Risk conferred by tagged SNPs of AGT gene in causing susceptibility to essential hypertension

Introduction: AGT gene harbors several variants of which 21 are found to be in high linkage disequilibrium as per Hapmap database. Studies delineating the importance of these tagged SNPs are very limited and lacking from Indian population. In the present study, we evaluated the contribution of four tagged SNPs namely, g.6635G?>?A, g.6506G?>?A, g.12840G?>?A, and g.13828T?>?C at AGT locus along with the analyses of haplotype and epistatic interactions in causing susceptibility to essential hypertension (EHT).

Methods: About 215 hypertensives and 230 normotensives were genotyped for selected tagged SNPs using PCR-RFLP method.

Results: Significant association was obtained for g.6635G?>?A and g.6506G?>?A polymorphisms wherein GG homozygotes for both the markers were at risk for developing the condition. g.13828T?>?C polymorphism specially, female heterozygotes (TC) were found to be at increased risk for EHT. Haplotype GGGC was found to have a significant protective effect (p?=?0.0059). Markers g.6506G?>?A and g.12840G?>?A resulted in the creation of new enhancer sites thereby affecting splicing process.

Conclusion: The present report is the first one in the literature showing general- and gender-specific association of g.6506G?>?A and g.13828T?>?C polymorphisms, respectively, with EHT. However, further studies for replication of present observations are warranted from other populations and other parts of India.     

Period 3 gene polymorphism and sleep adaptation to stressful urban environments

This study's objective was to investigate the relationship between a variable‐number tandem‐repeat (VNTR) Period 3 gene (PER3) polymorphism and sleep adaptation to stressful urban environments. Seventy‐five (49 female) African American participants (ages 18–35 years) living in neighbourhoods with high rates of violent crime were selected for the study based on converging criteria for good or poor sleep. Categorization of sleep quality was based on the Insomnia Severity Index (ISI), estimates of typical sleep duration and sleep efficiency. Other assessments included the Fear of Sleep Index (FOSI) and City Stress Inventory (CSI). Whole blood DNA was analysed for the 4 and 5 VNTR alleles using polymerase chain reaction (PCR) and restrictive enzyme digestion. Fifty‐seven per cent of those who were homo‐ or heterozygous for the 4‐repeat allele were poor sleepers versus 25% of those homozygous for the 5‐repeat allele; χ² = 4.17, P = 0.041. In a logistic regression model with all the variables with significant bivariate relationships to sleep quality group, FOSI was the only significant predictor (χ² = 5.68, P = 0.017). FOSI scores were higher among those with the 4‐repeat allele (t = 2.66, P = 0.013). The PER3 4 and 5 VNTR polymorphisms appear to influence sensitivity to the effects of stressful urban environments on sleep. While FOSI was the only variable associated independently with sleep quality category, the candidate vulnerability allele was also associated with greater ‘fear of sleep’.     

Association of an Intronic Variant of the Heme Oxygenase-1 Gene with Hypertension in Northern Chinese Han Population

Heme oxygenase was regarded as a regulator of oxidative stress, which was believed to underlie the etiology of hypertension. To assess the effect of its encoded genes (HMOX1 and HMOX2) on hypertension, we designed a case-control study in 503 cases and 490 controls. The results indicated that the rs9607267 of the HMOX1 gene was significantly associated with essential hypertension (EH) and the Hap3(T-C-G) of the HMOX1 gene was also significantly associated with the risk of EH. No association was observed between the HMOX2 gene and EH. The multifactor-dimensionality reduction analyses results did not show any interaction between the HMOX1 and HMOX2 genes underlying the development of hypertension.     

CHRNB3 is more strongly associated with Fagerström Test for Cigarette Dependence-based nicotine dependence than cigarettes per day: phenotype definition changes genome-wide association studies results

AIMS: Nicotine dependence is a highly heritable disorder associated with severe medical morbidity and mortality. Recent meta-analyses have found novel genetic loci associated with cigarettes per day (CPD), a proxy for nicotine dependence. The aim of this paper is to evaluate the importance of phenotype definition (i.e. CPD versus Fagerstr?m Test for Cigarette Dependence (FTCD) score as a measure of nicotine dependence) on genome-wide association studies of nicotine dependence. DESIGN: Genome-wide association study. SETTING: Community sample. PARTICIPANTS: A total of 3365 subjects who had smoked at least one cigarette were selected from the Study of Addiction: Genetics and Environment (SAGE). Of the participants, 2267 were European Americans, 999 were African Americans. MEASUREMENTS: Nicotine dependence defined by FTCD score ≥4, CPD. FINDINGS: The genetic locus most strongly associated with nicotine dependence was rs1451240 on chromosome 8 in the region of CHRNB3 [odds ratio (OR)?=?0.65, P?=?2.4?×?10(-8) ]. This association was further strengthened in a meta-analysis with a previously published data set (combined P?=?6.7?×?10(-16) , total n?=?4200). When CPD was used as an alternate phenotype, the association no longer reached genome-wide significance (β?=?-0.08, P?=?0.0004). CONCLUSIONS: Daily cigarette consumption and the Fagerstrom Test for Cigarette Dependence show different associations with polymorphisms in genetic loci.     

