SFEBES2013 Poster Presentations Steroids (37 abstracts)
Novel loci for familial autoimmune Addison's disease detected by linkage analysis
Anna L Mitchell 1 , Anette Boe Wolff 2 , Earn H Gan 1 , Katie MacArthur 1 , Martina M Erichsen 2 , Jolanta U Weaver 3 , Bijay Vaidya 4 , Sophie Bensing 5 , Eystein Husebye 2 , Heather J Cordell 1 & Simon H S Pearce 1
1Institute of Genetic Medicine, Newcastle upon Tyne, UK; 2Section of Endocrinology, Haukeland University Hospital, Bergen, Norway; 3Institute of Cellular Medicine, Newcastle upon Tyne, UK; 4Royal Devon and Exeter Hospital, Exeter, UK; 5Karolinska Institutet, Stockholm, Sweden.
Due to the rarity of autoimmune Addison’s disease (AAD), it has proved difficult to gather large case cohorts for genetic studies. Linkage analysis offers a powerful means of identifying genetic susceptibility loci but has never been applied to AAD because of the scarcity of families containing ≥2 affected individuals. We collected DNA from 23 such families to perform the first linkage study in AAD.
We genotyped 117 samples (50 cases, 67 controls) from 23 families with ≥2 affected individuals from the UK (n=12) and Norway (n=11), on the Affymetrix SNP-6.0 array. Data was formatted and quality controlled in PLINK and Merlin was used for linkage analysis. Results were validated by genotyping 65 SNPs (Sequenom) under two of the linkage peaks in 1097 unrelated AAD (693 21-hydroxylase autoantibody positive) and 1117 controls from the UK, Norway and Sweden.
Applying a rare dominant model, three loci on chromosomes 18, 9 and 7 had LOD scores >2.0. The maximum LOD score of 3.0 was observed within a linkage peak on chromosome 18 (75241668–77950543 kb). Non-parametric analysis revealed one locus on chromosome 6 with maximum LOD score 3.01, in a linkage peak spanning 22375648 – 35968100 kb, which contains the HLA complex. Meta-analysis of the validation study data in the whole cohort revealed association at 3 SNPs underlying the linkage peak on chromosome 18, with maximal association with an intergenic SNP rs7236339 (P<0.004). When those without 21-hydroxylase autoantibodies were excluded, 4 SNPs were associated. 3 of these were intergenic SNPs on chromosome 18, with maximal association at rs7231100 (P<0.004) and one was on chromosome seven, in the AUTS2 gene (rs12698902, P<0.01).
This is the first linkage study in AAD and the finding of linkage to the HLA region validates this approach. This study has generated some novel loci, which may cast light on the pathogenesis of AAD.
Declaration of funding: This work was supported by the Medical Research Council (G0900390) and a European Union Framework 7 grant (201167) to the Euradrenal Consortium.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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