are consistent with other studies, so replication and functional analyses are necessary.
PMCID: PMC3575678  PMID: 22914544
Blood pressure; Obesity; African Americans; Genetic Association Studies
3.  Proteasome Modulator 9 SNPs are linked to hypertension in type 2 diabetes families 
Chromosome 12q24 was recently associated with hypertension. Proteasome Modulator 9 (PSMD9) lies in the 12q24 locus and is in linkage with MODY3, type 2 diabetes (T2D), microvascular and macrovascular pathology, carpal tunnel syndrome, and hypercholesterolemia in Italian families.
Our goal was to determine whether PSMD9 is linked to elevated blood pressure/hypertension in T2D families.
We characterized the Italian T2D families' members for presence and/or absence of elevated blood pressure (≥ 130/80) and/or hypertension. The phenotypes were described as unknown in all cases in which the diagnosis was either unclear or the data were not available for the subject studied. We tested in the 200 Italians families for the presence of the linkage of the PSMD9 T2D risk single nucleotide polymorphisms (SNPs) IVS3+nt460 A > G, IVS3+nt437 T > C and E197G A > G with elevated blood pressure/hypertension. The non-parametric linkage analysis was performed for this qualitative phenotype by using the Merlin software; the Lod score and correspondent P-value were calculated. Parametric linkage analysis was also performed. For the significant linkage score, 1000 replicates were run to calculate the empirical P-value.
The PSMD9 gene SNPs studied are in linkage with elevated blood pressure/hypertension in our Italian families.
We conclude that the PSMD9 gene and/or any variant in linkage disequilibrium with the SNPs studied contribute to the linkage to hypertension within our family dataset. This is the first report of PSMD9 linkage to hypertension within the 12q24 locus.
PMCID: PMC3179710  PMID: 21871126
4.  Adrenergic Alpha-1 Pathway Is Associated with Hypertension among Nigerians in a Pathway-focused Analysis 
PLoS ONE  2012;7(5):e37145.
The pathway-focused association approach offers a hypothesis driven alternative to the agnostic genome-wide association study. Here we apply the pathway-focused approach to an association study of hypertension, systolic blood pressure (SBP), and diastolic blood pressure (DBP) in 1614 Nigerians with genome-wide data.
Methods and Results
Testing of 28 pathways with biological relevance to hypertension, selected a priori, containing a total of 101 unique genes and 4,349 unique single-nucleotide polymorphisms (SNPs) showed an association for the adrenergic alpha 1 (ADRA1) receptor pathway with hypertension (p<0.0009) and diastolic blood pressure (p<0.0007). Within the ADRA1 pathway, the genes PNMT (hypertension Pgene<0.004, DBP Pgene<0.004, and SBP Pgene<0.009, and ADRA1B (hypertension Pgene<0.005, DBP Pgene<0.02, and SBP Pgene<0.02) displayed the strongest associations. Neither ADRA1B nor PNMT could be the sole mediator of the observed pathway association as the ADRA1 pathway remained significant after removing ADRA1B, and other pathways involving PNMT did not reach pathway significance.
We conclude that multiple variants in several genes in the ADRA1 pathway led to associations with hypertension and DBP. SNPs in ADRA1B and PNMT have not previously been linked to hypertension in a genome-wide association study, but both genes have shown associations with hypertension through linkage or model organism studies. The identification of moderately significant (10−2>p>10−5) SNPs offers a novel method for detecting the “missing heritability” of hypertension. These findings warrant further studies in similar and other populations to assess the generalizability of our results, and illustrate the potential of the pathway-focused approach to investigate genetic variation in hypertension.
PMCID: PMC3353888  PMID: 22615923
5.  Genome-wide scan identifies CDH13 as a novel susceptibility locus contributing to blood pressure determination in two European populations 
Human Molecular Genetics  2009;18(12):2288-2296.
Hypertension is a complex disease that affects a large proportion of adult population. Although approximately half of the inter-individual variance in blood pressure (BP) level is heritable, identification of genes responsible for its regulation has remained challenging. Genome-wide association study (GWAS) is a novel approach to search for genetic variants contributing to complex diseases. We conducted GWAS for three BP traits [systolic and diastolic blood pressure (SBP and DBP); hypertension (HYP)] in the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) S3 cohort (n = 1644) recruited from general population in Southern Germany. GWAS with 395 912 single nucleotide polymorphisms (SNPs) identified an association between BP traits and a common variant rs11646213 (T/A) upstream of the CDH13 gene at 16q23.3. The initial associations with HYP and DBP were confirmed in two other European population-based cohorts: KORA S4 (Germans) and HYPEST (Estonians). The associations between rs11646213 and three BP traits were replicated in combined analyses (dominant model: DBP, P = 5.55 × 10–5, effect –1.40 mmHg; SBP, P = 0.007, effect –1.56 mmHg; HYP, P = 5.30 × 10−8, OR = 0.67). Carriers of the minor allele A had a decreased risk of hypertension. A non-significant trend for association was also detected with severe family based hypertension in the BRIGHT sample (British). The novel susceptibility locus, CDH13, encodes for an adhesion glycoprotein T-cadherin, a regulator of vascular wall remodeling and angiogenesis. Its function is compatible with the BP biology and may improve the understanding of the pathogenesis of hypertension.
PMCID: PMC2685752  PMID: 19304780
6.  Sequence Analysis of Six Blood Pressure Candidate Regions in 4,178 Individuals: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Targeted Sequencing Study 
PLoS ONE  2014;9(10):e109155.
Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes – ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3 – were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP).
Methods and Results
Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (≥50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF≤1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r2 = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r2 = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures.
Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.
PMCID: PMC4183565  PMID: 25275628
7.  A Genome-Wide Search for Linkage of Estimated Glomerular Filtration Rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND) 
PLoS ONE  2013;8(12):e81888.
Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR.
Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula.
The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4×10−5) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5×10−4) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5×10−4) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome.
The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN.
PMCID: PMC3866106  PMID: 24358131
8.  Suggestive linkage detected for blood pressure related traits on 2q and 22q in the population on the Samoan islands 
BMC Medical Genetics  2009;10:107.
