Localization of breast cancer susceptibility loci by genome-wide SNP linkage disequilibrium mapping

We studied the feasibility of a novel approach to localize breast cancer susceptibility genes, using a low-density genome-wide panel of single-nucleotide polymorphisms and taking advantage of large regions of linkage disequilibrium (LD) flanking Jewish disease genes in high-risk cases. With Affymetrix GeneChip arrays, we genotyped 8,576 polymorphisms in three sets of Ashkenazi Jewish breast cancer cases: a "validation" set of 27 breast cancer cases, all of whom carried the BRCA2*6174delT founder mutation; a "field" set of 19 breast cancer cases from male breast cancer kindreds, which simulated conditions for finding new genes; and a "test" set of 57 probands from breast cancer kindreds (4 or more cases/kindred), in which mutations in BRCA1 and BRCA2 had been excluded. To identify associations, we compared the frequency of genotypes and haplotypes in cases vs. controls by the Fisher's exact test and a maximum likelihood ratio test. In the "validation" set, we demonstrated the presence of a region of linkage disequilibrium on BRCA2*6174delT chromosomes that spanned over 5 million bases. In the "field" set, we showed that this large region of linkage disequilibrium flanking BRCA2 was detectable despite the presence of heterogeneity in the sample set. Finally, in the "test" set, at least three regions of interest emerged that could contain novel breast cancer genes, one of which had been identified previously by linkage analysis. While these results demonstrate the feasibility of genome-wide association strategies, further application of this approach will critically depend on optimizing the density and distribution of SNPs and the size and type of study design.     

Effects of chronic sympatho-inhibition on reflex control of renal blood flow and plasma renin activity in renovascular hypertension

Background and purpose:

We determined if chronic sympatho-inhibition with rilmenidine has functional significance for the kidney by altering responses of renal blood flow (RBF) and plasma renin activity (PRA) to stress and acute hypotension in rabbits with renovascular hypertension.

Experimental approach:

RBF to each kidney and renal sympathetic nerve activity (RSNA) to the left kidney were measured in rabbits in which a renal artery clip induced hypertension (2K1C) and in sham-operated rabbits. After 2 weeks, a subcutaneous minipump was implanted to deliver rilmenidine (2.5 mg·kg⁻¹·day⁻¹) to 2K1C rabbits for 3 weeks.

Key results:

After 5 weeks of renal artery stenosis, mean arterial pressure (MAP) was 23% higher and PRA 3-fold greater than in sham-operated rabbits. Blood flow and renal vascular conductance in the stenosed kidney were lower (−75% and −80%) compared with sham, and higher in the non-clipped kidney (68% and 39%). Responses of RBF and PRA to hypotension were similar in 2K1C and sham rabbits. Airjet stress evoked a greater increase in MAP in 2K1C rabbits than sham controls. Chronic rilmenidine normalized MAP, reduced RSNA and PRA, and did not reduce RBF in the stenosed kidney. Responses of RBF (clipped and non-clipped kidney), RSNA and PRA to hypotension and airjet were little affected by rilmenidine.

Conclusions and implications:

Our observations suggest that chronic sympatho-inhibition is an effective antihypertensive therapy in renovascular hypertension. It normalizes MAP and reduces basal PRA without compromising blood flow in the stenosed kidney or altering responses of MAP, haemodynamics and PRA to acute hypotension and stress.     

Association between anti-tumour necrosis factor therapy and risk of ischaemic stroke in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Registers-Rheumatoid Arthritis (BSRBR-RA)

BackgroundPeople with rheumatoid arthritis are at increased risk of cardiovascular morbidity and mortality, including stroke (cerebrovascular accident [CVA]). Anti-tumour necrosis factor (anti-TNF) therapy may influence the risk of CVA by reducing inflammation. The aim of the analysis was to study the association of anti-TNF therapy with risk of ischaemic CVA in rheumatoid arthritis.MethodsThe British Society for Rheumatology Biologics Registers-Rheumatoid Arthritis (BSRBR-RA) is an ongoing national prospective observational cohort study. Patients with rheumatoid arthritis recently started on anti-TNF therapy and a biologic-naive comparator group treated only with non-biologic disease modifying anti-rheumatic drugs (nbDMARDs) were recruited to the BSRBR-RA from 2001 to 2008. Patients were followed by physician and patient questionnaires and also linked to the national death register. Incident CVAs were identified from all three sources of follow-up. CVAs were validated against WHO criteria for CVA and further classified as ischaemic CVA using CT brain reports or if ischaemic CVA was reported as the underlying cause of death from death certificates according to International Classification of Diseases 10 (ICD-10) code I63. Patients with a previous CVA were excluded. Risk of ischaemic CVA was compared between the nbDMARD cohort and people ever exposed to anti-TNF using a Cox regression model. Missing baseline data were replaced by multiple imputation. Adjustment was made for confounders using propensity scores stratified by deciles.FindingsTo Oct 31, 2010, 130 verified incident ischaemic CVAs (21 in 3271 nbDMARD patients, 109 in 11 642 anti-TNF patients) had occurred during 11 973 and 61 226 person-years of observation, respectively (incidence rate 175 vs 178 per 100 000 person-years). After adjustment for confounders, there was no association between ever exposure to anti-TNF and ischaemic CVA risk (hazard ratio 0·88 [95% CI 0·46–1·71]).InterpretationExposure to anti-TNF therapy does not appear to be associated with risk of ischaemic CVA when compared with nbDMARD therapy. Further follow-up is needed to assess time-varying risk.FundingBritish Society for Rheumatology.     

An autosomal genome-wide screen for celiac disease in Bedouin families

Celiac disease is a common, familial autoimmune disease caused by exposure to gliadin in wheat, and related prolamins in barley and rye. The prevalence of the disease is approximately 1:133. Celiac disease can cause significant morbidity. The only treatment is a gluten-free diet. A genome-wide search of 405 microsatellite markers was performed on samples from 18 Bedouin families with a minimum of two cases of celiac disease. Non-parametric and parametric (including both dominant and recessive models of inheritance) linkage analyses were performed. The most significant genome-wide linkage evidence was at chromosome 3p26 with an HLod of 3.21, under the dominant model. The only other HLod or NPL greater than 2 was at 4q35, with an HLod of 2.15 under a dominant model. The region at 3p26, previously reported in two linkage analyses, harbors interleukin receptor genes, plausible candidates for celiac disease.     

Vitamin K epoxide reductase expression and prostate cancer risk

Purpose

Increasing evidence has demonstrated that men taking the anticoagulant warfarin have a lower risk of developing prostate cancer. This phenomenon is not observed in other cancers. We sought to determine if the target of warfarin, vitamin K epoxide reductase (VKOR), is expressed in benign and cancerous prostate tissues and if a functional single nucleotide polymorphism (SNP) in the VKOR gene is associated with prostate cancer risk.