Common genetic variation in multiple metabolic pathways influences susceptibility to low HDL-cholesterol and coronary heart disease

A low level of HDL-C is the most common plasma lipid abnormality observed in men with established coronary heart disease (CHD). To identify allelic variants associated with susceptibility to low HDL-C and CHD, we examined 60 candidate genes with key roles in HDL metabolism, insulin resistance, and inflammation using samples from the Veterans Affairs HDL Intervention Trial (VA-HIT; cases, n = 699) and the Framingham Offspring Study (FOS; controls, n = 705). VA-HIT was designed to examine the benefits of HDL-raising with gemfibrozil in men with low HDL-C (≤40 mg/dl) and established CHD. After adjustment for multiple testing within each gene, single-nucleotide polymorphisms (SNP) significantly associated with case status were identified in the genes encoding LIPC (rs4775065, P < 0.0001); CETP (rs5882, P = 0.0002); RXRA (rs11185660, P = 0.0021); ABCA1 (rs2249891, P = 0.0126); ABCC6 (rs150468, P = 0.0206; rs212077, P = 0.0443); CUBN (rs7893395, P = 0.0246); APOA2 (rs3813627, P = 0.0324); SELP (rs732314, P = 0.0376); and APOC4 (rs10413089, P = 0.0425). Included among the novel findings of this study are the identification of susceptibility alleles for low HDL-C/CHD risk in the genes encoding CUBN and RXRA, and the observation that genetic variation in SELP may influence CHD risk through its effects on HDL.     

Bacillus subtilis SbcC protein plays an important role in DNA inter-strand cross-link repair

Background  

Several distinct pathways for the repair of damaged DNA exist in all cells. DNA modifications are repaired by base excision or nucleotide excision repair, while DNA double strand breaks (DSBs) can be repaired through direct joining of broken ends (non homologous end joining, NHEJ) or through recombination with the non broken sister chromosome (homologous recombination, HR). Rad50 protein plays an important role in repair of DNA damage in eukaryotic cells, and forms a complex with the Mre11 nuclease. The prokaryotic ortholog of Rad50, SbcC, also forms a complex with a nuclease, SbcD, in Escherichia coli, and has been implicated in the removal of hairpin structures that can arise during DNA replication. Ku protein is a component of the NHEJ pathway in pro- and eukaryotic cells.     

Bayesian variable selection for the analysis of microarray data with censored outcomes

MOTIVATION: A common task in microarray data analysis consists of identifying genes associated with a phenotype. When the outcomes of interest are censored time-to-event data, standard approaches assess the effect of genes by fitting univariate survival models. In this paper, we propose a Bayesian variable selection approach, which allows the identification of relevant markers by jointly assessing sets of genes. We consider accelerated failure time (AFT) models with log-normal and log-t distributional assumptions. A data augmentation approach is used to impute the failure times of censored observations and mixture priors are used for the regression coefficients to identify promising subsets of variables. The proposed method provides a unified procedure for the selection of relevant genes and the prediction of survivor functions. RESULTS: We demonstrate the performance of the method on simulated examples and on several microarray datasets. For the simulation study, we consider scenarios with large number of noisy variables and different degrees of correlation between the relevant and non-relevant (noisy) variables. We are able to identify the correct covariates and obtain good prediction of the survivor functions. For the microarray applications, some of our selected genes are known to be related to the diseases under study and a few are in agreement with findings from other researchers. AVAILABILITY: The Matlab code for implementing the Bayesian variable selection method may be obtained from the corresponding author. CONTACT: mvannucci@stat.tamu.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.     

Maternal Mortality in Rural South Ethiopia: Outcomes of Community-Based Birth Registration by Health Extension Workers

Introduction

Rural communities in low-income countries lack vital registrations to track birth outcomes. We aimed to examine the feasibility of community-based birth registration and measure maternal mortality ratio (MMR) in rural south Ethiopia.

Methods

In 2010, health extension workers (HEWs) registered births and maternal deaths among 421,639 people in three districts (Derashe, Bonke, and Arba Minch Zuria). One nurse-supervisor per district provided administrative and technical support to HEWs. The primary outcomes were the feasibility of registration of a high proportion of births and measuring MMR. The secondary outcome was the proportion of skilled birth attendance. We validated the completeness of the registry and the MMR by conducting a house-to-house survey in 15 randomly selected villages in Bonke.

Results

We registered 10,987 births (81·4% of expected 13,492 births) with annual crude birth rate of 32 per 1,000 population. The validation study showed that, of 2,401 births occurred in the surveyed households within eight months of the initiation of the registry, 71·6% (1,718) were registered with similar MMRs (474 vs. 439) between the registered and unregistered births. Overall, we recorded 53 maternal deaths; MMR was 489 per 100,000 live births and 83% (44 of 53 maternal deaths) occurred at home. Ninety percent (9,863 births) were at home, 4% (430) at health posts, 2·5% (282) at health centres, and 3·5% (412) in hospitals. MMR increased if: the male partners were illiterate (609 vs. 346; p= 0·051) and the villages had no road access (946 vs. 410; p= 0·039). The validation helped to increase the registration coverage by 10% through feedback discussions.

Conclusion

It is possible to obtain a high-coverage birth registration and measure MMR in rural communities where a functional system of community health workers exists. The MMR was high in rural south Ethiopia and most births and maternal deaths occurred at home.