High blood pressure or hypertension is a major risk factor involved in the development of cardiovascular diseases. We conducted genome-wide variance component linkage analyses to search for loci influencing five blood pressure related traits including the quantitative traits systolic blood pressure (SBP), diastolic blood pressure (DBP) and pulse pressure (PP), the dichotomous trait hypertension (HT) and the bivariate quantitative trait SBP-DBP in families residing in American Samoa and Samoa, as well as in the combined sample from the two polities. We adjusted the traits for a number of environmental covariates such as smoking, alcohol consumption, physical activity and material life style.
We found suggestive univariate linkage for SBP on chromosome 2q35-q37 (LOD 2.4) and for PP on chromosome 22q13 (LOD 2.2), two chromosomal regions that recently have been associated with SBP and PP, respectively.
We have detected additional evidence for a recently reported locus associated with SBP on chromosome 2q and a susceptibility locus for PP on chromosome 22q. However, differences observed between the results from our three partly overlapping genetically homogenous study samples from the Samoan islands suggest that additional studies should be performed in order to verify these results.
PMCID: PMC2770055  PMID: 19852796
9.  Autonomic function in hypertension: Role of genetic variation at the catecholaminestorage vesicle protein chromogranin B (CHGB) 
Hypertension is a complex trait with deranged autonomic control of the circulation. Chromogranin B (CHGB) is the most abundant core protein in human catecholamine secretory vesicles, playing an important role in their biogenesis. Does common inter-individual variation at the CHGB locus contribute to phenotypic variation in CHGB and catecholamine secretion, autonomic stability of the circulation, or blood pressure in the population?
Methods and Results
To probe inter-individual variability in CHGB, we systematically studied polymorphism across the locus by re-sequencing CHGB (~6 kbp footprint spanning the promoter, 5 exons, exon/intron borders, UTRs) in n=160 subjects (2n=320 chromosomes) of diverse biogeographic ancestries. We identified 53 SNPs, of which 22 were common. We then studied n=1182 subjects drawn from the most extreme BP values in the population (highest and lowest 5th %iles), typing 4 common polymorphisms spanning the ~14 kbp locus. Sliding-window haplotype analysis indicated BP associations peaking in the 5′/promoter region, and most prominent in men, and a peak effect in the proximal promoter at variant A-261T (A>T), accounting for ~8/~6 mmHg SBP/DBP in males. The promoter allele (A-261) that was a predictor of higher DBP and SBP was also associated with lower circulating/plasma CHGB concentration (CHGB439-451 epitope) in twin pairs. In twins, the same CHGB variants that were predictors of lower basal CHGB secretion were also associated with exaggerated catecholamine secretion and BP response to environmental (cold) stress; likewise, women displayed increased plasma CHGB439–451, but decreased catecholamine secretion as well as BP response to environmental stress. The effect of A-261T on CHGB expression was confirmed in chromaffin cells by site-directed mutagenesis on transfected CHGB promoter/luciferase reporter activity, and the allelic effects of A-261T on gene expression were directionally coordinate in cella and in vivo. To confirm these clinical associations experimentally, we undertook targeted homozygous (−/−) ablation of the mouse Chgb gene; knockout mice displayed substantially increased BP, by ~20/~18 mmHg SBP/DBP, confirming the mechanistic basis of our findings in humans.
We conclude that common genetic variation at the CHGB locus, especially in the proximal promoter, influences CHGB expression, and later catecholamine secretion and the early heritable responses to environmental stress, eventuating in changes in resting/basal BP in the population. Both the early (gene expression) and late (population BP) consequences of CHGB variation are sex-dependent. The results point to new molecular strategies for probing autonomic control of the circulation, and ultimately the susceptibility to and pathogenesis of cardiovascular disease states such as hypertension.
PMCID: PMC2792940  PMID: 20011129
Genetics; hypertension; gene expression; catecholamine
10.  Ordered subset linkage analysis supports a susceptibility locus for age-related macular degeneration on chromosome 16p12 
BMC Genetics  2004;5:18.
Age-related macular degeneration (AMD) is a complex disorder that is responsible for the majority of central vision loss in older adults living in developed countries. Phenotypic and genetic heterogeneity complicate the analysis of genome-wide scans for AMD susceptibility loci. The ordered subset analysis (OSA) method is an approach for reducing heterogeneity, increasing statistical power for detecting linkage, and helping to define the most informative data set for follow-up analysis. OSA assesses the linkage evidence in subsets of potentially more homogeneous families by rank-ordering family-specific lod scores with respect to trait-associated covariates or phenotypic features. Here, we present results of incorporating five continuous covariates into our genome-wide linkage analysis of 389 microsatellite markers in 62 multiplex families: Body mass index (BMI), systolic (SBP) and diastolic (DBP) blood pressure, intraocular pressure (IOP), and pack-years of cigarette smoking. Chromosome-wide significance of increases in nonparametric multipoint lod scores in covariate-defined subsets relative to the overall sample was assessed by permutation.
Using a correction for testing multiple covariates, statistically significant lod score increases were observed for two chromosomal regions: 14q13 with a lod score of 3.2 in 28 families with average IOP ≤ 15.5 (p = 0.002), and 6q14 with a lod score of 1.6 in eight families with average BMI ≥ 30.1 (p = 0.0004). On chromosome 16p12, nominally significant lod score increases (p ≤ 0.05), up to a lod score of 2.9 in 32 families, were observed with several covariate orderings. While less significant, this was the only region where linkage evidence was associated with multiple clinically meaningful covariates and the only nominally significant finding when analysis was restricted to advanced forms of AMD. Families with linkage to 16p12 had higher averages of SBP, IOP and BMI and were primarily affected with neovascular AMD. For all three regions, linkage signals at or very near the peak marker have previously been reported.
Our results suggest that a susceptibility gene on chromosome 16p12 may predispose to AMD, particularly to the neovascular form, and that further research into the previously suggested association of neovascular AMD and systemic hypertension is warranted.
PMCID: PMC481059  PMID: 15238159
11.  Association of ATP1B1, RGS5 and SELE polymorphisms with hypertension and blood pressure in African–Americans 
Journal of hypertension  2011;29(10):10.1097/HJH.0b013e32834b000d.
