Kim Kwangwoo, Bang So-Young, Joo Young Bin, Kim Taehyeung, Lee Hye-Soon, Kang Changwon, Bae Sang-Cheol
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.
J Rheumatol. 2016 Jun;43(6):1045-9. doi: 10.3899/jrheum.150665. Epub 2016 Mar 15.
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.
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.
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%).
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.
环磷酰胺（CYC）是一种广泛用于治疗包括狼疮性肾炎在内的多种疾病的免疫抑制剂，但其疗效在个体间差异很大。这项药物基因组学关联研究旨在寻找与CYC疗效相关的基因变异。
对109例接受静脉注射CYC诱导治疗的韩国狼疮性肾炎（III - V级）系统性红斑狼疮患者进行全基因组关联扫描。使用 Cochr an - Armitage趋势检验检查反应者和无反应者之间的基因差异，并使用基因型填充来确定关联位点。
人类染色体1q23上的Fcγ受体基因（FCGR）簇中的基因多态性，先前与狼疮性肾炎易感性相关，与狼疮性肾炎CYC治疗的反应相关。在FCGR2B和FCRLA基因之间发现了3个完全相关（r(2)=1）的单核苷酸多态性（SNP）与显著的反应关联：rs6697139、rs10917686和rs10917688（p = 3.4×10(-8)）。这些SNP中的次要等位基因携带者仅在无反应者中发现（31%），而在反应者中未发现（0%）。
这种针对CYC反应的首次全基因组关联方法产生了一个强大的基因关联图谱，包括FCGR2B - FCRLA位点中的大效应SNP这可能为CYC代谢和疗效提供更好的见解。
