title: The effect of inversion at 8p23 on BLK association with lupus in Caucasian population.
abstract: 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Bahram
authors.initials: B
authors.lastname: Namjou
authors.affiliation: Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, United States of America.
authors.forename: Yizhao
authors.initials: Y
authors.lastname: Ni
authors.affiliation: 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 Rheumatology and Department of Internal Medicine, University of Colorado Denver, Aurora, CO, 80045, United States of America.
authors.forename: Isaac T W
authors.initials: IT
authors.lastname: Harley
authors.affiliation: 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.
authors.forename: Iouri
authors.initials: I
authors.lastname: Chepelev
authors.affiliation: 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.
authors.forename: Beth
authors.initials: B
authors.lastname: Cobb
authors.affiliation: 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.
authors.forename: Leah C
authors.initials: LC
authors.lastname: Kottyan
authors.affiliation: Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, 73104, United States of America.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Gaffney
authors.affiliation: Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, 73104, United States of America.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Guthridge
authors.affiliation: 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.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kaufman
authors.affiliation: 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; Department of Veteran Affairs Medical Center, Cincinnati, OH, United States of America.
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
mesh_terms: D016022:Case-Control Studies; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D005260:Female; D056426:Genetic Loci; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D057345:Sequence Inversion; D014481:United States; D044465:White People; D019061:src-Family Kinases / Q000235:genetics*
chemical_list: C584409:BLK protein, human; D019061:src-Family Kinases