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Genetic Risk Factors for Autoimmune Thyroid Disease might Affect the Susceptibility to and Modulate the Progression of Primary Biliary Cholangitis

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Aleksander Kuś1*, Magdalena Arłukowicz-Grabowska2*, Konrad Szymański3, Ewa Wunsch4, Małgorzata Milkiewicz5, Rafał Płoski3, Zakera Shums6, Gary L. Norman6, Piotr Milkiewicz2,4, Tomasz Bednarczuk1, Marcin Krawczyk7,8

1) Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw, Poland;
2) Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland;
3) Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland;
4) Translational Medicine Group, Pomeranian Medical University, Szczecin, Poland;
5) Department of Medical Biology, Pomeranian Medical University, Szczecin, Poland;
6) Inova Diagnostics, San Diego, CA, USA;
7) Department of Medicine II, Saarland University Medical Center, Homburg, Germany;
8) Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland

DOI: http://dx.doi.org/10.15403/jgld.2014.1121.263.kus

Background & Aims: Patients with primary biliary cholangitis (PBC) frequently suffer from extrahepatic autoimmune conditions, of which autoimmune thyroid disease (AITD) is one of the most common. Previous studies identified several genetic variants increasing the odds of developing AITD. Here we investigate whether AITD-associated polymorphisms might also play a role in the development and clinical course of PBC and PBC associated with AITD (PBC-AITD).
Methods: To this end, we prospectively recruited 230 patients with PBC and 421 healthy controls. Among recruited patients, 64 (30.9%) had PBC-AITD as diagnosed by elevated serum TPO-antibodies. In all subjects we genotyped 10 variants previously associated with AITD.
Results: We detected significant associations between the PTPN22 polymorphism and risk of developing PBC (rs2476601, OR=1.43, P=0.035) as well as PBC-AITD (OR=1.74, P=0.028). The IL2RA polymorphism was associated with liver cirrhosis (rs41295061, OR=1.76, P=0.033) whereas the MMEL1 polymorphism increased the risk of requiring liver transplantation (rs2843403, OR=1.70, P=0.023). Although no significant differences in clinical or biochemical characteristics between patients with PBC and PBC-AITD were seen (all P>0.05), liver function tests and metabolic traits in PBC patients were significantly (all P<0.05) affected by the CTLA4 (rs3087243), MMEL1 (rs2843403), PTPN22 (rs2476601) and RNASET2 (rs9355610) variants.
Conclusion: Our study demonstrates the existence of a genetic overlap between PBC and AITD. Apparently, genetic variants known to increase the AITD risk might affect the clinical course of PBC. On the other hand, AITD per se does not seem to significantly influence the natural history of PBC.
Key words: autoimmune liver disease – cholestasis – liver cirrhosis – liver transplantation – single nucleotide polymorphism – thyroid peroxidase antibody.
Abbreviations: AITD: autoimmune thyroid disease; ALP: alkaline phosphatase; ALT: alanine transaminase; AMA: anti-mitochondrial autoantibodies; AST: aspartate aminotransferase; DM1: diabetes mellitus type 1; ELISA: enzyme-linked immunosorbent assay method; GGT: gamma-glutamyl transpeptidase; GD: Graves’ disease; GWAS: genome-wide association studies; HT: Hashimoto thyroiditis; HWE: Hardy-Weinberg equilibrium; Lyp: lymphoid-specific protein tyrosine phosphatase non-receptor type 22; OR: odds ratio; PBC: primary biliary cholangitis; RA: rheumatoid arthritis; SLE: systemic lupus erythematosus; TPOAb: thyroid peroxidase antibody; UDCA: ursodeoxycholic acid.