Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL , and CARD9

Abstract

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1186PSC patients and 1748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1491 controls from the Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls) and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes2p16 (p value 4.12×10−4), 4q27 (p value 4.10×10−5) and 9q34 (p value 8.41×10−4) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease(IBD), SNPs at 4q27and9q34 were nominally associated (p<0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify non-random, evidence-based links we used GRAIL analysis showing interconnectivity between genes in six out of in total nine PSC-associated regions. Expression quantitative trait analysis from 1469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis-gene expression. These analyses prioritized IL2, CARD9 and REL as novel candidates. Conclusion We have identified three UC susceptibility loci to be associated with PSC, harboring the putative candidate genes REL, IL2 and CARD9. These results add to the scarce knowledge on the genetic background of PSC and imply an important role for both innate and adaptive immunological factors.

Biomarkers for disease progression of primary sclerosing cholangitis

“…[79][80][81][82] It is still unknown whether individual differences in PSC sub-phenotypes are driven by genetic background. The PSC Immunochip sub-phenotyping project, a study initiated by the International PSC study group (IPSCSG) is currently investigating, these possible associations between PSC risk loci and PSC sub-phenotype.…”

Genetic Approach to Frequently Seen Pediatric Gastrointestinal System Diseases: Review

“…Örneğin; "protein tyrosine phosphatase, non-receptor type (PTPN22)" genindeki R620W varyantı Tip 1 diyabet ve romatoid artrit için güçlü bir risk faktörü iken Crohn hastalığı için koruyucu etkiye sahiptir. 48 Bu ortak genlerin etkileri, bazen komplikasyon riskini belirlemeye de ışık tutabilir. "Macrophage stimulating 1 (MST1)", "interlökin 2 (IL2)", "caspase recruitment domain family, member 9 (CARD9)" ve "V-Rel avian reticuloendotheliosis viral oncogene homolog (REL)" genleri ülseratif kolit ve komplikasyonu olan primer sklerozan kolanjit ile ilişkilidir.…”

Liver Complications in Inflammatory Bowel Diseases

“…MST1 has been linked to IBD already before whereas BCL2L11 is known to be involved in apoptotic processes. Shortly afterwards, the same authors listed IL-2, CARD9 and REL, all involved in innate and adaptive immunity, linked to PSC [5]. The largest genetic study was reported recently [6].…”