TEAM: efficient two-locus epistasis tests in human genome-wide association study

As a promising tool for identifying genetic markers underlying phenotypic differences, genome-wide association study (GWAS) has been extensively investigated in recent years. In GWAS, detecting epistasis (or gene–gene interaction) is preferable over single locus study since many diseases are known to be complex traits. A brute force search is infeasible for epistasis detection in the genome-wide scale because of the intensive computational burden. Existing epistasis detection algorithms are designed for dataset consisting of homozygous markers and small sample size. In human study, however, the genotype may be heterozygous, and number of individuals can be up to thousands. Thus, existing methods are not readily applicable to human datasets. In this article, we propose an efficient algorithm, TEAM, which significantly speeds up epistasis detection for human GWAS. Our algorithm is exhaustive, i.e. it does not ignore any epistatic interaction. Utilizing the minimum spanning tree structure, the algorithm incrementally updates the contingency tables for epistatic tests without scanning all individuals. Our algorithm has broader applicability and is more efficient than existing methods for large sample study. It supports any statistical test that is based on contingency tables, and enables both family-wise error rate and false discovery rate controlling. Extensive experiments show that our algorithm only needs to examine a small portion of the individuals to update the contingency tables, and it achieves at least an order of magnitude speed up over the brute force approach

Dietary Patterns, Abdominal Visceral Adipose Tissue and Cardiometabolic Risk Factors in African Americans: the Jackson Heart Study

Dietary behavior is an important lifestyle factor to impact an individual’s risk of developing cardiovascular disease (CVD). However, the influence of specific dietary factors on CVD risk for African Americans remains unclear. We conducted a cross-sectional study of 1775 participants from Jackson Heart Study (JHS) Exam 2 (between 2006 and 2009) who were free of hypertension, diabetes and CVD at the baseline (between 2001 and 2004). Dietary intakes were documented using a validated food-frequency questionnaire (FFQ) and dietary patterns were generated by factor analysis. Three major dietary patterns were identified: a “southern”, a “fast food” and a “prudent” pattern. After adjustment for age, sex, smoking and alcohol status, education level and physical activity, high “southern” pattern score was associated with an increased odds ratio (OR) for high abdominal visceral adipose tissue (VAT) (OR:1.80, 95%CI:1.1–3.0, p=0.02), hypertension (OR:1.42, 95%CI:1.1–1.9, p=0.02), diabetes (OR:2.03, 95%CI:1.1–3.9, p=0.03) and metabolic syndrome (OR:2.16, 95%CI:1.3–3.6, p=0.004). Similar associations were also observed in the “fast food” pattern (p ranges 0.03–0.0001). The “prudent” pattern was significantly associated, in a protective direction, with hypertension (OR 0.69, 95%CI 0.5–0.9, p=0.02). In conclusion, dietary patterns, especially the “southern” pattern, identified from a regional specific FFQ in this Deep South African Americans, are correlated with abdominal VAT and cardiometabolic risk factors

Characterization of the c.190T>C missense mutation in BRCA1 codon 64 (Cys64Arg).

In the Milan area (Northern Italy), we identified a family characterized by a high prevalence of ovarian and breast cancer cases (5 out of 6 subjects, over 3 generations), and a predominant prevalence of ovarian lesions (4 out of 5 patients). Analysis of BRCA1 and BRCA2 genes allowed the identification of the missense c.190T>C mutation in codon 64 (Cys64Arg) of BRCA1. The aims of the present investigation were to characterize the functional implications of the c.190T>C mutation at the molecular level, and to search whether additional polymorphisms might be linked to the peculiar phenotypic features observed in the Italian pedigree. Molecular modelling studies suggested that substitution of the cysteine 64 with an arginine likely disrupts the architecture of the BRCA1 RING finger domain, responsible for the interaction with BARD1, essential for the tumor-suppressor activity of the BRCA1-BARD1 complex. By splicing site information analysis, exonic splicing enhancer site characterization, and analysis of transcript fragment length and sequence, we showed that the c.190T>C mutation was able to modulate the splicing of exon 5 in a fashion opposite to the c.190T>G transversion, responsible for the functionally-related Cys64Gly amino acid substitution. Genotyping of BRCA1 and BRCA2 in the Italian family revealed the presence of two significant polymorphisms: the cancer-associated c.2612C>T SNP in BRCA1, and the c.-26G>A SNP in the BRCA2 gene, acting as an ovarian cancer risk modifier in carriers of deleterious BRCA1 mutations. Analysis of these SNPs in a genotypically-unrelated Polish family, characterized by prevalent breast neoplasms in carriers of the c.190T>C mutation, revealed a genetic profile consistent with the hypothetic role of both polymorphisms

The combined effects of genetic risk and perceived discrimination on blood pressure among African Americans in the Jackson Heart Study

Both genomics and environmental stressors play a significant role in increases in blood pressure (BP). In an attempt to further explain the hypertension (HTN) disparity among African Americans (AA), both genetic underpinnings (selected candidate genes) and stress due to perceived racial discrimination (as reported in the literature) have independently been linked to increased BP among AAs. Although Gene x Environment interactions on BP have been examined, the environmental component of these investigations has focused more on lifestyle behaviors such as smoking, diet, and physical activity, and less on psychosocial stressors such as perceived discrimination

