Genomic Polymorphism at the Interferon-Induced Helicase (IFIH1) Locus Contributes to Graves’ Disease Susceptibility

• Published in: The journal of clinical endocrinology and metabolism Vol. 92; no. 8; pp. 3338 - 3341
• Main Authors: Sutherland, Alison, Davies, Jocelyn, Owen, Catherine J., Vaikkakara, Suresh, Walker, Christine, Cheetham, Timothy D., James, R. Andrew, Perros, Petros, Donaldson, Peter T., Cordell, Heather J., Quinton, Richard, Pearce, Simon H. S.
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.08.2007
• Subjects: Adult; Alleles; Biological and medical sciences; Cohort Studies; DEAD-box RNA Helicases - biosynthesis; DEAD-box RNA Helicases - genetics; Endocrinopathies; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Genotype; Graves Disease - genetics; Graves Disease - physiopathology; Humans; Interferon-Induced Helicase, IFIH1; Male; Medical sciences; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Odds Ratio; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Thyroid. Thyroid axis (diseases); Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Endocrinopathy; Immunopathology; Obesity; Genetic variability; Nutrition; Hyperthyroidism; Genomics; Cytokine; Thyroid diseases; Nutrition disorder; Autoimmune disease; Genotype; Metabolic diseases; Sensitivity; Predisposition; Graves disease; Interferon; Genome; Locus; Endocrinology; Nutritional status; Polymorphism
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2007-0173

Context: A recent large-scale analysis of nonsynonymous coding polymorphisms showed strong evidence that an alanine to threonine amino acid change at codon 946 of the interferon-induced helicase (IFIH1) gene (SNP ID rs1990760) was associated with type 1 diabetes. Previous investigations have also demonstrated that an intronic polymorphism (termed PD1.3; SNP ID rs11568821) in the programmed cell death (PDCD1) gene was associated with systemic lupus erythematosus and rheumatoid arthritis. Objective: We sought to replicate these genetic associations in Graves’ disease and autoimmune Addison’s disease patient cohorts. Patients and Methods: A total of 602 Graves’ disease subjects, 214 Addison’s disease subjects, and 446 healthy controls were genotyped for the IFIH1 and PDCD1 single-nucleotide polymorphisms using mass spectrometer analysis of primer extension products (Sequenom). Results: The alanine-carrying allele at the IFIH1 codon 946 polymorphism was present in 796 of 1204 (66%) Graves’ disease patient alleles compared with 508 of 892 (57%) control subject alleles [odds ratio 1.47 (5–95% confidence interval, 1.23–1.76); P = 1.9 × 10−5]. In contrast, there was no association of alleles at this marker in autoimmune Addison’s disease. Neither was there evidence for association in either patient cohort at the PD1.3 polymorphism. Conclusions: We confirm a significant contribution of the Ala946Thr IFIH1 polymorphism to organ-specific autoimmune diseases, extending the range of conditions associated with this variant to include Graves’ disease. This polymorphism may also contribute to several other autoimmune disorders.