Genetic profiling in Graves' disease: further evidence for lack of a distinct genetic contribution to Graves' ophthalmopathy.
BACKGROUND
Graves' disease (GD), including Graves' ophthalmopathy or orbitopathy (GO), is an autoimmune disease with an environmental and genetic component to its etiology. The genetic contribution to the GO clinical phenotype remains unclear. Previous data from our laboratory and others have suggested that GO has no specific genetic component distinct from GD itself, while other reports have occasionally appeared suggesting that polymorphisms in genes such as CTLA4 and IL23R specifically increase the risk for GO. One of the criticisms of all these reports has been the clinical definition of the GO phenotype as distinct from hyperthyroid GD devoid of clinically significant eye involvement. The objective of this study was to take advantage of a phenotypically pure group of GD patients with GO and examine a series of genes associated with GD to determine if any were more definitively associated with GO rather than Graves' thyroid disease itself.


METHODS
To further examine whether specific susceptibility genes are associated with GO, we have performed further genetic association studies using highly characterized GO patients, many of whom had undergone orbital decompression surgery for their exophthalmos. We genotyped HLA, CTLA4, IL23R, and TSHR genes in a group of 256 Caucasian patients with severe GO (n=199) and less severe GO (n=57), and 90 patients with GD but no clinically apparent GO.


RESULTS
We found that the allele and genotype frequencies were not statistically different between GO and non-GO patients for any of the genes and gene combinations assessed.


CONCLUSIONS
These results provide further evidence that patients with GO do not have a distinct genetic susceptibility to their eye disease and again suggest that environmental and/or epigenetic influences are at play.
Thyroid Research Unit, Mount Sinai School of Medicine, James J. Peters VA Medical Center, New York, New York 10468, USA. xiaoming.yin@mssm.edu
Xiaoming
X
Yin
Rauf
R
Latif
Rebecca
R
Bahn
Terry F
TF
Davies
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060908:CTLA-4 Antigen / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006111:Graves Disease / Q000235:genetics*; D049970:Graves Ophthalmopathy / Q000235:genetics*; D015803:HLA-DR3 Antigen / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D018123:Receptors, Interleukin / Q000235:genetics*; D011989:Receptors, Thyrotropin / Q000235:genetics*; D044465:White People / Q000235:genetics
D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D015803:HLA-DR3 Antigen; C515500:IL23R protein, human; D018123:Receptors, Interleukin; D011989:Receptors, Thyrotropin