DNA variation in myoMIRs of the 1, 133, and 208 families in hypertrophic cardiomyopathy

MicroRNAs (miRNAs) are small RNAs that bind to mRNAs and regulate gene expression. MyoMirs are miRNAs implicated in cardiogenesis. Some MyoMirs have been found deregulated in hearts from patients with left ventricular hypertrophy (LVH). DNA variants at these miRNAs could contribute to the risk of developing hypertrophic cardiomyopathy (HCM). To test this hypothesis we used single strand conformation analysis and direct sequencing to search for DNA variants in the mir-208a, miR-208b, miR-133a-1, miR-133a-2, miR-133b, miR-1-1, and miR-1-2 genes in patients with HCM (n=245), LVH secondary to hypertension (n=120), and healthy controls (n=250). We found several nucleotide variants. Genotyping of patients and healthy controls showed significantly associations between a 133a-1 polymorphism and HCM and a 133b polymorphism and hypertensive-LVH. We concluded that rare variants in these mature miRNAs would be rarely found among HCM patients, but miR-133a-1 and 133b polymorphisms could contribute to the risk of developing cardiac hypertrophy.this work was supported by grants from the Spanish Fondo de Investigaciones Sanitarias-Fondos FEDER European Union (FIS-00/0172), and Red de Investigación Renal-REDINREN (RD06/0016). MP a predoctoral fellow from FICYT-Principado de Asturias. MD is the recipient of a Contrato de Apoyo a la Investigación- Fondo de Investigaciones Sanitarias

Functional polymorphisms in the CYP3A4, CYP3A5, and CYP21A2 genes in the risk for hypertension in pregnancy

An intronic single nucleotide polymorphism (SNP) in the CYP3A5 gene (CYP3A5*3; SNP rs776746) affects RNA splicing and enzymatic activity. The CYP3A5*3 frequency increased with distance from the equator and natural selection has been proposed to explain the worldwide distribution of this allele. CYP3A activity has been related with the risk for hypertension in pregnancy, a major cause of morbidity and mortality among women, and CYP3A5*3 could reduce the risk for this disease in populations from regions with high sodium and water availability. The CYP3A5 genotype was related with blood pressure in the general population, but the effect on the risk for hypertension in pregnancy has not been evaluated. We compared the allele and genotype frequencies of three functional SNPs in the CYP3A5 (rs776746), CYP3A4 (rs2740574), and CYP21A2 (rs6471) genes between pregnant women who developed hypertension (n=250) or who remained normotensive (control group, n=250). In addition, we sequenced the full CYP3A5 coding sequence in 40 women from the two groups to determine whether some gene variants could explain the risk for hypertensive pregnancies in our population. Allele and genotype frequencies did not differ between hypertensive and normotensive women for the three CYP variants. We did not find CYP3A5 nucleotide changes that could explain a higher risk for hypertension in pregnancy. Our data suggests that the variation in CYP3A5, CYP3A4, and CYP21A2 did not contribute to the risk for hypertension in pregnancy in our populationThe author´s work is supported by a grant from the Spanish Fondo de Investigaciones Sanitarias/Fondos FEDER European Union (ETS PI08/90008)

Functional polymorphisms in genes of the Angiotensin and Serotonin systems and risk of hypertrophic cardiomyopathy: AT1R as a potential modifier

<p>Abstract</p> <p>Background</p> <p>Angiotensin and serotonin have been identified as inducers of cardiac hypertrophy. DNA polymorphisms at the genes encoding components of the angiotensin and serotonin systems have been associated with the risk of developing cardiovascular diseases, including left ventricular hypertrophy (LVH).</p> <p>Methods</p> <p>We genotyped five polymorphisms of the <it>AGT</it>, <it>ACE</it>, <it>AT1R</it>, <it>5-HT2A</it>, and <it>5-HTT </it>genes in 245 patients with Hypertrophic Cardiomyopathy (HCM; 205 without an identified sarcomeric gene mutation), in 145 patients with LVH secondary to hypertension, and 300 healthy controls.</p> <p>Results</p> <p>We found a significantly higher frequency of <it>AT1R </it>1166 C carriers (CC+AC) among the HCM patients without sarcomeric mutations compared to controls (p = 0.015; OR = 1.56; 95%CI = 1.09-2.23). The <it>AT1R </it>1166 C was also more frequent among patients who had at least one affected relative, compared to sporadic cases. This allele was also associated with higher left ventricular wall thickness in both, HCM patients with and without sarcomeric mutations.</p> <p>Conclusions</p> <p>The 1166 C <it>AT1R </it>allele could be a risk factor for cardiac hypertrophy in patients without sarcomeric mutations. Other variants at the <it>AGT</it>, <it>ACE</it>, <it>5-HT2A </it>and <it>5-HTT </it>did not contribute to the risk of cardiac hypertrophy.</p