Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe

Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial

Background : Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections (LRTI). Severe asthma is heterogeneous, encompassing eosinophilic and non-eosinophilic (mainly neutrophilic) phenotypes. Patients with neutropilic airway diseases may benefit from macrolides. Methods : We performed a randomised double-blind placebo-controlled trial in subjects with exacerbation-prone severe asthma. Subjects received low-dose azithromycin (n=55) or placebo (n=54) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting beta(2) agonists for 6 months. The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase. Secondary efficacy outcomes included lung function and scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ). Results : The rate of primary endpoints (PEPs) during 6 months was not significantly different between the two treatment groups: 0.75 PEPs (95% CI 0.55 to 1.01) per subject in the azithromycin group versus 0.81 PEPs (95% CI 0.61 to 1.09) in the placebo group (p=0.682). In a predefined subgroup analysis according to the inflammatory phenotype, azithromycin was associated with a significantly lower PEP rate than placebo in subjects with non-eosinophilic severe asthma (blood eosinophilia <= 200/mu l): 0.44 PEPs (95% CI 0.25 to 0.78) versus 1.03 PEPs (95% CI 0.72 to 1.48) (p=0.013). Azithromycin significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function. Azithromycin was well tolerated, but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci. Conclusions : Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma. However, the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study