Although an increasing number of hypertension-associated genetic variants is being reported, replication of these findings in independent studies has been challenging. Several genes in a human chromosome 1q linkage region have been reported to be associated with hypertension. We examined polymorphisms in three of these genes (ATP1B1, RGS5 and SELE) in relation to hypertension and blood pressure in a cohort of African–Americans.
We genotyped 87 single nucleotide polymorphisms (SNPs) from the ATP1B1, RGS5 and SELE genes in a well characterized cohort of 968 African–Americans and performed a case–control study to identify susceptibility alleles for hypertension and blood pressure regulation. Single SNP and haplotype association testing was done under an additive genetic model with adjustment for age, sex, BMI and ancestry-by-genotype (principal components).
A total of 12 SNPs showed nominal association with hypertension and/or blood pressure. The strongest signal for hypertension was for rs2815272 in the RGS5 gene (P = 9.3 × 10–3). For SBP, rs3917420 in the SELE gene (P = 9.0 × 10–4) and rs4657251 in the RGS5 gene (P = 9.7 × 10–3) were the top hits. Effect size for each of these variants was approximately 2–3 mmHg. A five-SNP haplotype in the SELE gene also showed significant association with SBP after correction for multiple testing (P < 0.01).
These findings provide additional support for the genetic role of ATP1B1, RGS5 and SELE in hypertension and blood pressure regulation.
PMCID: PMC3862027  PMID: 21881522
African–Americans; candidate gene; haplotype; hypertension; single nucleotide polymorphism
12.  The role of SNP-loop diuretic interactions in hypertension across ethnic groups in HyperGEN 
Frontiers in Genetics  2013;4:304.
Blood pressure (BP) is significantly influenced by genetic factors; however, less than 3% of the BP variance has been accounted for by variants identified from genome-wide association studies (GWAS) of primarily European-descent cohorts. Other genetic influences, including gene-environment (GxE) interactions, may explain more of the unexplained variance in BP. African Americans (AA) have a higher prevalence and earlier age of onset of hypertension (HTN) as compared with European Americans (EA); responses to anti-hypertensive drugs vary across race groups. To examine potential interactions between the use of loop diuretics and HTN traits, we analyzed systolic (SBP) and diastolic (DBP) blood BP from 1222 AA and 1231 EA participants in the Hypertension Genetic Epidemiology Network (HyperGEN). Population-specific score tests were used to test associations of SBP and DBP, using a panel of genotyped and imputed single nucleotide polymorphisms (SNPs) for AA (2.9 million SNPs) and EA (2.3 million SNPs). Several promising loci were identified through gene-loop diuretic interactions, although no SNP reached genome-wide significance after adjustment for genomic inflation. In AA, SNPs in or near the genes NUDT12, CHL1, GRIA1, CACNB2, and PYHIN1 were identified for SBP, and SNPs near ID3 were identified for DBP. For EA, promising SNPs for SBP were identified in ESR1 and for DBP in SPATS2L and EYA2. Among these SNPs, none were common across phenotypes or population groups. Biologic plausibility exists for many of the identified genes, suggesting that these are candidate genes for regulation of BP and/or anti-hypertensive drug response. The lack of genome-wide significance is understandable in this small study employing gene-drug interactions. These findings provide a set of prioritized SNPs/candidate genes for future studies in HTN. Studies in more diversified population samples may help identify previously missed variants.
PMCID: PMC3872290  PMID: 24400021
blood pressure; hypertension; loop diuretic; gene-drug interaction; genome-wide association; african americans; european americans
13.  Follow-up of a major linkage peak on chromosome 1 reveals suggestive QTLs associated with essential hypertension: GenNet study 
Essential hypertension is a major cardiovascular risk factor and a large proportion of this risk is genetic. Identification of genomic regions consistently associated with hypertension has been difficult in association studies to date since this requires large sample sizes.
We previously published a large genome-wide linkage scan in Americans of African (AA) and European (EA) descent in the GenNet Network of the Family Blood Pressure Program (FBPP). A highly significant linkage peak was identified on chr1q spanning a region of 100cM. In the current study, we genotyped 1,569 SNPs under this linkage peak in 2,379 individuals in order to identify whether common genetic variants were associated with blood pressure (BP) at this locus.
Our analysis, using two different family-based association tests, provides suggestive evidence (P≤2×10-5) for a collection of single nucleotide polymorphisms (SNPs) associated with BP. In EAs, using diastolic BP as a quantitative phenotype, three variants located in or near the GPA33, CD247, and F5 genes, emerge as our top hits; for systolic BP, variants in GPA33, CD247, and REN are our best findings. No variant in AAs came close to suggestive evidence (P≥8×10-5) after multiple-test corrections.
In summary, we show that systematic follow-up of a linkage signal can help discover candidate variants for essential hypertension that require follow-up in yet larger samples. The failure to identify common variants is either due to low statistical power or the existence of rare coding variants in specific families or both, that require additional studies to clarify.
PMCID: PMC2783544  PMID: 19536175
essential hypertension; complex disease genetics; association mapping; F5; GPA33; CD247; REN
14.  Follow-up of a major linkage peak on chromosome 1 reveals suggestive QTLs associated with essential hypertension: GenNet study 
European Journal of Human Genetics  2009;17(12):1650-1657.
Essential hypertension is a major cardiovascular risk factor and a large proportion of this risk is genetic. Identification of genomic regions consistently associated with hypertension has been difficult in association studies to date as this requires large sample sizes.
We previously published a large genome-wide linkage scan in Americans of African (AA) and European (EA) descent in the GenNet Network of the Family Blood Pressure Program (FBPP). A highly significant linkage peak was identified on chr1q spanning a region of 100 cM. In this study, we genotyped 1569 SNPs under this linkage peak in 2379 individuals to identify whether common genetic variants were associated with blood pressure (BP) at this locus.
Our analysis, using two different family-based association tests, provides suggestive evidence (P≤2 × 10−5) for a collection of single nucleotide polymorphisms (SNPs) associated with BP. In EAs, using diastolic BP as a quantitative phenotype, three variants located in or near the GPA33, CD247, and F5 genes, emerge as our top hits; for systolic BP, variants in GPA33, CD247, and REN are our best findings. No variant in AAs came close to suggestive evidence after multiple-test corrections (P≥8 × 10−5).
