Large-scale sequencing identifies multiple genes and rare variants associated with Crohn's disease susceptibility

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn's disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Ancestral diversity in pharmacogenomics affects treatment for Hispanic/Latine populations with inflammatory bowel disease

The prevalence of inflammatory bowel disease (IBD) among Hispanic/Latine communities is increasing. Pharmacogenomic studies reveal genetic markers that influence treatment decisions. The aim of our study was to examine the frequency and impact of genetic polymorphisms on thiopurine-associated leukopenia (NUDT15, TPMT) and anti-TNF immunogenicity (HLA-DQA1*05) in a cohort of Hispanic patients of diverse ancestral backgrounds. We performed a multicenter, retrospective cohort study comprised of 2225 Hispanic participants. We measured the frequency of variation affecting drug response in NUDT15, TPMT, and HLA-DQA1*05, their ancestral origin (European, African, or Amerindian), and the rate of development of myelosuppression and immunogenicity to thiopurines and anti-TNFs, respectively, in exposed patients. NUDT15 and TPMT variants were rare, except for rs116855232 in NUDT15 which was common only in alleles of Amerindian origin. All NUDT15 variant alleles were inherited on an Amerindian haplotype, and among the Amerindian allele subset, the variant frequency of NUDT15*4 (rs147390019) was a remarkable 23% in patients with leukopenia but only 3% in patients without leukopenia. HLA-DQA1*05 and its European tagging variant rs2097432 were common in alleles from all ancestral origins and demonstrated association with immunogenicity to anti-TNFs. However, rs2097432 was only correlated with HLA-DQA1*05 in the European allele subset. These findings indicate that NUDT15 testing should become standard clinical practice before prescribing thiopurines in individuals with Amerindian ancestry, including Hispanic individuals. Additionally, rs2097432 should not be used as a surrogate for HLA-DQA1*05 testing for diverse populations. Ultimately, incorporating ancestry in personalized therapeutic approaches is important for treatment of Hispanic patients with IBD