Susceptibility of CTLA-4 -1661A/G polymorphism towards severity of rheumatic heart disease.

AIM: Genetic contribution in acute rheumatic fever (ARF)/rheumatic heart disease (RHD) has been suggested but not according to severity of the valve involvement. This study attempts to identify the relevance of CTLA-4 polymorphism with severity of the disease. METHODS: In a case-control design, 291 healthy controls and 83 patients were genotyped for association between RHD and single-nucleotide polymorphisms -1661A/G of CTLA-4. RESULTS: Segregation of patients on the basis of severity i.e., MVL (Mitral Valve Lesion) and CVL (Combined Valve Lesion) revealed that the frequency of CTLA-4 -1661G allele depleted as the disease progressed to CVL (p < 0.05). Patients in the age group of 31-45 years were significantly more susceptible (p < 0.046). Whereas, female patients were more susceptible than the male patients. CONCLUSION: Our study suggests the risk associated with decreased frequency of CTLA-4 -1661G allele in the CVL group and in females.

Tumor necrosis factor-alpha -308G/A gene polymorphism and novel biomarker profiles in patients with Takayasu arteritis.

BACKGROUND: Takayasu arteritis (TA) is an idiopathic chronic inflammatory disease of the aorta and its branches, leading to stenosis, occlusion, and aneurysmal dilatation. Tumor necrosis factor-alpha (TNF-α) is a cytokine with pleomorphic actions and plays a pivotal role in inflammation; the serum level of TNF-α is genetically determined. However, the literature lacks adequate information on the association of TNF-α polymorphisms with TA. Hence, the present study investigates the contribution of TNF-α polymorphism toward the complex etiology of TA. METHODS: A cross-sectional study was performed in 87 patients with TA and 90 controls. A promoter region polymorphism of TNF-α, rs1800629 G/A, or -308G/A was genotyped in all the study subjects followed by a case-control association study. Furthermore, to understand the biomarker profile, levels of specific markers such as erythrocyte sedimentation rate, serum high-sensitivity C-reactive protein, interleukin-18, interleukin-6, and TNF-α were measured in all the study subjects. RESULTS: All the inflammatory markers were significantly higher in the TA patients than in the controls. The genetic study (available for 57 TA patients and 36 controls) revealed that the TNF-α -308A allele was overrepresented in the TA patients (12% vs 7%). The TNF-α -308A allele correlated with the increased TNF-α levels, but it could not attain significance because of a small sample size. CONCLUSION: The TNF-α -308G/A polymorphism is associated with TNF-α levels in Indian population, which might have implications for clinical risk stratification and treatment. The different TNF-α gene promoter polymorphism might contribute to the molecular pathogenesis of TA. However, further study of the underlying mechanism is warranted.

Impact of interactions between risk alleles on clinical endpoints in hypertension.

OBJECTIVE: Impairment of the renin-angiotensinogen-aldosterone system (RAAS), one of the characteristics of essential hypertension (EH), imbalances vascular homeostasis. Despite inconsistent reports on individual single nucleotide polymorphisms (SNPs) as a major predictor of EH, interactions among RAAS genetic variants are rarely investigated. METHODS: Using SNP markers, we studied potential interactions between angiotensin 1 converting enzyme (ACE), angiotensinogen (AGT), angiotensin II-type 1 receptor (AGTR1), and α adducin (ADD1) variants and their correlation with clinical endpoints in 545 individuals with hypertension and 400 age- and ethnicity-matched unrelated controls. Generalised multifactor dimensionality reduction (GMDR) analysis identified the models for genotype interaction. RESULTS: Although the results on single genes were significant, gene-gene interactions were more reliable and promising as markers in predisposing hypertension. The best models to represent association of multi-locus interactions with augmented hypertension susceptibility were: (a) within gene 4-locus model comprised of AGT SNPs -217G/A, -20A/C, -6G/A and 235M/T (p=0.022, OR 6.1); and (b) between genes 5-locus model comprised of AGT -217G/A, -20A/C, -6G/A, 235M/T and ACE I/D (p=0.05, OR 4.6). Stratification of 4- and 5-locus GMDR models on the basis of risk alleles from ≤1 to ≥7 increased the ORs from 2.8 to 36.1 and from 0.9 to 16.1, respectively. Moreover, compared to ≤1 risk alleles the ≥7 interacting risk alleles in both 4- and 5-locus models showed an increment of 14.2% and 11.1% in systolic blood pressure, 7.7% and 1.1% in diastolic blood pressure, and 10.5% and 5.1% in mean arterial pressure, respectively, in patients. CONCLUSIONS: Interactions among the genetic loci of RAAS components may be used as a predictor for susceptibility to hypertension.