In summary, we show that systematic follow-up of a linkage signal can help discover candidate variants for essential hypertension that require a follow-up in yet larger samples. The failure to identify common variants is either because of low statistical power or the existence of rare coding variants in specific families or both, which require additional studies to clarify.
PMCID: PMC2783544  PMID: 19536175
essential hypertension; complex disease genetics; association mapping
15.  Neuropeptide Y (NPY) 
This study sought to understand whether genetic variation at the Neuropeptide Y (NPY) locus governs secretion and stress responses in vivo as well as NPY gene expression in sympathochromaffin cells.
The NPY is a potent pressor peptide co-released with catecholamines during stress by sympathetic axons. Genome-wide linkage on NPY secretion identified a LOD (logarithm of the odds ratio) peak spanning the NPY locus on chromosome 7p15.
Our approach began with genomics (linkage and polymorphism determination), extended into NPY genetic control of heritable stress traits in twin pairs, established transcriptional mechanisms in transfected chromaffin cells, and concluded with observations on blood pressure (BP) in the population.
Systematic polymorphism tabulation at NPY (by re-sequencing across the locus: promoter, 4 exons, exon/intron borders, and untranslated regions; on 2n = 160 chromosomes of diverse biogeographic ancestries) identified 16 variants, of which 5 were common. We then studied healthy twin/sibling pairs (n = 399 individuals), typing 6 polymorphisms spanning the locus. Haplotype and single nucleotide polymorphism analyses indicated that proximal promoter variant ∇−880Δ (2-bp TG/—, Ins/Del, rs3037354) minor/Δ allele was associated with several heritable (h2) stress traits: higher NPY secretion (h2 = 73 ± 4%) as well as greater BP response to environmental (cold) stress, and higher basal systemic vascular resistance. Association of ∇−880Δ and plasma NPY was replicated in an independent sample of 361 healthy young men, with consistent allelic effects; genetic variation at NPY also associated with plasma NPY in another independent series of 2,212 individuals derived from Australia twin pairs. Effects of allele −880Δ to increase NPY expression were directionally coordinate in vivo (on human traits) and in cells (transfected NPY promoter/luciferase reporter activity). Promoter −880Δ interrupts a novel glucocorticoid response element motif, an effect confirmed in chromaffin cells by site-directed mutagenesis on the transfected promoter, with differential glucocorticoid stimulation of the motif as well as alterations in electrophoretic mobility shifts. The same −880Δ allele also conferred risk for hypertension and accounted for approximately 4.5/approximately 2.1 mm Hg systolic BP/diastolic BP in a population sample from BP extremes.
We conclude that common genetic variation at the NPY locus, especially in proximal promoter ∇−880Δ, disrupts glucocorticoid signaling to influence NPY transcription and secretion, raising systemic vascular resistance and early heritable responses to environmental stress, eventuating in elevated resting BP in the population. The results point to new molecular strategies for probing autonomic control of the human circulation and ultimately susceptibility to and pathogenesis of cardiovascular and neuropsychiatric disease states.
PMCID: PMC3687554  PMID: 23021333
genetics; glucocorticoid receptor; hypertension; neuropeptide Y
16.  Genome-Wide Linkage Screen for Systolic Blood Pressure in the Veterans Administration Genetic Epidemiology Study (VAGES) of Mexican-Americans and Confirmation of a Major Susceptibility Locus on Chromosome 6q14.1 
Human Heredity  2011;71(1):1-10.
Hypertension or high blood pressure is a strong correlate of diseases such as obesity and type 2 diabetes. We conducted a genome-wide linkage screen to identify susceptibility genes influencing systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Mexican-Americans from the Veterans Administration Genetic Epidemiology Study (VAGES).
Using data from 1,089 individuals distributed across 266 families, we performed a multipoint linkage analysis to localize susceptibility loci for SBP and DBP by applying two models. In model 1, we added a sensible constant to the observed BP values in treated subjects [Tobin et al.; Stat Med 2005;24:2911–2935] to account for antihypertensive use (i.e. 15 and 10 mm Hg to SBP and DBP values, respectively). In model 2, we fixed values of 140 mm Hg for SBP and 90 mm Hg for DBP, if the treated values were less than the standard referenced treatment thresholds of 140/90 mm Hg for hypertensive status. However, if the observed treated BP values were found to be above these standard treatment thresholds, the actual observed treated BP values were retained in order not to reduce them by substitution of the treatment threshold values.
The multipoint linkage analysis revealed strong linkage signals for SBP compared with DBP. The strongest evidence for linkage of SBP (model 1, LOD = 5.0; model 2, LOD = 3.6) was found on chromosome 6q14.1 near the marker D6S1031 (89 cM) in both models. In addition, some evidence for SBP linkage occurred on chromosomes 1q, 4p, and 16p. Most importantly, our major SBP linkage finding on chromosome 6q near marker D6S1031 was independently confirmed in a Caucasian population (LOD = 3.3). In summary, our study found evidence for a major locus on chromosome 6q influencing SBP levels in Mexican-Americans.
