Association of Polymorphisms in MACRO Domain Containing 2 With Thyroid-Associated Orbitopathy.
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.



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.



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.



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.
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.
Jwu Jin
JJ
Khong
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.
Kathryn P
KP
Burdon
Statistical Genetics, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Yi
Y
Lu
Department of Ophthalmology, Flinders University of South Australia, Bedford Park, South Australia, Australia.
Lefta
L
Leonardos
Department of Ophthalmology, Flinders University of South Australia, Bedford Park, South Australia, Australia.
Kate J
KJ
Laurie
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.
John P
JP
Walsh
Centre for Ophthalmology and Visual Sciences, University of Western Australia, Western Australia, Australia.
Adam D
AD
Gajdatsy
Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Victoria, Australia.
Peter R
PR
Ebeling
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.
Alan A
AA
McNab
Orbital, Plastics and Lacrimal Unit, The Royal Victorian Eye and Ear Hospital, Victoria, Australia 3Department of Surgery, University of Melbourne, Victoria, Australia.
Thomas G
TG
Hardy
Centre for Eye Research Australia, University of Melbourne, East Melbourne, Victoria, Australia.
Richard J
RJ
Stawell
South Australian Institute of Ophthalmology, University of Adelaide, South Australia, Australia.
Garry J
GJ
Davis
South Australian Institute of Ophthalmology, University of Adelaide, South Australia, Australia.
Dinesh
D
Selva
Australian School of Advanced Medicine, Macquarie University, Sydney, Australia.
Angelo
A
Tsirbas
Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Grant W
GW
Montgomery
Statistical Genetics, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Stuart
S
Macgregor
Department of Ophthalmology, Flinders University of South Australia, Bedford Park, South Australia, Australia.
Jamie E
JE
Craig
D000328:Adult; D004247:DNA / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D049970:Graves Ophthalmopathy / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000235:genetics* / Q000378:metabolism; D015994:Incidence; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014739:Victoria / Q000453:epidemiology
C523332:MACROD2 protein, human; D004247:DNA; D006867:Hydrolases; D045643:DNA Repair Enzymes