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Polymorphisms in CLEC16A and CIITA at 16p13 Are Associated with Primary Adrenal Insufficiency

Department of Medical Genetics (B.S., K.B., T.E., D.E.U.), Ullevål University Hospital, N-0407 Oslo, Norway; Institute of Medical Genetics (B.S., D.E.U.), University of Oslo, N-0315 Oslo, Norway; Section of Endocrinology (E.S.H., A.B.W., K.L.), Institute of Medicine, University of Bergen, N-5021 Bergen, Norway; Department of Medicine (E.S.H., K.L.), Haukeland University Hospital, N-5021 Bergen, Norway; and Institute of Human Genetics (S.H.P., D.O.M.), Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom

Address all correspondence and requests for reprints to: Beate Skinningsrud, Department of Medical Genetics, Ullevål University Hospital, University of Oslo, Kirkeveien 166, N-0407 Oslo, Norway. E-mail: beate.skinningsrud{at}medisin.uio.no.

Context/Objectives: It is known that different autoimmune diseases often share the same susceptibility genes. In this study we aimed to investigate if loci found associated with common autoimmune diseases in recent genome-wide association studies also could be susceptibility loci for autoimmune Addison’s disease (primary adrenal insufficiency).

Design/Patients: A total of 139 tagging single nucleotide polymorphisms (SNPs) in 11 candidate genes (IL2, IL21, IL2RA, CLEC2D, CD69, ERBB3, PTPN11, SH2B3, CLEC16A, CIITA, and PTPN2) were genotyped in a case/control study design consisting of Norwegian Addison’s disease patients (n = 332) and Norwegian healthy control individuals (n = 1029). Five SNPs were subsequently selected for analysis in a United Kingdom sample set consisting of Addison’s disease patients (n = 210) and controls (n = 191).

Results: Polymorphisms in CLEC16A and CIITA remained significantly associated with Addison’s disease in the Norwegian sample set at the 0.05 level, even after correction for multiple testing. CLEC16A and CIITA are both located at 16p13, but linkage disequilibrium patterns and logistical regression analyses suggest that SNPs in these two genes are independently associated with Addison’s disease. We were not able to confirm these associations in the United Kingdom material, however, this may well be due to the limited sample size and lack of statistical power.

Conclusion: Two alleles at 16p13 are independently associated with the risk of Addison’s disease in the Norwegian population, suggesting this chromosomal region to harbor common autoimmunity gene(s), CLEC16A and CIITA being possible independent candidates.