PMCID: PMC3152483  PMID: 21293138
Hypertension; Linkage; Antihypertensive medication; Genetic location; Heritability
17.  Adrenergic Polymorphism and the Human Stress Response 
Tyrosine hydroxylase (TH) is the rate-limiting enzyme in catecholamine biosynthesis. Does common genetic variation at human TH alter autonomic activity and predispose to cardiovascular disease? We undertook systematic polymorphism discovery at the TH locus, and then tested variants for contributions to sympathetic function and blood pressure. We resequenced 80 ethnically diverse individuals across the TH locus. One hundred seventy-two twin pairs were evaluated for sympathetic traits, including catecholamine production and environmental (cold) stress responses. To evaluate hypertension, we genotyped subjects selected from the most extreme diastolic blood pressure percentiles in the population. Human TH promoter haplotype/reporter plasmids were transfected into chromaffin cells. Forty-nine single nucleotide polymorphisms (SNPs) and one tetranucleotide repeat were discovered, but coding region polymorphism did not account for common phenotypic variation. A block of linkage disequilibrium spanned four common variants in the proximal promoter. Catecholamine secretory traits were significantly heritable, as were stress-induced blood pressure changes. In the TH promoter, significant associations were found for urinary catecholamine excretion, as well as blood pressure response to stress. TH promoter haplotype #2 (TGGG) showed pleiotropy, increasing both norepinephrine excretion and blood pressure during stress. In hypertension, a case–control study (1266 subjects, 53% women) established the effect of C-824T in determination of blood pressure. We conclude that human catecholamine secretory traits are heritable, displaying joint genetic determination (pleiotropy) with autonomic activity and finally with blood pressure in the population. Catecholamine secretion is influenced by genetic variation in the adrenergic pathway encoding catecholamine synthesis, especially at the classically rate-limiting step, TH. The results suggest novel pathophysiological links between a key adrenergic locus, catecholamine metabolism, and blood pressure, and suggest new strategies to approach the mechanism, diagnosis, and treatment of systemic hypertension.
PMCID: PMC2743085  PMID: 19120120
blood pressure; cold pressor test; heart rate; (TCAT)n polymorphism in the first TH intron; tyrosine hydroxylase
18.  Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study 
BMC Medical Genetics  2007;8(Suppl 1):S12.
Increased circulating levels of hemostatic factors as well as anemia have been associated with increased risk of cardiovascular disease (CVD). Known associations between hemostatic factors and sequence variants at genes encoding these factors explain only a small proportion of total phenotypic variation. We sought to confirm known putative loci and identify novel loci that may influence either trait in genome-wide association and linkage analyses using the Affymetrix GeneChip 100K single nucleotide polymorphism (SNP) set.
Plasma levels of circulating hemostatic factors (fibrinogen, factor VII, plasminogen activator inhibitor-1, von Willebrand factor, tissue plasminogen activator, D-dimer) and hematological phenotypes (platelet aggregation, viscosity, hemoglobin, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin concentration) were obtained in approximately 1000 Framingham Heart Study (FHS) participants from 310 families. Population-based association analyses using the generalized estimating equations (GEE), family-based association test (FBAT), and multipoint variance components linkage analyses were performed on the multivariable adjusted residuals of hemostatic and hematological phenotypes.
In association analysis, the lowest GEE p-value for hemostatic factors was p = 4.5*10-16 for factor VII at SNP rs561241, a variant located near the F7 gene and in complete linkage disequilibrium (LD) (r2 = 1) with the Arg353Gln F7 SNP previously shown to account for 9% of total phenotypic variance. The lowest GEE p-value for hematological phenotypes was 7*10-8 at SNP rs2412522 on chromosome 4 for mean corpuscular hemoglobin concentration. We presented top 25 most significant GEE results with p-values in the range of 10-6 to 10-5 for hemostatic or hematological phenotypes. In relating 100K SNPs to known candidate genes, we identified two SNPs (rs1582055, rs4897475) in erythrocyte membrane protein band 4.1-like 2 (EPB41L2) associated with hematological phenotypes (GEE p < 10-3). In linkage analyses, the highest linkage LOD score for hemostatic factors was 3.3 for factor VII on chromosome 10 around 15 Mb, and for hematological phenotypes, LOD 3.4 for hemoglobin on chromosome 4 around 55 Mb. All GEE and FBAT association and variance components linkage results can be found at
Using genome-wide association methodology, we have successfully identified a SNP in complete LD with a sequence variant previously shown to be strongly associated with factor VII, providing proof of principle for this approach. Further study of additional strongly associated SNPs and linked regions may identify novel variants that influence the inter-individual variability in hemostatic factors and hematological phenotypes.
PMCID: PMC1995619  PMID: 17903294
19.  Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study 
