Jwu Jin Khong1, Kathryn P Burdon2, Yi Lu3, Lefta Leonardos4, Kate J Laurie4, John P Walsh5, Adam D Gajdatsy6, Peter R Ebeling7, Alan A McNab8, Thomas G Hardy9, Richard J Stawell10, Garry J Davis11, Dinesh Selva11, Angelo Tsirbas12, Grant W Montgomery13, Stuart Macgregor3, Jamie E Craig4. 1. Melbourne Clinical School-Western Campus Department of Medicine, University of Melbourne, Sunshine Hospital, St. Albans, Victoria, Australia 2Orbital, Plastics and Lacrimal Unit, The Royal Victorian Eye and Ear Hospital, Victoria, Australia 3Department of. 2. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. 3. Statistical Genetics, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. 4. Department of Ophthalmology, Flinders University of South Australia, Bedford Park, South Australia, Australia. 5. Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia 8School of Medicine and Pharmacology, The University of Western Australia, Crawley, Western Australia, Australia. 6. Centre for Ophthalmology and Visual Sciences, University of Western Australia, Western Australia, Australia. 7. Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia. 8. Orbital, Plastics and Lacrimal Unit, The Royal Victorian Eye and Ear Hospital, Victoria, Australia 11Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia. 9. Orbital, Plastics and Lacrimal Unit, The Royal Victorian Eye and Ear Hospital, Victoria, Australia 3Department of Surgery, University of Melbourne, Victoria, Australia. 10. Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia. 11. South Australian Institute of Ophthalmology, University of Adelaide, South Australia, Australia. 12. Australian School of Advanced Medicine, Macquarie University, Sydney, Australia. 13. Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Abstract
PURPOSE: Thyroid-associated orbitopathy (TO) is an autoimmune-mediated orbital inflammation that can lead to disfigurement and blindness. Multiple genetic loci have been associated with Graves' disease, but the genetic basis for TO is largely unknown. This study aimed to identify loci associated with TO in individuals with Graves' disease, using a genome-wide association scan (GWAS) for the first time to our knowledge in TO. METHODS: Genome-wide association scan was performed on pooled DNA from an Australian Caucasian discovery cohort of 265 participants with Graves' disease and TO (cases) and 147 patients with Graves' disease without TO (controls). Top-ranked single nucleotide polymorphisms (SNPs) then were genotyped in individual DNA samples from the discovery cohort, and two replication cohorts totaling 584 cases and 367 controls. RESULTS: In the GWAS of pooled DNA samples, several SNPs showed suggestive association with TO at genome-wide P ≤ 10-6; rs953128 located on chr10q21.1, rs2867161 on chr7q11.22, rs13360861 on chr5q12.3, rs7636326 on chr3q26.2, rs10266576 on chr 7q11.22, rs60457622 on chr3q23, and rs6110809 on chr20p12.1. However, the only SNP consistently associated with TO on individual genotyping in the discovery and replication cohorts was rs6110809, located within MACROD2 on chromosome 20p12.1. On combined analysis of discovery and replication cohorts, the minor A allele of rs6110809 was more frequent in TO than in Graves' disease controls without TO (P = 4.35 × 10-5; odds ratio [OR] = 1.77; 95% confidence interval [CI], 1.35-2.32) after adjusting for age, sex, duration of Graves' disease, and smoking. CONCLUSIONS: In patients with Graves' disease, a common genetic variant in MACROD2 may increase susceptibility for thyroid-associated orbitopathy. This association now requires confirmation in additional independent cohorts.
PURPOSE:Thyroid-associated orbitopathy (TO) is an autoimmune-mediated orbital inflammation that can lead to disfigurement and blindness. Multiple genetic loci have been associated with Graves' disease, but the genetic basis for TO is largely unknown. This study aimed to identify loci associated with TO in individuals with Graves' disease, using a genome-wide association scan (GWAS) for the first time to our knowledge in TO. METHODS: Genome-wide association scan was performed on pooled DNA from an Australian Caucasian discovery cohort of 265 participants with Graves' disease and TO (cases) and 147 patients with Graves' disease without TO (controls). Top-ranked single nucleotide polymorphisms (SNPs) then were genotyped in individual DNA samples from the discovery cohort, and two replication cohorts totaling 584 cases and 367 controls. RESULTS: In the GWAS of pooled DNA samples, several SNPs showed suggestive association with TO at genome-wide P ≤ 10-6; rs953128 located on chr10q21.1, rs2867161 on chr7q11.22, rs13360861 on chr5q12.3, rs7636326 on chr3q26.2, rs10266576 on chr 7q11.22, rs60457622 on chr3q23, and rs6110809 on chr20p12.1. However, the only SNP consistently associated with TO on individual genotyping in the discovery and replication cohorts was rs6110809, located within MACROD2 on chromosome 20p12.1. On combined analysis of discovery and replication cohorts, the minor A allele of rs6110809 was more frequent in TO than in Graves' disease controls without TO (P = 4.35 × 10-5; odds ratio [OR] = 1.77; 95% confidence interval [CI], 1.35-2.32) after adjusting for age, sex, duration of Graves' disease, and smoking. CONCLUSIONS: In patients with Graves' disease, a common genetic variant in MACROD2 may increase susceptibility for thyroid-associated orbitopathy. This association now requires confirmation in additional independent cohorts.