dbSNP in the detail and copy number complexities

dbSNP is a general catalog of genetic polymorphism maintained by NCBI, mainly collating information for single nucleotide variations, many of which will be single nucleotide polymorphisms (SNPs), but also including small indels. It takes submissions from many sources, now also including large numbers of sequence variants identified by next‐generation sequencing. A number of differently designed studies have attempted to estimate the error rates in data archived in dbSNP. Most recently, a study added to earlier studies identifying specific issues for duplicons and copy number variations (CNVs); earlier analyses have focused on stop codons, splice sites, and the general content of dbSNP. This article overviews dbSNP itself, these studies, and their implications. Hum Mutat 30:1–3, 2009. © 2009 Wiley‐Liss, Inc.     

Synthesis of a [14C]‐steroid intermediate: an application of a nonstabilized Horner–Wadsworth–Emmons olefination approach

Radiolabeled steroid derivative 1 was successfully prepared using a Horner–Wadsworth–Emmons approach: a [¹⁴C]‐label was efficiently incorporated into the C‐18 position of the molecule. Previously published procedures employing other olefination methods are either not applicable due to unavailability of [¹⁴C]‐precursors or suffer from poor reactivity.     

The A640G polymorphism in the NAD(P)H oxidase p22phox gene (CYBA) is associated with risk reduction of coronary heart disease: A meta-analysis

Background

Recently, studies have focused on the association between the p22phox gene A640G polymorphism and coronary heart disease (CHD). However, the results are inconsistent. In this study, we aimed to further evaluate this association by using meta-analysis.

Methods

The PubMed, Embase, CBM, CNKI, WanFang and Chongqing VIP databases were searched for relevant articles. Hardy–Weinberg equilibrium (HWE) of the distribution of genotypes was tested using Pearson's chi-squared test. Odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) were used to assess the strength of the association; Cochran's Q test and the I² statistic were used to evaluate heterogeneity. The random effects model and the fixed effects model were used according to heterogeneity; Begg's test and Egger's test were used to analyze publication bias. Sensitivity analysis was carried out to guarantee the stability of the results. Cumulative analysis was used to evaluate tendencies in the pooled OR.

Results

A total of eight articles including 3904 CHD cases and 3498 controls were included. A significant association between the A640G polymorphism and CHD was observed in codominant model 2 (AG versus AA: OR = 0.86, 95% CI: 0.77–0.96). In the subgroup analysis, a significant association was observed between the A640G polymorphism and CHD in Caucasians, and in PB (population-based), non-PB, HWE (studies followed HWE) and non-HWE studies.

Conclusions

Our results reveal that the A640G polymorphism may play a protective role in CHD.     

Frequencies of gene variant CCR5-Δ32 in 87 countries based on next-generation sequencing of 1.3 million individuals sampled from 3 national DKMS donor centers

Homozygous carriers of CCR5-Δ32, a gene variant of CC-type chemokine receptor 5 (CCR5), are highly resistant to infections with human immunodeficiency virus type 1 (HIV-1) and therefore preferred stem cell donors for HIV-infected patients. We analyzed CCR5 typing data of 1,333,035 potential hematopoietic stem cell donors enlisted with three national DKMS donor centers. Allele and genotype frequencies were determined for 87 countries of origin as self-assessed by the donors. CCR5-Δ32 allele frequencies ranged from 16.4% in the Norwegian sample to 0 in donors from Ethiopia. The highest CCR5-Δ32/Δ32 genotype frequency was found in the sample from the Faroe Islands (2.3%), whereas in 27 samples, predominantly of donors from Africa, Asia and South America, none of the individuals carried this genotype. The characteristic CCR5-Δ32 allele frequency decline from Northern to Southeastern Eurasia supports findings of earlier studies. With available HLA haplotype frequency information for the patient’s ethnicity, our data allows upfront estimation of the probability that an HLA-matched donor with CCR5-Δ32/Δ32 genotype can be found for a patient in need of hematopoietic stem cell transplantation.     