Fox, Ervin R. | Young, J. Hunter | Li, Yali | Dreisbach, Albert W. | Keating, Brendan J. | Musani, Solomon K. | Liu, Kiang | Morrison, Alanna C. | Ganesh, Santhi | Kutlar, Abdullah | Ramachandran, Vasan S. | Polak, Josef F. | Fabsitz, Richard R. | Dries, Daniel L. | Farlow, Deborah N. | Redline, Susan | Adeyemo, Adebowale | Hirschorn, Joel N. | Sun, Yan V. | Wyatt, Sharon B. | Penman, Alan D. | Palmas, Walter | Rotter, Jerome I. | Townsend, Raymond R. | Doumatey, Ayo P. | Tayo, Bamidele O. | Mosley, Thomas H. | Lyon, Helen N. | Kang, Sun J. | Rotimi, Charles N. | Cooper, Richard S. | Franceschini, Nora | Curb, J. David | Martin, Lisa W. | Eaton, Charles B. | Kardia, Sharon L.R. | Taylor, Herman A. | Caulfield, Mark J. | Ehret, Georg B. | Johnson, Toby | Chakravarti, Aravinda | Zhu, Xiaofeng | Levy, Daniel | Munroe, Patricia B. | Rice, Kenneth M. | Bochud, Murielle | Johnson, Andrew D. | Chasman, Daniel I. | Smith, Albert V. | Tobin, Martin D. | Verwoert, Germaine C. | Hwang, Shih-Jen | Pihur, Vasyl | Vollenweider, Peter | O'Reilly, Paul F. | Amin, Najaf | Bragg-Gresham, Jennifer L. | Teumer, Alexander | Glazer, Nicole L. | Launer, Lenore | Zhao, Jing Hua | Aulchenko, Yurii | Heath, Simon | Sõber, Siim | Parsa, Afshin | Luan, Jian'an | Arora, Pankaj | Dehghan, Abbas | Zhang, Feng | Lucas, Gavin | Hicks, Andrew A. | Jackson, Anne U. | Peden, John F. | Tanaka, Toshiko | Wild, Sarah H. | Rudan, Igor | Igl, Wilmar | Milaneschi, Yuri | Parker, Alex N. | Fava, Cristiano | Chambers, John C. | Kumari, Meena | JinGo, Min | van der Harst, Pim | Kao, Wen Hong Linda | Sjögren, Marketa | Vinay, D.G. | Alexander, Myriam | Tabara, Yasuharu | Shaw-Hawkins, Sue | Whincup, Peter H. | Liu, Yongmei | Shi, Gang | Kuusisto, Johanna | Seielstad, Mark | Sim, Xueling | Nguyen, Khanh-Dung Hoang | Lehtimäki, Terho | Matullo, Giuseppe | Wu, Ying | Gaunt, Tom R. | Charlotte Onland-Moret, N. | Cooper, Matthew N. | Platou, Carl G.P. | Org, Elin | Hardy, Rebecca | Dahgam, Santosh | Palmen, Jutta | Vitart, Veronique | Braund, Peter S. | Kuznetsova, Tatiana | Uiterwaal, Cuno S.P.M. | Campbell, Harry | Ludwig, Barbara | Tomaszewski, Maciej | Tzoulaki, Ioanna | Palmer, Nicholette D. | Aspelund, Thor | Garcia, Melissa | Chang, Yen-Pei C. | O'Connell, Jeffrey R. | Steinle, Nanette I. | Grobbee, Diederick E. | Arking, Dan E. | Hernandez, Dena | Najjar, Samer | McArdle, Wendy L. | Hadley, David | Brown, Morris J. | Connell, John M. | Hingorani, Aroon D. | Day, Ian N.M. | Lawlor, Debbie A. | Beilby, John P. | Lawrence, Robert W. | Clarke, Robert | Collins, Rory | Hopewell, Jemma C. | Ongen, Halit | Bis, Joshua C. | Kähönen, Mika | Viikari, Jorma | Adair, Linda S. | Lee, Nanette R. | Chen, Ming-Huei | Olden, Matthias | Pattaro, Cristian | Hoffman Bolton, Judith A. | Köttgen, Anna | Bergmann, Sven | Mooser, Vincent | Chaturvedi, Nish | Frayling, Timothy M. | Islam, Muhammad | Jafar, Tazeen H. | Erdmann, Jeanette | Kulkarni, Smita R. | Bornstein, Stefan R. | Grässler, Jürgen | Groop, Leif | Voight, Benjamin F. | Kettunen, Johannes | Howard, Philip | Taylor, Andrew | Guarrera, Simonetta | Ricceri, Fulvio | Emilsson, Valur | Plump, Andrew | Barroso, Inês | Khaw, Kay-Tee | Weder, Alan B. | Hunt, Steven C. | Bergman, Richard N. | Collins, Francis S. | Bonnycastle, Lori L. | Scott, Laura J. | Stringham, Heather M. | Peltonen, Leena | Perola, Markus | Vartiainen, Erkki | Brand, Stefan-Martin | Staessen, Jan A. | Wang, Thomas J. | Burton, Paul R. | SolerArtigas, Maria | Dong, Yanbin | Snieder, Harold | Wang, Xiaoling | Zhu, Haidong | Lohman, Kurt K. | Rudock, Megan E. | Heckbert, Susan R. | Smith, Nicholas L. | Wiggins, Kerri L. | Shriner, Daniel | Veldre, Gudrun | Viigimaa, Margus | Kinra, Sanjay | Prabhakaran, Dorairajan | Tripathy, Vikal | Langefeld, Carl D. | Rosengren, Annika | Thelle, Dag S. | MariaCorsi, Anna | Singleton, Andrew | Forrester, Terrence | Hilton, Gina | McKenzie, Colin A. | Salako, Tunde | Iwai, Naoharu | Kita, Yoshikuni | Ogihara, Toshio | Ohkubo, Takayoshi | Okamura, Tomonori | Ueshima, Hirotsugu | Umemura, Satoshi | Eyheramendy, Susana | Meitinger, Thomas | Wichmann, H.-Erich | Cho, Yoon Shin | Kim, Hyung-Lae | Lee, Jong-Young | Scott, James | Sehmi, Joban S. | Zhang, Weihua | Hedblad, Bo | Nilsson, Peter | Smith, George Davey | Wong, Andrew | Narisu, Narisu | Stančáková, Alena | Raffel, Leslie J. | Yao, Jie | Kathiresan, Sekar | O'Donnell, Chris | Schwartz, Steven M. | Arfan Ikram, M. | Longstreth, Will T. | Seshadri, Sudha | Shrine, Nick R.G. | Wain, Louise V. | Morken, Mario A. | Swift, Amy J. | Laitinen, Jaana | Prokopenko, Inga | Zitting, Paavo | Cooper, Jackie A. | Humphries, Steve E. | Danesh, John | Rasheed, Asif | Goel, Anuj | Hamsten, Anders | Watkins, Hugh | Bakker, Stephan J.L. | van Gilst, Wiek H. | Janipalli, Charles S. | Radha Mani, K. | Yajnik, Chittaranjan S. | Hofman, Albert | Mattace-Raso, Francesco U.S. | Oostra, Ben A. | Demirkan, Ayse | Isaacs, Aaron | Rivadeneira, Fernando | Lakatta, Edward G. | Orru, Marco | Scuteri, Angelo | Ala-Korpela, Mika | Kangas, Antti J. | Lyytikäinen, Leo-Pekka | Soininen, Pasi | Tukiainen, Taru | Würz, Peter | Twee-Hee Ong, Rick | Dörr, Marcus | Kroemer, Heyo K. | Völker, Uwe | Völzke, Henry | Galan, Pilar | Hercberg, Serge | Lathrop, Mark | Zelenika, Diana | Deloukas, Panos | Mangino, Massimo | Spector, Tim D. | Zhai, Guangju | Meschia, James F. | Nalls, Michael A. | Sharma, Pankaj | Terzic, Janos | Kranthi Kumar, M.J. | Denniff, Matthew | Zukowska-Szczechowska, Ewa | Wagenknecht, Lynne E. | Fowkes, Gerald R. | Charchar, Fadi J. | Schwarz, Peter E.H. | Hayward, Caroline | Guo, Xiuqing | Bots, Michiel L. | Brand, Eva | Samani, Nilesh J. | Polasek, Ozren | Talmud, Philippa J. | Nyberg, Fredrik | Kuh, Diana | Laan, Maris | Hveem, Kristian | Palmer, Lyle J. | van der Schouw, Yvonne T. | Casas, Juan P. | Mohlke, Karen L. | Vineis, Paolo | Raitakari, Olli | Wong, Tien Y. | Shyong Tai, E. | Laakso, Markku | Rao, Dabeeru C. | Harris, Tamara B. | Morris, Richard W. | Dominiczak, Anna F. | Kivimaki, Mika | Marmot, Michael G. | Miki, Tetsuro | Saleheen, Danish | Chandak, Giriraj R. | Coresh, Josef | Navis, Gerjan | Salomaa, Veikko | Han, Bok-Ghee | Kooner, Jaspal S. | Melander, Olle | Ridker, Paul M. | Bandinelli, Stefania | Gyllensten, Ulf B. | Wright, Alan F. | Wilson, James F. | Ferrucci, Luigi | Farrall, Martin | Tuomilehto, Jaakko | Pramstaller, Peter P. | Elosua, Roberto | Soranzo, Nicole | Sijbrands, Eric J.G. | Altshuler, David | Loos, Ruth J.F. | Shuldiner, Alan R. | Gieger, Christian | Meneton, Pierre | Uitterlinden, Andre G. | Wareham, Nicholas J. | Gudnason, Vilmundur | Rettig, Rainer | Uda, Manuela | Strachan, David P. | Witteman, Jacqueline C.M. | Hartikainen, Anna-Liisa | Beckmann, Jacques S. | Boerwinkle, Eric | Boehnke, Michael | Larson, Martin G. | Järvelin, Marjo-Riitta | Psaty, Bruce M. | Abecasis, Gonçalo R. | Elliott, Paul | van Duijn , Cornelia M. | Newton-Cheh, Christopher