Suggestive evidence of genetic association of −572G > C polymorphism with primary open angle glaucoma in a North Indian Punjabi population

BackgroundIL6 is an important candidate gene implicated in the pathogenesis of glaucoma. The present study assessed the genetic association of −174G > C and −572G > C polymorphisms in the IL6 promoter region with primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) in a north Indian Punjabi cohort.Methods910 subjects (313 POAG, 148 PACG cases and 449 controls) were recruited. Genotyping was done by TaqMan assays. Genetic association was tested under different genetic models using Plink. Diplotype and linkage disequilibrium (LD) analysis was done through Haploview. Association of clinical parameters with the genotypes was assessed by one-way ANOVA. Adjustment for potential confounding variables was done by binary logistic regression. IL6 levels were measured in POAG patients and controls.Results572G > C variant showed marginal difference in genotype frequency between pooled cases and POAG subgroup with respect to controls (p = 0.042; OR = 1.33; and p = 0.041; OR = 1.37). The GC genotype conferred 1.37-fold protection under codominant model in POAG cases (p = 0.034, OR = 1.37, 95% CI = 1.02–1.85; p_corr = 0.025, OR = 1.45, 95% CI = 1.04–2.02). The mean value for IOP was elevated among cases having ‘CC’ genotype at the −572G > C locus (p = 0.037).Lower levels of IL6 were detected in POAG patients in plasma samples (p = 0.0001).ConclusionThe study reports suggestive evidence for −572G > C variant in IL6 in affecting genetic susceptibility to POAG in the targeted North Indian Punjabi cohort. A correlation of IL6 levels in aqueous humor (AH) and systemic circulation in POAG was observed, the functional and diagnostic relevance of which may be further investigated.     

The Astounding Breadth of Health Disparity: Phenome-Wide Effects of Race on Disease Risk

ObjectiveWe conducted a phenotype-wide association study (PheWAS) to compare diagnoses among Blacks with those of Whites in one health center in Tennessee using data from 1,883,369 patients.MethodsWe used our deidentified EHR, the Synthetic Derivative, to assess risk of diagnoses associated with Black as compared with White race using Firth logistic regression with covariates including age, sex, and density of clinical encounters.ResultsThere were anchoring associations in both directions, including the highest increased risk for Blacks of having sickle cell anemia, and strongest decreased risk of basal cell carcinoma. Results included established areas of disparity and many novel associations.ConclusionsPheWAS is a viable tool for calculating risk associated with any biomarker. The current analysis provide a new approach to generating hypotheses and understanding the breadth of health disparities. Future analyses will further explore causality, risk factors, and potential confounders not accounted for here.     

Piccolo genotype modulates neural correlates of emotion processing but not executive functioning

Major depressive disorder (MDD) is characterized by affective symptoms and cognitive impairments, which have been associated with changes in limbic and prefrontal activity as well as with monoaminergic neurotransmission. A genome-wide association study implicated the polymorphism rs2522833 in the piccolo (PCLO) gene—involved in monoaminergic neurotransmission—as a risk factor for MDD. However, the role of the PCLO risk allele in emotion processing and executive function or its effect on their neural substrate has never been studied. We used functional magnetic resonance imaging (fMRI) to investigate PCLO risk allele carriers vs noncarriers during an emotional face processing task and a visuospatial planning task in 159 current MDD patients and healthy controls. In PCLO risk allele carriers, we found increased activity in the left amygdala during processing of angry and sad faces compared with noncarriers, independent of psychopathological status. During processing of fearful faces, the PCLO risk allele was associated with increased amygdala activation in MDD patients only. During the visuospatial planning task, we found no genotype effect on performance or on BOLD signal in our predefined areas as a function of increasing task load. The PCLO risk allele was found to be specifically associated with altered emotion processing, but not with executive dysfunction. Moreover, the PCLO risk allele appears to modulate amygdala function during fearful facial processing in MDD and may constitute a possible link between genotype and susceptibility for depression via altered processing of fearful stimuli. The current results may therefore aid in better understanding underlying neurobiological mechanisms in MDD.     

Effects in Adherent Subjects

Dropouts confound the treatment effect when the outcome and the dropout process both depend on subject characteristics. If dropout is unrelated to treatment, there is an unconfounded effect, but it is the effect in a principal stratum, rather than a de jure effect. There are at least two different definitions of the effect if all subjects adhered, giving effects different numerically from each other and from the effect in the adherent principal stratum. Estimation of either of these two effects requires an assumption (MAR) different from but sometimes confused with the assumption that dropout is unrelated to treatment.