A novel approach to genome-wide association analysis identifies genetic associations with primary biliary cholangitis and primary sclerosing cholangitis in Polish patientsReport as inadecuate

A novel approach to genome-wide association analysis identifies genetic associations with primary biliary cholangitis and primary sclerosing cholangitis in Polish patients - Download this document for free, or read online. Document in PDF available to download.

BMC Medical Genomics

, 10:2

Functional and structural genomics


BackgroundPrimary biliary cholangitis PBC and primary sclerosing cholangitis PSC are forms of hepatic autoimmunity, and risk for both diseases has a strong genetic component. This study aimed to define the genetic architecture of PBC and PSC within the Polish population.

MethodsSubjects were 443 women with PBC, 120 patients with PSC, and 934 healthy controls recruited from Gastroenterology Departments in various Polish hospitals. Allelotyping employed a pooled-DNA sample-based genome-wide association study GWAS approach, using Illumina Human Omni2.5-Exome BeadChips and the following novel selection criteria for risk loci: blocks of at least 10 single nucleotide polymorphisms SNPs in strong linkage disequilibrium, where the distance between each adjacent SNP pair in the block was less than 30 kb, and each SNP was associated with disease at a significance level of P < 0.005. A selected index SNP from each block was validated using TaqMan SNP genotyping assays.

ResultsNineteen and twenty-one SNPs were verified as associated with PBC and PSC, respectively, by individual genotyping; 19 10-9, PBC-PSC SNPs reached a stringent corrected significance threshold and a further 21 9-12, PBC-PSC reached a nominal level of significance P < 0.05 with odds ratio OR > 1.2 or < 0.83, providing suggestive evidence of association. The SNPs mapped to seven 1p31.3, 3q13, 6p21, 7q32.1, 11q23.3, 17q12, 19q13.33 and one 6p21 chromosome region previously associated with PBC and PSC, respectively. The SNP, rs35730843, mapping to the POLR2G gene promoter P = 1.2 × 10, OR = 0.39 demonstrated the highest effect size, and was protective for PBC, whereas for PSC respective SNPs were: rs13191240 in the intron of ADGRB3 gene P = 0.0095, OR = 0.2 and rs3822659 P = 0.0051, OR = 0.236 along with rs9686714 P = 0.00077, OR = 0.2, both located in the WWC1 gene.

ConclusionsOur cost-effective GWAS approach followed by individual genotyping confirmed several previously identified associations and discovered new susceptibility loci associated with PBC and-or PSC in Polish patients. However, further functional studies are warranted to understand the roles of these newly identified variants in the development of the two disorders.

KeywordsGenome-wide association study Primary biliary cholangitis Primary sclerosing cholangitis AbbreviationsGWASGenome-wide association study

IBDInflammatory bowel disease

MHCMajor histocompatibility complex

OROdds ratio

PBCPrimary biliary cholangitis

PSCPrimary sclerosing cholangitis

SNPSingle nucleotide polymorphism

Electronic supplementary materialThe online version of this article doi:10.1186-s12920-016-0239-9 contains supplementary material, which is available to authorized users.

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Author: Agnieszka Paziewska - Andrzej Habior - Agnieszka Rogowska - Włodzimierz Zych - Krzysztof Goryca - Jakub Karczmarski - Micha

Source: https://link.springer.com/

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