Human Molecular Genetics  2011;20(11):2273-2284.
The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.
PMCID: PMC3090190  PMID: 21378095
20.  Genes and environment: novel, functional polymorphism in the human cathepsin L (CTSL1) promoter disrupts a xenobiotic response element (XRE) to alter transcription and blood pressure 
Journal of hypertension  2012;30(10):1961-1969.
Cathepsin L (CTSL1) catalyzes the formation of peptides that influence blood pressure (BP). Naturally occurring genetic variation or targeted ablation of the Ctsl1 locus in mice yield cardiovascular pathology. Here, we searched for genetic variation across the human CTSL1 locus and probed its functional effects, especially in the proximal promoter.
Methods and results
Systematic polymorphism discovery by re-sequencing across CTSL1 in 81 patients uncovered 38 genetic variants, five of which were relatively common (MAF >5%), creating a single linkage disequilibrium block in multiple biogeographic ancestries. One of these five common variants lay in a functional domain of the gene: promoter C-171A (rs3118869), which disrupts a predicted xenobiotic response element (XRE; match C>A). In transfected CTSL1 promoter/luciferase reporter plasmids, C-171A allele influenced transcription (C>A, P = 3.36E-6), and transcription was also augmented by co-exposure to the aryl hydrocarbon receptor (AHR) complex (AHR:ARNT) in the presence of their ligand dioxin (P = 6.81E-8); allele (C vs. A) and AHR:ARNT/dioxin stimulus interacted to control gene expression (interaction P = 0.033). Endogenous Ctsl1, Ahr, and Arnt transcripts were present in chromaffin cells. Promoter functional C-171A genotype also predicted hypertension (P = 1.0E–3), SBP (P = 4.0E–4), and DBP (P = 3.0E–3), in an additive pattern for diploid genotypes (A/A > C/A > C/C) in 868 patients, and the results were extended by validation analysis into an independent population sample of 986 patients.
We conclude that common genetic variation in the proximal CTSL1 promoter, especially at position C-171A, is functional in cells, and alters transcription so as to explain the association of CTSL1 with BP in vivo. At the XRE, endogenous genetic variation plus exogenous aryl hydrocarbon stimulation interact to control CTSL1 gene expression. These results unveil a novel control point whereby heredity and environment can intersect to control a complex trait, and point to new transcriptional strategies for intervention into transmitter biosynthesis and its cardiovascular consequences.
PMCID: PMC3478326  PMID: 22871890
autonomic; genetics; hypertension; nervous system
American journal of hypertension  2008;21(1):117-121.
Increased erythrocyte sodium-lithium countertransport (SLC) has been observed in patients with essential hypertension. Consistent evidence of genetic linkage was shown for SLC on chromosome 10, and a region of interest was localized between 26 and 56 Mb.
This study surveyed single nucleotide polymorphisms (SNPs) in 54 genes that reside in the region of interest and investigated their association with SLC and blood pressure. These SNPs were genotyped in 1133 non-Hispanic White individuals from 255 pedigrees comprising the second phase of the Rochester Family Heart Study. The variance components-based genetics software package SOLAR was used to evaluate whether a SNP contributes to a significant fraction of the trait heritability.
Of the 77 SNPs surveyed in this study across the region of interest, four SNPs were associated with SLC (p<0.04), five SNPs were associated with blood pressure (p<0.04), and two SNPs in mannose-binding lectin 2 (MBL2) were associated with both phenotypes. In general, the pairwise linkage disequilibrium among the genotyped SNPs was low.
This fine-mapping survey of genetic variation in a linkage region of interest provides overall support for association mapping for SLC on chromosome 10. Genes significantly associated with systolic blood pressure and/or SLC in these families will be prioritized for future studies.
PMCID: PMC2645713  PMID: 18091754
sodium-lithium countertransport; blood pressure; association; polymorphism; chromosome
22.  Polymorphisms in the WNK1 Gene Are Associated with Blood Pressure Variation and Urinary Potassium Excretion 
PLoS ONE  2009;4(4):e5003.
WNK1 - a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control - is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively). The major allele (A) of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95%CI:1.23–4.9), DBP 1.9 mmHg (95%CI:0.7–3.2) and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0–1.7]).We genotyped this variant in six independent populations (n = 14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p = 7×10−3, combined with BRIGHT data-set p = 2×10−4, n = 17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p<10−7). We identified several common haplotypes to be associated with increased BP and multiple low frequency haplotypes significantly associated with lower BP (>10 mmHg reduction) and risk for hypertension (OR<0.60). Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH.
