Genome-wide association study identifies CAMKID variants involved in blood pressure response to losartan: the SOPHIA study.

BACKGROUND: Essential hypertension arises from the combined effect of genetic and environmental factors. A pharmacogenomics approach could help to identify additional molecular mechanisms involved in its pathogenesis. AIM: The aim of SOPHIA study was to identify genetic polymorphisms regulating blood pressure response to the angiotensin II receptor blocker, losartan, with a whole-genome approach. MATERIALS & METHODS: We performed a genome-wide association study on blood pressure response in 372 hypertensives treated with losartan and we looked for replication in two independent samples. RESULTS: We identified a peak of association in CAMK1D gene (rs10752271, effect size -5.5 ± 0.94 mmHg, p = 1.2 × 10(-8)). CAMK1D encodes a protein that belongs to the regulatory pathway involved in aldosterone synthesis. We tested the specificity of rs10752271 for losartan in hypertensives treated with hydrochlorothiazide and we validated it in silico in the GENRES cohort. CONCLUSION: Using a genome-wide approach, we identified the CAMK1D gene as a novel locus associated with blood pressure response to losartan. CAMK1D gene characterization may represent a useful tool to personalize the treatment of essential hypertension.

DEspR T/CATAAAA-box promoter variant decreases DEspR transcription and is associated with increased BP in Sardinian males.

Essential hypertension is highly prevalent in the elderly population, exceeding 70% in people older than 60 yr of age, and remains a leading risk factor for heart disease, stroke, and chronic renal disease. Elucidation of genetic determinants is critical but remains a challenge due to its complex, multifactorial pathogenesis. We investigated the role DEspR promoter variants, previously associated with male essential hypertension susceptibility, in blood pressure (BP) regulation. We detected a single nucleotide polymorphism within the DEspR 5'-regulatory region associated with increased BP in a male Sardinian cohort accounting for 11.0 mmHg of systolic BP (P<10(-15)) and 9.3 mmHg of diastolic BP (P<10(-15)). Sequence analysis of three normotensive subjects homozygous for the rs6535847 "normotension-associated T-allele" identified a canonical TATAAAA-box in contrast to a CATAAAA-motif in three hypertensive subjects homozygous for the rs6535847 "hypertension-associated C-allele." In vitro analysis detected decreased transcription activity with the CATAAAA-motif promoter-construct compared with the canonical TATAAAA-box promoter-construct. Although BP did not differ between DEspR+/- knockout male mice and wild-type littermates at 6 mo of age, radiotelemetric BP measurements in 18 mo old inbred DEspR+/- knockout male mice known to have decreased DEspR RNA and protein detected higher systolic, mean, and diastolic BPs in DEspR+/- mice compared with littermate wild-type controls (P<0.05). Our results demonstrate that promoter variants in DEspR associated with hypertension susceptibility and increased BP in Sardinian males affect transcription levels, which then affect BP in an age-dependent and male-specific manner. This finding is concordant with the late-onset and sex-specific characteristics of essential hypertension, thus reiterating the mandate for sex-specific analyses and treatment approaches for essential hypertension.

Haplotypes of the adrenergic system predict the blood pressure response to beta-blockers in women with essential hypertension.

AIMS: To analyze the association of haplotypes of the adrenergic system with essential hypertension and with the blood pressure response to beta-blockers. MATERIALS & METHODS: In 1112 never-treated essential hypertension patients and 203 normotensive controls, tightly linked SNPs of beta-adrenergic receptors (ADRB1 - Ser49Gly and Arg389Gly; ADRB2 - Cys19Arg, Gly16Arg and Gln27Glu) and the G-protein beta3-subunit (GNB3 - A3882C, G5249A and C825T) were genotyped. Association of haplotypes with essential hypertension and with the blood pressure response to atenolol 50 mg twice daily in a subgroup of essential hypertension patients (n = 340) was evaluated (Haploview 3.2). RESULTS: No SNPs or haplotypes were associated with essential hypertension. In females only, GNB3 SNPs and haplotypes were associated with the blood pressure response (p < 0.05). CONCLUSION: Our study confirmed the sex-specific association of GNB3 with the blood pressure response to atenolol with no substantial advantage of the analysis of haplotypes over SNPs.

Prevalence and clinical features of heterozygous carriers of autosomal recessive hypercholesterolemia in Sardinia.

