Il Gene del cotrasportatore NaCl tiazide-sensibile è associato con l'attività reninica plasmatica e l'effetto antiipertensivo dei diuretici tiaridici nell'ipertensione arteriosa essenziale

Essential hypertension originates from gene-environment interaction. Thiazide diuretics play a key role in the treatment of essential hypertension. Several gene polymorphisms have been inconclusively associated with the antihypertensive effect of thiazides because of: 1. small sample size> 2. evaluation of patients with short wash-out period from previous therapy 3. genetic heterogeneity 4. no intermediate phenotypes 5. uncertainties in gene interactions In a cohort of genetically homogeneous, never treated essential hypertensives we analyzed the association of the “Thiazide Sensitive Channel” gene with 1. the effect of hydrochlorothiazide on blood pressure, and 2. coherent intermediate phenotypes, by means of Linkage Disequilibrium analysis [Single Nucleotide Polymorphisms (SNPs) inside “haplotype blocks”]. Several SNPs in different haplotype blocks are associated with indexes of "volume status" while other SNPs are associated with the effect of hydrochlorothiazide on blood pressure. No association with pre-treatment blood pressure was found. Our study confirms that 1. different polymorphisms inside the same gene may regulate different phenotypic expression, and 2. blood pressure regulation and the antihypertensive effect of drugs may be regulated by independent genetic mechanisms

Impulsivity is a heritable trait in rodents and associated with a novel quantitative trait locus on chromosome 1

Abstract: Impulsivity describes the tendency to act prematurely without appropriate foresight and is symptomatic of a number of neuropsychiatric disorders. Although a number of genes for impulsivity have been identified, no study to date has carried out an unbiased, genome-wide approach to identify genetic markers associated with impulsivity in experimental animals. Herein we report a linkage study of a six-generational pedigree of adult rats phenotyped for one dimension of impulsivity, namely premature responding on the five-choice serial reaction time task, combined with genome wide sequencing and transcriptome analysis to identify candidate genes associated with the expression of the impulsivity trait. Premature responding was found to be heritable (h2 = 13–16%), with significant linkage (LOD 5.2) identified on chromosome 1. Fine mapping of this locus identified a number of polymorphic candidate genes, however only one, beta haemoglobin, was differentially expressed in both the founder strain and F6 generation. These findings provide novel insights into the genetic substrates and putative neurobiological mechanisms of impulsivity with broader translational relevance for impulsivity-related disorders in humans

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 similar to 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. (C) 2009 Elsevier Ireland Ltd. All rights reserved

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 \ub1 0.94 mmHg, p = 1.2 7 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