Newly identified genetic risk variants for celiac disease related to the immune response

Abstract

Statement LF and DAvH analysed UK GWAS data, selected SNPs and designed assays for golden gate genotyping. Substantial contributions to sample collections were made by DAvH, LD, GKTH, PH, JRFW, DSS (UK2 cases); DPS, WLMcA (1958 cohort controls); CJM, WV, MLM (DUTCH samples); VT, FMS, COM, NPK, DK (IRISH samples). UKGWAS genotyping was performed as described in PD lab2. KAH extracted UKGWAS and UK2 celiac DNA samples and performed UK2 sample golden gate genotyping. GrahamT and AWR prepared Irish DNA samples. GrahamT, AWR and KAH performed Irish sample golden gate genotyping. UK2 and IRISH genotyping was performed in CAM lab, DP performed quality control steps. AZ prepared DUTCH celiac and control DNA samples, and AZ and JR performed DUTCH sample golden gate genotyping in CW lab. DVH and KAH performed final golden gate genotype clustering on all samples, with assistance from RG. LD and DAvH collected Paxgene RNA celiac blood samples, GH extracted Paxgene RNA, GH and MB performed expression chips in CW lab, GH and LF analysed expression data. GosiaT performed IL18RAP re-sequencing. MCW processed intestinal biopsies, MB and MCW performed expression chips in CW lab, MCW and GH analysed expression data. DJP performed analysis of genes in intestinal T cell subsets. KAH and GH performed bioinformatics and annotation of celiac risk variant regions DAvH, RMM, CW were Principal Investigators and directed respectively the UK, IRISH and DUTCH sample collections and with RJP designed overall strategy and obtained funding for the study. DAvH directed the entire study, performed statistical analysis and generated the figures. DAvH and CW wrote the paper. RMcG, FT and WMMcL performed additional statistical analysis. To identify additional celiac disease susceptibility genes, we recently tested 310,605 SNPs in a genome wide association study of 778 celiac cases and 1,422 population controls from the United Kingdom (UKGWAS), using the Illumina HumanHap300 BeadChip2. The only SNP outside the HLA region demonstrating genome-wide significance was rs13119723 on 4q27, located in a ∼500 kb block of linkage disequilibrium (LD) containing the IL2 and IL21 genes2. Independent replication of SNPs from the IL2-IL21 region was established in both Dutch and Irish collections of celiac patients and controls. We estimate, using the current markers, that the IL2-IL21 region explains less than 1% of the increased familial risk to celiac disease, suggesting that there are additional unidentified susceptibility genes. Since we observed a greater number of significantly associated SNPs in the UKGWAS than would be expected by chance, we proceeded to study >1,000 of the most significant UKGWAS association results in a further 1,643 celiac cases and 3,406 controls from three independent European celiac disease collections. This two-stage strategy, involving a joint analysis of all data, substantially reduces the genotyping requirements versus performing whole genome genotyping on all samples and has been shown to maintain sufficient statistical power3. ...

Dynamic Role of trans Regulation of Gene Expression in Relation to Complex Traits

“…Not only was the cis-locus found to be associated with risk of CAD/ MI, 37 recent studies describe the trans-regulation of MYADM (MIM: 609959) and TAGAP (MIM: 609667) expression by the same trans-eQTL. 38,39 In addition, we found on average that 11% of trans-regulation of transeGenes for this module is mediated through expression of ALDH2, suggesting a new target and regulatory mechanism related to this CAD/MI module. Two additional causal loci are RAB3GAP1 (MIM: 602536) for total cholesterol (eGenes MCM6 [MIM: 601806] and DARS [MIM: 603084]) and LOC105375745 for triglycerides (eGene TRIB1 [MIM: 609461]).…”

Differential contribution of CDKAL1 variants to psoriasis, Crohn's disease and type II diabetes

“…13 Similarly, TNFAIP3 alleles have been associated with rheumatoid arthritis, 14 systemic lupus erythematosus 15 and type I diabetes. 16 Similar instances of genes conferring susceptibility to multiple conditions (for example, PTPN2, IL2RA and IL2) have emerged from other genome-wide association scans, 17,18 highlighting unexpected connections between clinically distinct disorders.…”

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

“…Besides the platelet phenotypes (Soranzo et al , 2009; Takizawa et al , 2010) and the also known association with blood pressure (Levy et al , 2009; Newton‐Cheh et al , 2009), SH2B3 seems to mainly influence inflammatory processes. From a genetic point of view, this is already noticeable from the associations of the locus with different inflammatory diseases, for example coeliac disease (Hunt et al , 2008), type 1 diabetes (Barrett et al , 2009; Concannon et al , 2009) and high eosinophil numbers (Gudbjartsson et al , 2009). An experimental study revealed that Sh2b3/Lnk influences the activation of dendritic cells, thereby modulating the immune response, that is dendritic cells from Lnk −/− mice are hyper‐responsive to IL‐15, resulting in an excessive production of IFN‐γ (Mori et al , 2014).…”