PMCID: PMC2661139  PMID: 19347040
23.  The Association of the Vanin-1 N131S Variant with Blood Pressure Is Mediated by Endoplasmic Reticulum-Associated Degradation and Loss of Function 
PLoS Genetics  2014;10(9):e1004641.
High blood pressure (BP) is the most common cardiovascular risk factor worldwide and a major contributor to heart disease and stroke. We previously discovered a BP-associated missense SNP (single nucleotide polymorphism)–rs2272996–in the gene encoding vanin-1, a glycosylphosphatidylinositol (GPI)-anchored membrane pantetheinase. In the present study, we first replicated the association of rs2272996 and BP traits with a total sample size of nearly 30,000 individuals from the Continental Origins and Genetic Epidemiology Network (COGENT) of African Americans (P = 0.01). This association was further validated using patient plasma samples; we observed that the N131S mutation is associated with significantly lower plasma vanin-1 protein levels. We observed that the N131S vanin-1 is subjected to rapid endoplasmic reticulum-associated degradation (ERAD) as the underlying mechanism for its reduction. Using HEK293 cells stably expressing vanin-1 variants, we showed that N131S vanin-1 was degraded significantly faster than wild type (WT) vanin-1. Consequently, there were only minimal quantities of variant vanin-1 present on the plasma membrane and greatly reduced pantetheinase activity. Application of MG-132, a proteasome inhibitor, resulted in accumulation of ubiquitinated variant protein. A further experiment demonstrated that atenolol and diltiazem, two current drugs for treating hypertension, reduce the vanin-1 protein level. Our study provides strong biological evidence for the association of the identified SNP with BP and suggests that vanin-1 misfolding and degradation are the underlying molecular mechanism.
Author Summary
Hypertension (HTN) or high blood pressure (BP) is common worldwide and a major risk factor for cardiovascular disease and all-cause mortality. Identification of genetic variants of consequence for HTN serves as the molecular basis for its treatment. Using admixture mapping analysis of the Family Blood Pressure Program data, we recently identified that the VNN1 gene (encoding the protein vanin-1), in particular SNP rs2272996 (N131S), was associated with BP in both African Americans and Mexican Americans. Vanin-1 was reported to act as an oxidative stress sensor using its pantetheinase enzyme activity. Because a linkage between oxidative stress and HTN has been hypothesized for many years, vanin-1's pantetheinase activity offers a physiologic rationale for BP regulation. Here, we first replicated the association of rs2272996 with BP in the Continental Origins and Genetic Epidemiology Network (COGENT), which included nearly 30,000 African Americans. We further demonstrated that the N131S mutation in vanin-1 leads to its rapid degradation in cells, resulting in loss of function on the plasma membrane. The loss of function of vanin-1 is associated with reduced BP. Therefore, our results indicate that vanin-1 is a new candidate to be manipulated to ameliorate HTN.
PMCID: PMC4169380  PMID: 25233454
24.  Genome-wide association study of blood pressure and hypertension 
Nature genetics  2009;41(6):677-687.
Blood pressure (BP) is a major cardiovascular disease risk factor. To date, few variants associated with inter-individual BP variation have been identified. A genome-wide association study of systolic (SBP), diastolic BP (DBP), and hypertension in the CHARGE Consortium (n=29,136) identified 13 SNPs for SBP, 20 for DBP, and 10 for hypertension at p <4×10-7. The top 10 loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to number of risk alleles carried. When 10 CHARGE SNPs for each trait were meta-analyzed jointly with the Global BPgen Consortium (n=34,433), four CHARGE loci attained genome-wide significance (p<5×10-8) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK/ULK3, SH2B3, TBX3/TBX5, ULK4), and one for hypertension (ATP2B1). Identifying novel BP genes advances our understanding of BP regulation and highlights potential drug targets for the prevention or treatment of hypertension.
PMCID: PMC2998712  PMID: 19430479
25.  Maternal but Not Paternal Association of Ambulatory Blood Pressure With Albumin Excretion in Young Offspring With Type 1 Diabetes 
Diabetes Care  2009;33(2):366-371.
Familial predisposition to hypertension has been associated with the development of diabetic nephropathy in adults, but there are limited data in adolescents. Our aim was to assess whether parental ambulatory blood pressure (ABP) was associated with ABP and albumin excretion in young offspring with type 1 diabetes.
Twenty-four-hour ABP monitoring was performed in 509 young offspring (mean ± SD age 15.8 ± 2.3 years) with type 1 diabetes, 311 fathers, and 444 mothers. Systolic (SBP) and diastolic blood pressure (DBP) measurements during 24 h, daytime, and nighttime were calculated. Three early morning urinary albumin-to-creatinine ratios (ACRs), A1C, and anthropometric parameters were available for the offspring.
All paternal ABP parameters, except for nighttime SBP, were independently related to the offspring's ABP (24-h SBP β = 0.18, 24-h DBP β = 0.22, daytime SBP β = 0.25, daytime DBP β = 0.23, and nighttime DBP β = 0.18; all P < 0.01). Maternal 24-h DBP (β = 0.19, P = 0.004), daytime DBP (β = 0.09, P = 0.04), and nighttime SBP (β = 0.24 P = 0.001) were related to the corresponding ABP parameter in the offspring. Significant associations were found between the offspring's logACR and maternal ABP. The association with 24-h DBP (β = 0.16, P = 0.02), daytime DBP (β = 0.16 P = 0.02), and nighttime DBP (β = 0.15 P = 0.03) persisted even after adjustment for the offspring's ABP. Mothers of offspring with microalbuminuria had higher ABP than mothers of offspring without microalbuminuria (all P < 0.05).
In this cohort, parental ABP significantly influenced offspring blood pressure, therefore confirming familial influences on this trait. In addition, maternal ABP, particularly DBP, was closely related to ACR in the offspring, suggesting a dominant effect of maternal genes or an effect of the intrauterine environment on microalbuminuria risk.
PMCID: PMC2809284  PMID: 19918004

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