Screening currency notes for microbial pathogens and antibiotic resistance genes using a shotgun metagenomic approach.

Fomites are a well-known source of microbial infections and previous studies have provided insights into the sojourning microbiome of fomites from various sources. Paper currency notes are one of the most commonly exchanged objects and its potential to transmit pathogenic organisms has been well recognized. Approaches to identify the microbiome associated with paper currency notes have been largely limited to culture dependent approaches. Subsequent studies portrayed the use of 16S ribosomal RNA based approaches which provided insights into the taxonomical distribution of the microbiome. However, recent techniques including shotgun sequencing provides resolution at gene level and enable estimation of their copy numbers in the metagenome. We investigated the microbiome of Indian paper currency notes using a shotgun metagenome sequencing approach. Metagenomic DNA isolated from samples of frequently circulated denominations of Indian currency notes were sequenced using Illumina Hiseq sequencer. Analysis of the data revealed presence of species belonging to both eukaryotic and prokaryotic genera. The taxonomic distribution at kingdom level revealed contigs mapping to eukaryota (70%), bacteria (9%), viruses and archae (~1%). We identified 78 pathogens including Staphylococcus aureus, Corynebacterium glutamicum, Enterococcus faecalis, and 75 cellulose degrading organisms including Acidothermus cellulolyticus, Cellulomonas flavigena and Ruminococcus albus. Additionally, 78 antibiotic resistance genes were identified and 18 of these were found in all the samples. Furthermore, six out of 78 pathogens harbored at least one of the 18 common antibiotic resistance genes. To the best of our knowledge, this is the first report of shotgun metagenome sequence dataset of paper currency notes, which can be useful for future applications including as bio-surveillance of exchangeable fomites for infectious agents.

Genetic differences and aberrant methylation in the apelin system predict the risk of high-altitude pulmonary edema.

Hypoxia-inducible factor stimulates the expression of apelin, a potent vasodilator, in response to reduced blood arterial oxygen saturation. However, aberrations in the apelin system impair pulmonary vascular function, potentially resulting in the development of high-altitude (HA)-related disorders. This study aimed to elucidate the genetic and epigenetic regulation of apelin, apelin receptor (APLNR), and endothelial nitric oxide synthase (NOS3) in HA adaptation and HA pulmonary edema (HAPE). A genome-wide association study and sequencing identified variants of apelin, APLNR, and NOS3 that were validated in a larger sample size of HAPE-patients (HAPE-p), HAPE-free controls (HAPE-f), and healthy highland natives (HLs). Apelin-13 and nitrite levels and apelin and NOS3 expression were down-regulated in HAPE-p (P < 0.001). Among the several studied polymorphisms, apelin rs3761581, rs2235312, and rs3115757; APLNR rs11544374 and rs2282623; and NOS3 4b/4a, rs1799983, and rs7830 were associated with HAPE (P < 0.03). The risk allele rs3761581G was associated with a 58.6% reduction in gene expression (P = 0.017), and the risk alleles rs3761581G and rs2235312T were associated with low levels of apelin-13 and nitrite (P < 0.05). The latter two levels decreased further when both of these risk alleles were present in the patients (P < 0.05). Methylation of the apelin CpG island was significantly higher in HAPE-p at 11.92% than in HAPE-f and HLs at ≤ 7.1% (P < 0.05). Moreover, the methylation effect was 9% stronger in the 5' UTR and was associated with decreased apelin expression and apelin-13 levels. The rs3761581 and rs2235312 polymorphisms and methylation of the CpG island influence the expression of apelin in HAPE.

