The interaction among G-6A, M235T and T174M polymorphisms in combinations or haplotypes emerged significant. These findings, conjoint with significant high plasma aldosterone concentration and low plasma renin activity, suggest low-renin hypertension in our study population.
The genes of the renin--angiotensin system (RAS) play an important role in the regulation of pulmonary vascular tone. Although studies on individual genes polymorphisms have reported association with high-altitude pulmonary oedema (HAPE), studies on multiple genes or epistasis are lacking. We therefore investigated the association of the RAS polymorphisms with HAPE. In a case-control design, we screened 163 HAPE-resistant/controls (HAPE-r) and 160 HAPEpatients (HAPE-p) of Indian origin for eight polymorphisms of four RAS genes, ACE, AGT, AGTR1 and AGTR2. Significant difference in genotype and allele frequencies of the ACE I/D and AGT M235T polymorphisms was observed between HAPE-p and HAPE-r (p< 0.05). In three-locus haplotype analysis of AGT the haplotype GTM was significantly higher in HAPE-p (29%) and haplotype GTT in HAPE-r (27%) after Bonferroni correction (p < 0.006). The differences were insignificant for polymorphisms from AGTR1 and AGTR2. The MDR (multifactor dimensional reduction) approach for gene--gene interaction depicted individual polymorphism M235T as the best disease predicting model (cross validation consistency, CVC = 10/10). We found a significant association of D allele of ACE and M allele of AGT with HAPE. The findings are supported at the haplotypic level as well as through nested genetic interaction between the RAS gene polymorphisms using the MDR approach.
ObjectiveTo date, a major class of kinases, serine–threonine kinase, has been scantly investigated in stress-induced rare, fatal (if not treated early), and morbid disorder, high altitude pulmonary edema (HAPE). This study examined three major serine–threonine kinases, ROCK2, MYLK, and JNK1, along with six other genes, tyrosine hydroxylase, G-protein subunits GNA11 and GNB3, and alpha1 adrenergic receptor isoforms 1A, 1B, and 1D as candidate gene markers of HAPE and adaptation.MethodsFor this, 57 variants across these nine genes were genotyped in HAPE patients (n=225), HAPE controls (n=210), and highlanders (n=259) by Sequenom MS (TOF)-based MassARRAY® platform using iPLEX™ Gold technology. In addition, to study the gene expression, quantitative real-time polymerase chain reaction was performed in human peripheral blood mononuclear cells of the three study groups.ResultsA significant association was observed for C allele (ROCK2 single-nucleotide polymorphism, rs10929728) with HAPE (P=0.03) and C, T, and A alleles (MYLK single-nucleotide polymorphisms, rs11717814, rs40305, and rs820336) with both HAPE and adaptation (P=0.001, P=0.006, and P=0.02, respectively). ROCK2 88 kb GGGTTGGT haplotype was associated with lower risk of HAPE (P=0.0009). MYLK 7 kb haplotype CTA, composed of variant alleles, was associated with higher risk of HAPE (P=0.0006) and lower association with adaptation (P=1E–06), whereas haplotype GCG, composed of wild-type alleles, was associated with lower risk of HAPE (P=0.001) and higher association with adaptation (P=1E–06). Haplotype–haplotype and gene–gene interactions demonstrated a correlation in working of ROCK2 and MYLK.ConclusionThe data suggest the association of ROCK2 with HAPE and MYLK with HAPE and adaptation in Indian population. The outcome has provided new insights into the physiology of HAPE and adaptation.
CYBA (p22(phox)) is an integral constituent of the NADPH oxidases and is consequently a main component of oxidative stress, which is strongly associated with hypertension. This study investigates the contribution of CYBA polymorphisms toward the complex etiology of hypertension in two ethnically different populations, one located at a high altitude and the other at a low altitude. The significance of CYBA single nucleotide polymorphisms and their correlation with clinical and biochemical phenotypes were investigated in age- and ethnicity-matched unrelated permanent high-altitude residents (>3500 m) comprising 245 controls and 241 patients. The results were replicated in a second population comprising 935 controls and 545 patients who lived at a low altitude (<200 m). The analysis of covariance revealed that CYBA risk alleles and their haplotypes, rs8854A/rs9932581G/rs4873C and rs8854G/rs9932581G/rs4873C, were positively correlated with clinical parameters, for example, systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP), and biochemical parameters, for example, 8-isoPGF2α level, and inversely correlated with catalase activity in patients compared with controls (P⩽0.01, each). Conversely, the protective alleles and their haplotype, rs8854G/rs9932581A/rs4873T, were inversely correlated with SBP, DBP, MAP and 8-isoPGF2α level, and positively correlated with catalase activity (P⩽0.001, each). Furthermore, correlation analysis between the clinical and biochemical parameters revealed a positive correlation of SBP, DBP and MAP with 8-isoPGF2α levels and a negative correlation with catalase activity in both populations (P<0.0001, each). CYBA (p22(phox)) variants influence the markers of oxidative stress and are associated with hypertension.
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