Namjou Bahram, Ni Yizhao, Harley Isaac T W, Chepelev Iouri, Cobb Beth, Kottyan Leah C, Gaffney Patrick M, Guthridge Joel M, Kaufman Kenneth, Harley John B
Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center (CCHMC), 3333 Burnet Avenue, Cincinnati, OH, 45229, United States of America; University of Cincinnati, College of Medicine, Cincinnati, OH, United States of America.
Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, United States of America.
PLoS One. 2014 Dec 29;9(12):e115614. doi: 10.1371/journal.pone.0115614. eCollection 2014.
To explore the potential influence of the polymorphic 8p23.1 inversion on known autoimmune susceptibility risk at or near BLK locus, we validated a new bioinformatics method that utilizes SNP data to enable accurate, high-throughput genotyping of the 8p23.1 inversion in a Caucasian population.
Principal components analysis (PCA) was performed using markers inside the inversion territory followed by k-means cluster analyses on 7416 European derived and 267 HapMaP CEU and TSI samples. A logistic regression conditional analysis was performed.
Three subgroups have been identified; inversion homozygous, heterozygous and non-inversion homozygous. The status of inversion was further validated using HapMap samples that had previously undergone Fluorescence in situ hybridization (FISH) assays with a concordance rate of above 98%. Conditional analyses based on the status of inversion were performed. We found that overall association signals in the BLK region remain significant after controlling for inversion status. The proportion of lupus cases and controls (cases/controls) in each subgroup was determined to be 0.97 for the inverted homozygous group (1067 cases and 1095 controls), 1.12 for the inverted heterozygous group (1935 cases 1717 controls) and 1.36 for non-inverted subgroups (924 cases and 678 controls). After calculating the linkage disequilibrium between inversion status and lupus risk haplotype we found that the lupus risk haplotype tends to reside on non-inversion background. As a result, a new association effect between non-inversion status and lupus phenotype has been identified ((p = 8.18×10(-7), OR = 1.18, 95%CI = 1.10-1.26).
Our results demonstrate that both known lupus risk haplotype and inversion status act additively in the pathogenesis of lupus. Since inversion regulates expression of many genes in its territory, altered expression of other genes might also be involved in the development of lupus.
为了探究8p23.1多态性倒位对BLK基因座或其附近已知自身免疫易感性风险的潜在影响，我们验证了一种新的生物信息学方法，该方法利用单核苷酸多态性（SNP）数据，能够在白种人群体中对8p23.1倒位进行准确、高通量基因分型。
使用倒位区域内的标记进行主成分分析（PCA），随后对7416份欧洲裔样本以及267份HapMaP CEU和TSI样本进行k均值聚类分析。进行了逻辑回归条件分析。
已识别出三个亚组；倒位纯合子、杂合子和非倒位纯合子。使用先前进行过荧光原位杂交（FISH）检测的HapMap样本进一步验证了倒位状态，一致率超过98%。基于倒位状态进行了条件分析。我们发现，在控制倒位状态后，BLK区域的总体关联信号仍然显著。确定每个亚组中狼疮病例与对照的比例（病例/对照），倒位纯合子组为0.97（1067例病例和1095例对照），倒位杂合子组为1.12（1935例病例和1717例对照），非倒位亚组为1.36（924例病例和678例对照）。在计算倒位状态与狼疮风险单倍型之间的连锁不平衡后，我们发现狼疮风险单倍型倾向于存在于非倒位背景上。因此，已确定非倒位状态与狼疮表型之间存在新的关联效应（（p = 8.18×10⁻⁷，OR = 1.18，95%CI = 1.10 - 1.26）。
我们的结果表明，已知的狼疮风险单倍型和倒位状态在狼疮发病机制中具有累加作用。由于倒位调节其区域内许多基因的表达，其他基因表达的改变可能也参与了狼疮的发展。