CYBA (p22phox) variants associate with blood pressure and oxidative stress markers in hypertension: a replication study in populations of diverse altitudes.

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.

Interactions between the genes of vasodilatation pathways influence blood pressure and nitric oxide level in hypertension.

BACKGROUND: This study investigates the contribution of genetic interactions between the ß-2 adrenergic receptor (ADRB2) and nitric oxide synthase (NOS3) genes to the complex etiology of hypertension. METHODS: Using single nucleotide polymorphism (SNP) markers, we studied potential interactions between ADRB2 and NOS3 variants and their correlation with clinical, biochemical, and expression levels in 546 individuals with hypertension and 884 age-, sex-, and ethnicity-matched unrelated control subjects. Generalized multifactor dimensionality reduction (GMDR) analysis identified the models for genotype interaction. RESULTS: The best models to represent association of genotypes with augmented hypertension susceptibility were the 4- and 5-locus interacting GMDR models of ADRB2 and NOS3 compared with within-gene 6-locus ADRB2 and 2-locus NOS3 (odds ratio (OR) = 4.8, P = 0.04; OR = 5.6, P = 0.02, respectively). Stratification of 4- and 5-locus GMDR models on the basis of risk alleles (in increasing order) increased the ORs from 1.26 to 14.17 and from 0.81 to 14.18, respectively, and correlated linearly with increased systolic blood pressure, diastolic blood pressure, and mean arterial pressure and decreased nitric oxide level (P ≤ 0.0004). We performed various analyses, such as single-locus, genetic interactions, sliding-window, and comparative analysis. Each analysis consistently revealed the 46A allele of ADRB2 46G/A SNP and 4a allele of NOS3 4b/4a SNP to be associated with risk of hypertension. These risk-conferring markers were associated with decreased ADRB2 and NOS3 expression and decreased nitric oxide level in the patients (P ≤ 0.04). CONCLUSIONS: Evidence of interaction between the genetic loci of ADRB2 and NOS3 points to varied clinical, biochemical, and expression levels and a role in hypertension susceptibility.

Interactions between the FTO and GNB3 genes contribute to varied clinical phenotypes in hypertension.

BACKGROUND: The genes FTO and GNB3 are implicated in essential hypertension but their interaction remains to be explored. This study investigates the role of interaction between the two genes in the pathophysiology of essential hypertension. METHODS/PRINCIPAL FINDINGS: In a case-control study comprising 750 controls and 550 patients, interaction between the polymorphisms of FTO and GNB3 was examined using multifactor dimensionality reduction (MDR). The influence of interaction on clinical phenotypes like systolic and diastolic blood pressure, mean arterial pressure and body mass index was also investigated. The 3-locus MDR model comprising FTO rs8050136C/A and GNB3 rs1129649T/C and rs5443C/T emerged as the best disease conferring model. Moreover, the interacted-genotypes having either 1, 2, 3, 4 or 5 risk alleles correlated with linearly increasing odds ratios of 1.91 (P = 0.027); 3.93 (P = 2.08E-06); 4.51 (P = 7.63E-07); 7.44 (P = 3.66E-08) and 11.57 (P = 1.18E-05), respectively, when compared with interacted-genotypes devoid of risk alleles. Furthermore, interactions among haplotypes of FTO (H1-9) and GNB3 (Ha-d) differed by >1.5-fold for protective-haplotypes, CTGGC+TC [H2+Ha] and CTGAC+TC [H4+Ha] (OR = 0.39, P = 0.003; OR = 0.22, P = 6.86E-05, respectively) and risk-haplotypes, AAAGC+CT [H3+Hc] and AAAGC+TT [H3+Hd] (OR = 2.91, P = 9.98E-06; OR = 2.50, P = 0.004, respectively) compared to individual haplotypes. Moreover, the effectiveness of gene-gene interaction was further corroborated with a 1.29-, 1.25- and 1.38-fold higher SBP, MAP and BMI, respectively, in patients having risk interacted-haplotype H3+Hc and 2.48-fold higher SBP having risk interacted-haplotype H3+Hd compared to individual haplotypes. CONCLUSION: Interactions between genetic variants of FTO and GNB3 influence clinical parameters to augment hypertension.