1. ¹Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
2. ²Program in Human Genetics, Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA
3. ³Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
4. ⁴Institute of Public Health, National Yang-Ming University, Taipei, Taiwan
5. ⁵Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan
6. ⁶Department of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

Correspondence: Dr W-S Yang or T-C Chang, Department of Internal Medicine, Graduate Institute of Clinical Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. E-mails: wsyang@ntu.edu.tw or tienchunchang@ntu.edu.tw

Received 5 September 2007; Revised 17 October 2007; Accepted 17 October 2007; Published online 6 December 2007.

Abstract

Graves' disease (GD) is a common organ-specific autoimmune disorder inherited as a complex trait. Although there has not been consensus regarding the genuine susceptibility alleles, many population-based genetic studies showed association of the cytotoxic T-lymphocyte antigen-4 (CTLA4) gene with GD. In contrast, evidence utilizing family-based studies came only from the Caucasian population. Here we performed a family-based association study in the Han population in Taiwan. We enrolled 374 affected individuals and 347 unaffected family members in 151 GD pedigrees. Four single-nucleotide polymorphisms (SNP) and a short tandem repeat polymorphism (STRP) at CTLA4 were genotyped. Association of GD with a novel risk SNP at the 5' upstream region, CTLA4_-1722_T/C (rs733618), was demonstrated (P=0.0096). We also replicated the association signal of a coding SNP, CTLA4_+49_G/A (rs231775, P=0.0219). A common haplotype composed of CTLA4_-1722_T/C and CTLA4_(AT)n (an STRP marker: UniSTS:48500) showed protective effect (P=0.0004). Our results of family-based association study, taken together with those from the Caucasian population, provide evidence that CTLA4 confers susceptibility to GD across different ethnic backgrounds.