Cytokine gene polymorphisms in Tunisian endemic pemphigus foliaceus: A possible role of il-4 variants

Polymorphism in the genes of TH2 cytokines and/or theirs receptors can influence serum cytokine levels in and the switch to the pathologic IgG4 auto-antibodies. In order to underline the role of these genes in the aethiopathogenesis of Pemphigus Foliaceus, we conduct a familial and a case control studies including 80 Tunisian patients, 147 related subjects and 160 matched healthy controls. We investigated, by PCR-RFLP technique, seven nucleotide polymorphisms: rs2243250 in promoter region of IL4 gene, rs47877948, rs3024530 and rs30246223 in the IL4R gene, rs1881457and rs205412 SNPs in IL13 gene and rs535036 in IL13RA2 gene.     

Omega-3 fatty acids and the genetic risk of early onset acute coronary syndrome

Background and aimsRecent gene-environment interaction studies suggest that diet may influence an individual's genetic predisposition to cardiovascular risk. We evaluated whether omega-3 fatty acid intake may influence the risk for acute coronary syndrome (ACS) conferred by genetic polymorphisms among patients with early onset ACS.Methods and resultsOur population consisted of 705 patients of white European descent enrolled in GENESIS-PRAXY, a multicenter cohort study of patients aged 18–55 years and hospitalized with ACS. We used a case-only design to investigate interactions between the omega-3 index (a validated biomarker of omega-3 fatty acid intake) and 30 single nucleotide polymorphisms (SNPs) robustly associated with ACS. We used logistic regression to assess the interaction between each SNP and the omega-3 index. Interaction was also assessed between the omega-3 index and a genetic risk score generated from the 30 SNPs. All models were adjusted for age and sex. An interaction for increased ACS risk was found between carriers of the chromosome 9p21 variant rs4977574 and low omega-3 index (OR 1.57, 95% CI 1.07–2.32, p = 0.02), but this was not significant after correction for multiple testing. Similar results were obtained in the adjusted model (OR 1.55, 95% CI 1.05–2.29, p = 0.03). We did not observe any interaction between the genetic risk score or any of the other SNPs and the omega-3 index.ConclusionOur results suggest that omega-3 fatty acid intake may modify the genetic risk conferred by chromosome 9p21 variation in the development of early onset ACS and requires independent replication.     

A guide to genome‐wide association analysis and post‐analytic interrogation

This tutorial is a learning resource that outlines the basic process and provides specific software tools for implementing a complete genome‐wide association analysis. Approaches to post‐analytic visualization and interrogation of potentially novel findings are also presented. Applications are illustrated using the free and open‐source R statistical computing and graphics software environment, Bioconductor software for bioinformatics and the UCSC Genome Browser. Complete genome‐wide association data on 1401 individuals across 861,473 typed single nucleotide polymorphisms from the PennCATH study of coronary artery disease are used for illustration. All data and code, as well as additional instructional resources, are publicly available through the Open Resources in Statistical Genomics project: http://www.stat-gen.org . © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.     

Genetic association analysis of NRG1 with methamphetamine-induced psychosis in a Japanese population

The neuregulin 1 gene (NRG1) has been identified as a candidate gene for schizophrenia in a linkage study in the Icelandic population. Recent evidence also suggested that it might be related to the neurodevelopmental hypothesis and glutamate hypothesis for schizophrenia. Because the symptomatology of methamphetamine (METH) use disorder with accompanying psychosis is similar to that of patients with schizophrenia, NRG1 is an appropriate candidate gene for METH-induced psychosis. We conducted a case-control association study between NRG1 and METH-induced psychosis in a Japanese population (184 subjects with METH-induced psychosis and 534 controls). Written informed consent was obtained from each subject. We selected four SNPs (SNP8NRG221533, SNP8NRG241930, SNP8NRG243177, and rs3924999) in NRG1 from previous reports. No significant association was found between NRG1 and METH-induced psychosis in the allele/genotype-wise or haplotype-wise analyses. In conclusion, NRG1 might not contribute to the risk of METH-induced psychosis in the Japanese population.