doi: 10.1111/j.1744-313X.2008.00817.x © 2008 The Authors Journal compilation © 2008 Blackwell Publishing Ltd, International Journal of Immunogenetics 36, 33–37 33 Blackwell Publishing Ltd Analysis of ERCC2/XPD functional polymorphisms in systemic lupus erythematosus L. Wan,*† Y. J. Lin,*‡ J. J. Sheu,*† C. M. Huang,§ Y. Tsai,† C. H. Tsai,† W. Wong¶ & F. J. Tsai*† Summary Sunlight/ultraviolet (UV) irradiation has been recognized as an important risk factor for developing systemic lupus erythematosus (SLE). However, the interpretation of genetic variations involved in UV-light sensitivity is largely unknown. Recent studies indicated that two genetic variations of ERCC2/XPD gene (rs1799793 in exon 10 and rs13181 in exon 23) have been found to exert negative influences on nucleotide excision repair system. To analyse the possible contribution of the ERCC2/XPD functional single nucleotide polymorphisms in genetic susceptibility to SLE, the rs13181 and rs1799793 SNPs in ERCC2/XPD were genotyped by polymerase chain reaction followed by restriction fragment length polymor- phism analysis. Association was studied by case–control analyses using samples from 172 SLE patients and 160 healthy controls. Haplotype analysis was performed to detect the association with genetic predisposition to SLE and the clinical features. Although these two functional genetic variations are linked to several immune dysfunction- induced diseases, no statistically significant differences in allele or genotype frequencies were observed between SLE patients and controls. Haplotype analysis showed that none of ERCC2/XPD haplotypes was associated with the incidence of SLE disease, nor the preference of clinical features. In conclusion, the ERCC2/XPD functional polymorphisms analysed in this study showed no associ- ation in genetic susceptibility to SLE. Introduction Systemic lupus erythematosus (SLE) is a multisystem inflammatory autoimmune disease with the prevalence ranging from 36 to 375 cases per 100 000 population worldwide (Molokhia & McKeigue, 2000). Clinical stud- ies indicated that both genetic and environmental factors contribute to the pathogenesis of SLE. For example, DNA damaging agents, such as genotoxic chemicals and (UV) ultraviolet (sunlight) irradiation, are potent inducers to incur erythematous eruption. Recently, defective DNA repair activity for DNA damage and the consequent abnormal apoptosis have been implicated as causative factors for SLE (Herrick et al., 1995; McCurdy et al., 1997; Wong & Tsao, 2006). Elevated levels of circulating nucle- osomal DNA from the dead cells are strong immunogens to induce autoantibodies, which exacerbate lupus condi- tions in patients (Bruns et al., 2000; Koutouzov et al., 2004; Holdenrieder et al., 2006). Previous studies also indicated that SLE patients with hypersensitivity to UV irradiation as well as the disease animal models were found related to limited cellular DNA repair capacity (Golan & Borel, 1984; Zamansky et al., 1985; Foltyn & Golan, 2001). These studies suggested that DNA repair deficiencies may result in accumulation of pathogenic immune complexes during SLE development. DNA repair systems in mammalian cells are evolution- ally sophisticated machinery that can maintain DNA integrity when cells are under exposure of genotoxic com- pounds or oxidative attacks. At least four main repair pathways were defined operating in mammals, including base-excision repair (BER), nucleotide excision repair (NER), recombinational repair and mismatch repair (Lin- dahl & Wood, 1999; Hoeijmakers, 2001). Of all repair systems, NER is the most versatile for lesion recognition and DNA repair. Two subpathways, global genome NER (GG-NER) and transcription-coupled NER (TC-NER), are involved in NER system (de Laat et al., 1999; Tornal- etti & Hanawalt, 1999; Batty & Wood, 2000). Hundreds of polymorphisms in DNA repair genes have been identi- fied; however, for many of these polymorphisms, the impact on SLE susceptibility remains uncertain. ERCC2 gene (also known as XPD) was first found to be able to correct the sensitivity to UV radiation and defective nucleotide excision repair in a UV light sensitive cell line (Flejter et al., 1992). This gene is also a key DNA helicase L. Wan, Y.J. Lin and J.J. Sheu contributed equally to this work. * Human Genetic Center, China Medical University Hospital, Taichung, Taiwan, † Graduate Institute of Chinese Medical Science, China Medical University, Taichung, Taiwan, ‡ Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan, § Division of Immunology and Rheumatology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, and ¶ Rheumatology Department, Puli Christian Hospital, Nantou, Taiwan Received 11 June 2008; revised 11 June 2008; accepted 9 October 2008 Correspondence: Fuu-Jen Tsai, Human Genetic Center, China Medical University Hospital, 2 Yu-Der Rd., Taichung City 40447, Taiwan. Tel: +886 4 2205 2121 ext. 7080; Fax: +886 4 2203 3295; E-mail: d0704@mail.cmuh.org.tw and Wai Wong, Rheumatology Department, Puli Christian Hospital, 1 Teh-Shan Rd, Puli, Nantou 545, Taiwan. Tel: +886 49 291 2151 ext. 3301; Fax: +886 49 291 6901; E-mail: chihkuei@mail.pch.org.tw