Common variability in oestrogen-related genes and pancreatic ductal adenocarcinoma risk in women

The incidence of pancreatic ductal adenocarcinoma (PDAC) is different among males and females. This disparity cannot be fully explained by the difference in terms of exposure to known risk factors; therefore, the lower incidence in women could be attributed to sex-specific hormones. A two-phase association study was conducted in 12,387 female subjects (5436 PDAC cases and 6951 controls) to assess the effect on risk of developing PDAC of single nucleotide polymorphisms (SNPs) in 208 genes involved in oestrogen and pregnenolone biosynthesis and oestrogen-mediated signalling. In the discovery phase 14 polymorphisms showed a statistically significant association (P < 0.05). In the replication none of the findings were validated. In addition, a gene-based analysis was performed on the 208 selected genes. Four genes (NR5A2, MED1, NCOA2 and RUNX1) were associated with PDAC risk, but only NR5A2 showed an association (P = 4.08 × 10−5) below the Bonferroni-corrected threshold of statistical significance. In conclusion, despite differences in incidence between males and females, our study did not identify an effect of common polymorphisms in the oestrogen and pregnenolone pathways in relation to PDAC susceptibility. However, we validated the previously reported association between NR5A2 gene variants and PDAC risk

IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases

The Helicobacter pylori Genome Project : insights into H. pylori population structure from analysis of a worldwide collection of complete genomes

Helicobacter pylori, a dominant member of the gastric microbiota, shares co-evolutionary history with humans. This has led to the development of genetically distinct H. pylori subpopulations associated with the geographic origin of the host and with differential gastric disease risk. Here, we provide insights into H. pylori population structure as a part of the Helicobacter pylori Genome Project (HpGP), a multi-disciplinary initiative aimed at elucidating H. pylori pathogenesis and identifying new therapeutic targets. We collected 1011 well-characterized clinical strains from 50 countries and generated high-quality genome sequences. We analysed core genome diversity and population structure of the HpGP dataset and 255 worldwide reference genomes to outline the ancestral contribution to Eurasian, African, and American populations. We found evidence of substantial contribution of population hpNorthAsia and subpopulation hspUral in Northern European H. pylori. The genomes of H. pylori isolated from northern and southern Indigenous Americans differed in that bacteria isolated in northern Indigenous communities were more similar to North Asian H. pylori while the southern had higher relatedness to hpEastAsia. Notably, we also found a highly clonal yet geographically dispersed North American subpopulation, which is negative for the cag pathogenicity island, and present in 7% of sequenced US genomes. We expect the HpGP dataset and the corresponding strains to become a major asset for H. pylori genomics

Less functional variants of TLR-1/-6/-10 genes are associated with age.

BACKGROUND: Determining the prerequisites for healthy aging is a major task in the modern world characterized by a longer lifespan of the individuals. Besides lifestyle and environmental influences genetic factors are involved as shown by several genome-wide association studies. Older individuals are known to have an impaired immune response, a condition recently termed inflamm-aging . We hypothesize that the induction of this condition in the elderly is influenced by the sensitivity of the innate immune system. Therefore, we investigated genetic variants of the Toll-like receptor (TLR) family, one of the major family of innate immune receptors, for association with age in two cohorts of healthy, disease-free subjects. RESULTS: According to sex we found a positive association of loss-of-function variants of TLR-1 and -6 with healthy aging with odds ratios of 1.54 in males for TLR-6 (249 S/S), and 1.41, 1.66, and 1.64 in females for TLR-1 prom., TLR-1 (248 S/S), and TLR-1 (602 S/S), respectively. Thus, the presence of these variants increases the probability of achieving healthy old age and indicates that a reduced TLR activity may be beneficial in the elderly. CONCLUSIONS: This is the first report showing an association of TLR variants with age. While a loss of function of an important immune receptor may be a risk factor for acute infections as has been shown previously, in the setting of healthy ageing it appears to be protective, which may relate to inflamm-aging . These first results should be reproduced in larger trials to confirm this hypothesis

Application of the distance-based F test in an mGWAS investigating β diversity of intestinal microbiota identifies variants in SLC9A8 (NHE8) and 3 other loci

Factors shaping the human intestinal microbiota range from environmental influences, like smoking and exercise, over dietary patterns and disease to the host's genetic variation. Recently, we could show in a microbiome genome-wide association study (mGWAS) targeting genetic variation influencing the β diversity of gut microbial communities, that approximately 10% of the overall gut microbiome variation can be explained by host genetics. Here, we report on the application of a new method for genotype-β-diversity association testing, the distance-based F (DBF) test. With this we identified 4 loci with genome-wide significant associations, harboring the genes CBEP4, SLC9A8, TNFSF4, and SP140, respectively. Our findings highlight the utility of the high-performance DBF test in β diversity GWAS and emphasize the important role of host genetics and immunity in shaping the human intestinal microbiota