OBJECTIVE: Autosomal recessive hypercholesterolemia (ARH) is a lipid disorder caused by mutations in a specific adaptor protein for the LDL receptor. ARH is rare except in Sardinia where three alleles (ARH1, ARH2 and ARH3) explain most of cases. The prevalence of ARH heterozygotes in Sardinia is not well determined as well as inconclusive data are available on the effect of the ARH carrier status on LDL cholesterol (LDL-C) and coronary risk. METHODS: 3410 Sardinians (986 blood donors, 1709 with hypertension and 715 with myocardial infarction (MI)) were screened for ARH alleles. For comparison purposes, lipid data of 60 ARH heterozygous carriers and 60 non-carriers identified within 24 ARH families were also considered. RESULTS: In the whole study cohort, no ARH homozygotes were found, but 15 ARH1 (0.44%) and 9 ARH2 (0.26%) heterozygous carriers were identified. The frequency of ARH alleles in blood donors was 0.0030, not different from that in hypertensive subjects (0.0032). ARH alleles tended to be more common in MI patients (0.0049), but no association between ARH carrier status and MI risk was detected after controlling for conventional risk factors. ARH carriers and non-carriers showed similar LDL-C levels. This result was confirmed when ARH carriers and non-carriers identified throughout family-based and population-based screenings were combined and compared (141.0+/-41 mg/dl vs. 137.0+/-41 mg/dl, respectively; p=0.19). CONCLUSIONS: These data indicate that the frequency of ARH heterozygotes in Sardinia is approximately 1:143 individuals, thus making this condition one of the most common in the Sardinian population. However, ARH carrier status does not influence LDL-C concentration and coronary risk, thus suggesting that ARH can be regarded as a truly recessive disorder.

Clinical variables, not RAAS polymorphisms, predict blood pressure response to ACE inhibitors in Sardinians.

AIM: No definite factors predict blood pressure response to angiotensin-converting enzyme-inhibitors. The aim of this study was to test the association of gene polymorphisms of the renin-angiotensin-aldosterone system with essential hypertension and anthropometric variables, intermediate phenotypes and gene polymorphisms with blood pressure after fosinopril in a genetically homogeneous cohort. METHODS: A total of 630 essential hypertension patients, not previously treated or out of antihypertensive treatment for at least 6 months versus 219 normotensives (genotype frequencies, chi(2)). A total of 191 patients were randomly assigned to fosinopril 20 mg/day. Samples for plasma renin activity and aldosterone, 24-h urinary sodium (flame photometry) were collected. Gene polymorphisms--angiotensin-converting enzyme (insertion/deletion), angiotensin II type 1-receptor (A1166C), aldosterone synthase (-344C/T) and angiotensinogen (-6A/G)--were analyzed by standard techniques. The association of anthropometric variables, intermediate phenotypes and gene polymorphisms with blood pressure after 4 weeks therapy was tested by univariate analysis and analysis of covariance model (Intercooled Stata SE 9.2). RESULTS: No genetic polymorphisms were associated with essential hypertension, blood pressure response and intermediate phenotypes (p > 0.05). Systolic blood pressure after therapy was associated with baseline systolic blood pressure, age and sex. CONCLUSIONS: Our results confirm the difficulty in dissecting both essential hypertension and pharmacogenomics when analyzing the effect of single genes in complex multifactorial traits.

Association of ATP1A1 and dear single-nucleotide polymorphism haplotypes with essential hypertension: sex-specific and haplotype-specific effects.

Essential hypertension remains a major risk factor for cardiovascular and cerebrovascular diseases. As a complex multifactorial disease, elucidation of susceptibility loci remains elusive. ATP1A1 and Dear are candidate genes for 2 closely linked rat chromosome-2 blood pressure quantitative trait loci. Because corresponding human syntenic regions are on different chromosomes, investigation of ATP1A1 (chromosome [chr]-1p21) and Dear (chr-4q31.3) facilitates genetic analyses of each blood pressure quantitative trait locus in human hypertension. Here we report the association of human ATP1A1 (P<0.000005) and Dear (P<0.03) with hypertension in a relatively isolated, case/control hypertension cohort from northern Sardinia by single-nucleotide polymorphism haplotype analysis. Sex-specific haplotype analyses detected stronger association of both loci with hypertension in males than in females. Haplotype trend-regression analyses support ATP1A1 and Dear as independent susceptibility loci and reveal haplotype-specific association with hypertension and normotension, thus delineating haplotype-specific subsets of hypertension. Although investigation in other cohorts needs to be performed to determine genetic effects in other populations, haplotype subtyping already allows systematic stratification of susceptibility and, hence, clinical heterogeneity, a prerequisite for unraveling the polygenic etiology and polygene-environment interactions in essential hypertension. As hypertension susceptibility genes, coexpression of ATP1A1 and Dear in both renal tubular cells and vascular endothelium suggest a cellular pathogenic scaffold for polygenic mechanisms of hypertension, as well as the hypothesis that ATP1A1 and/or Dear could contribute to the known renal and vascular endothelial dysfunction associated with essential (polygenic) hypertension.