Haplotype association and synergistic effect of human aldosterone synthase (CYP11B2) gene polymorphisms causing susceptibility to essential hypertension in Indian patients.

BACKGROUND: Aldosterone synthase (CYP11B2) is a key enzyme involved in the terminal steps of aldosterone biosynthesis. Genetic variability in CYP11B2 gene has been associated with heterogeneous aldosterone production, which can affect sodium homeostasis and thereby regulation of blood pressure. Hence, the present study was aimed to explore the single-locus variations, haplotype and epistasis patterns of CYP11B2 (C-344T, intron-2 gene conversion and Lys173Arg) gene polymorphisms, and the risk contributed by them to the development of essential hypertension (EHT). METHODS: A total of 279 hypertensive patients and 200 normotensive controls were enrolled in this study. C-344T and Lys173Arg polymorphisms of CYP11B2 gene were genotyped by PCR-RFLP method and intron-2 gene conversion (IC) polymorphism by allele-specific PCR analysis. RESULTS: Single-locus analysis revealed significant association of CYP11B2 C-344T and Lys173Arg polymorphisms with EHT (p < 0.05). Considering the sexes, Lys173 allele was found to be at risk for hypertension in males (OR 1.40; 95% CI = 1.01-1.96). Unphased haplotype analysis revealed H1 (T-Conv-Lys; p = 0.0017) to have significant risk for EHT, while haplotype H4 (T-Wt-Arg) had a significant protective effect. Multifactor dimensionality reduction (MDR) interaction analysis found the overall best model with C-344T and IC polymorphisms exhibiting strong synergistic effect. CONCLUSION: The present study revealed a strong synergistic effect of CYP11B2 C-344T and IC polymorphisms causing susceptibility to EHT and haplotype H1 (-344T-Conv-Lys173) as the risk-conferring factor for hypertension predisposition.

High risk for essential hypertension in males conferred by g.15241A>G polymorphism in intron 3 of AGT gene.

A total of 180 hypertensive and 188 normotensive subjects were studied for demographic features and for variations in exon 4 including exon-intron boundary of AGT gene using single-strand conformation polymorphism analysis. Sequencing of the samples showing mobility shift revealed a single-nucleotide polymorphism variant g.15241A>G in intron 3 of the gene. The polymorphism was consistent with Hardy-Weinberg equilibrium in both the cases and the controls. Although the genotype distribution and allele frequencies did not differ significantly in general, high risk was observed for males with G allele (OR = 2.08; 95% CI = 1.02-4.21; P = .04). Similar results were obtained when the genotypes were tested in dominant model wherein G allele carriers were found to be at twofold risk for developing essential hypertension (OR = 2.09; 95% CI = 0.99-4.41; P = 0.05). This report is the first one in the literature showing association of g.15241A>G polymorphism with a clinical condition.

Novel mutations affecting the secondary structure of MT-RNR1 gene: a causal relationship with profound nonsyndromic hearing impairment.

Mutations in mitochondrial DNA (mtDNA) are one of the most important causes of sensorineural hearing loss, especially in the MT-RNR1 gene. In the present study we have performed mutational screening for m.1555A>G and a region of the MT-RNR1 gene in 303 unrelated patients (including family members of 25 probands) with nonsyndromic hearing loss and 200 controls. Three homoplasmic variants, namely, m.1453A>G, 1462G>A, and 1508C>T, were identified in addition to the known deafness-associated m.1555A>G mutation in the MT-RNR1 gene. All the variants were detected only in the patients and not in the controls. m.1555A>G was detected in three probands amounting to 1.0%. Prediction of RNA secondary structure showed changes in all the three variants, the most severe being in m.1453A>G that was inherited in a typical maternal pattern in two families. Screening of GJB2 and GJB6 genes in all these probands revealed cosegregation of the p.W24X mutation (GJB2) in one family with m.1453A>G. Only the proband carrying the p.W24X mutation in a homozygous state expressed the condition while heterozygous and normal homozygous relatives had normal hearing in spite of having the mutation in MT-RNR1. The conservation index (CI) of m.1453A>G was found to be 82%, suggesting it to be a possibly deleterious mutation. Functional studies using cell lines derived from muscle tissue of these patients may reveal the pathogenic mechanism of deafness in them.