Kwangwoo Kim1, So-Young Bang1, Young Bin Joo1, Taehyeung Kim1, Hye-Soon Lee1, Changwon Kang2, Sang-Cheol Bae2. 1. From the Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon; and the Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.K. Kim*, PhD, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, and Hanyang University Hospital for Rheumatic Diseases; S.Y. Bang*, MD, PhD, Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases; Y.B. Joo, MD, PhD, Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases; T. Kim, PhD, Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases; H.S. Lee, MD, PhD, Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases; C. Kang, PhD, Department of Biological Sciences, Korea Advanced Institute of Science and Technology; S.C. Bae, MD, PhD, MPH, Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases. 2. From the Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon; and the Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea.K. Kim*, PhD, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, and Hanyang University Hospital for Rheumatic Diseases; S.Y. Bang*, MD, PhD, Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases; Y.B. Joo, MD, PhD, Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases; T. Kim, PhD, Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases; H.S. Lee, MD, PhD, Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases; C. Kang, PhD, Department of Biological Sciences, Korea Advanced Institute of Science and Technology; S.C. Bae, MD, PhD, MPH, Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases. ckang@kaist.ac.kr scbae@hanyang.ac.kr.
Abstract
OBJECTIVE: Cyclophosphamide (CYC) is an immunosuppressant drug widely used to treat various diseases including lupus nephritis, but its efficacy highly varies from individual to individual. This pharmacogenomics association study searched for genetic variations associated with CYC efficacy. METHODS: Genome-wide association scan was performed for 109 Korean patients with systemic lupus erythematosus with lupus nephritis (classes III-V) who received intravenous CYC induction therapy. Genetic differences between responders and nonresponders were examined using Cochran-Armitage trend tests, and genotype imputation was used for defining the association locus. RESULTS: Genetic polymorphisms in the Fcγ receptor gene (FCGR) cluster at human chromosome 1q23, previously associated with lupus nephritis susceptibility, were associated with the response to CYC treatment for lupus nephritis. Significant response association was found for 3 perfectly correlated (r(2) = 1) single-nucleotide polymorphisms (SNP): rs6697139, rs10917686, and rs10917688, located between the FCGR2B and FCRLA genes (p = 3.4 × 10(-8)). Carriage of the minor alleles in these SNP was found only in nonresponders (31%) and none in responders (0%). CONCLUSION: This first genome-wide association approach for CYC response yielded a robust profile of genetic associations including large-effect SNP in the FCGR2B-FCRLA locus, which may provide better insights to CYC metabolism and efficacy.
OBJECTIVE:Cyclophosphamide (CYC) is an immunosuppressant drug widely used to treat various diseases including lupus nephritis, but its efficacy highly varies from individual to individual. This pharmacogenomics association study searched for genetic variations associated with CYC efficacy. METHODS: Genome-wide association scan was performed for 109 Korean patients with systemic lupus erythematosus with lupus nephritis (classes III-V) who received intravenous CYC induction therapy. Genetic differences between responders and nonresponders were examined using Cochran-Armitage trend tests, and genotype imputation was used for defining the association locus. RESULTS: Genetic polymorphisms in the Fcγ receptor gene (FCGR) cluster at human chromosome 1q23, previously associated with lupus nephritis susceptibility, were associated with the response to CYC treatment for lupus nephritis. Significant response association was found for 3 perfectly correlated (r(2) = 1) single-nucleotide polymorphisms (SNP): rs6697139, rs10917686, and rs10917688, located between the FCGR2B and FCRLA genes (p = 3.4 × 10(-8)). Carriage of the minor alleles in these SNP was found only in nonresponders (31%) and none in responders (0%). CONCLUSION: This first genome-wide association approach for CYC response yielded a robust profile of genetic associations including large-effect SNP in the FCGR2B-FCRLA locus, which may provide better insights to CYC metabolism and efficacy.