Tools for efficient epistasis detection in genome-wide association study

<p>Abstract</p> <p>Background</p> <p>Genome-wide association study (GWAS) aims to find genetic factors underlying complex phenotypic traits, for which epistasis or gene-gene interaction detection is often preferred over single-locus approach. However, the computational burden has been a major hurdle to apply epistasis test in the genome-wide scale due to a large number of single nucleotide polymorphism (SNP) pairs to be tested.</p> <p>Results</p> <p>We have developed a set of three efficient programs, FastANOVA, COE and TEAM, that support epistasis test in a variety of problem settings in GWAS. These programs utilize permutation test to properly control error rate such as family-wise error rate (FWER) and false discovery rate (FDR). They guarantee to find the optimal solutions, and significantly speed up the process of epistasis detection in GWAS.</p> <p>Conclusions</p> <p>A web server with user interface and source codes are available at the website <url>http://www.csbio.unc.edu/epistasis/</url>. The source codes are also available at SourceForge <url>http://sourceforge.net/projects/epistasis/</url>.</p

Drug-gene interactions of antihypertensive medications and risk of incident cardiovascular disease: a pharmacogenomics study from the CHARGE consortium

Background Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. Methods Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). Results Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction &gt; 5.0×10−8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD

Development and Validation of Risk Prediction Models for Cardiovascular Events in Black Adults: The Jackson Heart Study Cohort

Cardiovascular risk assessment is a fundamental component of prevention of cardiovascular disease (CVD). However, commonly used prediction models have been formulated in primarily or exclusively white populations. Whether risk assessment in black adults is dissimilar to that in white adults is uncertain

Efficacy and Safety of Tunneled Pleural Catheters in Adults with Malignant Pleural Effusions: A Systematic Review

BackgroundMalignant pleural effusions (MPE) are a frequent cause of dyspnea and discomfort at the end of cancer patients' lives. The tunneled indwelling pleural catheter (TIPC) was approved by the FDA in 1997 and has been investigated as a treatment for MPE.ObjectiveTo systematically review published data on the efficacy and safety of the TIPC for treatment of MPE.DesignWe searched the MEDLINE, EMBASE, and ISI Web of Science databases to identify studies published through October 2009 that reported outcomes in adult patients with MPE treated with a TIPC. Data were aggregated using summary statistics when outcomes were described in the same way among multiple primary studies.Main measuresSymptomatic improvement and complications associated with use of the TIPC.Key resultsNineteen studies with a total of 1,370 patients met criteria for inclusion in the review. Only one randomized study directly compared the TIPC with the current gold standard treatment, pleurodesis. All other studies were case series. Symptomatic improvement was reported in 628/657 patients (95.6%). Quality of life measurements were infrequently reported. Spontaneous pleurodesis occurred in 430/943 patients (45.6%). Serious complications were rare and included empyema in 33/1168 patients (2.8%), pneumothorax requiring a chest tube in 3/51 (5.9%), and unspecified pneumothorax in 17/439 (3.9%). Minor complications included cellulitis in 32/935 (3.4%), obstruction/clogging in 33/895 (3.7%) and unspecified malfunction of the catheter in 11/121 (9.1%). The use of the TIPC was without complication in 517/591 patients (87.5%).ConclusionsBased on low-quality evidence in the form of case series, the TIPC may improve symptoms for patients with MPE and does not appear to be associated with major complications. Prospective randomized studies comparing the TIPC to pleurodesis are needed before the TIPC can be definitively recommended as a first-line treatment of MPE

AGT M235T Genotype/Anxiety Interaction and Gender in the HyperGEN Study

BACKGROUND. Both anxiety and elevated heart rate (HR) have been implicated in the development of hypertension. The HyperGen cohort, consisting of siblings with severe and mild hypertension, an age-matched random sample of persons from the same base populations, and unmedicated adult offspring of the hypertensive siblings (N=1,002 men and 987 women), was analyzed for an association of the angiotenisinogen AGTM235T genotype (TT, MT, MM) with an endophenotype, heart rate (HR) in high and low anxious groups. METHODOLOGY. The interaction of AGTM genotype with anxiety, which has been independently associated with hypertension, was investigated adjusting for age, hypertension status, smoking, alcohol consumption, beta blocker medication, body mass index, physical activity and hours of television viewing (sedentary life style). PRINCIPAL FINDINGS. Although there was no main effect of genotype on HR in men or women, high anxious men with the TT genotype had high HR, whereas high anxious men with the MM genotype had low HR. In women, HR was inversely associated with anxiety but there was no interaction with genotype. CONCLUSION/SIGNIFICANCE. The results suggest that high anxiety in men with the TT genotype may increase risk for hypertension whereas the MM genotype may be protective in high anxious men. This type of gene x environment interaction may be one reason why genome wide association studies sometimes fail to replicate. The locus may be important only in combination with certain environmental factors.National Heart, Lung and Blood Institute (UT FC, HL54472, HL54473, HL54495, HL54496, HL54497, HL54509, HL54515