title: Genomic copy number variants: evidence for association with antibody response to anthrax vaccine adsorbed.
abstract: BACKGROUND
  Anthrax and its etiologic agent remain a biological threat. Anthrax vaccine is highly effective, but vaccine-induced IgG antibody responses vary widely following required doses of vaccinations. Such variation can be related to genetic factors, especially genomic copy number variants (CNVs) that are known to be enriched among genes with immunologic function. We have tested this hypothesis in two study populations from a clinical trial of anthrax vaccination.
  
  
  METHODS
  We performed CNV-based genome-wide association analyses separately on 794 European Americans and 200 African-Americans. Antibodies to protective antigen were measured at week 8 (early response) and week 30 (peak response) using an enzyme-linked immunosorbent assay. We used DNA microarray data (Affymetrix 6.0) and two CNV detection algorithms, hidden markov model (PennCNV) and circular binary segmentation (GeneSpring) to determine CNVs in all individuals. Multivariable regression analyses were used to identify CNV-specific associations after adjusting for relevant non-genetic covariates.
  
  
  RESULTS
  Within the 22 autosomal chromosomes, 2,943 non-overlapping CNV regions were detected by both algorithms. Genomic insertions containing HLA-DRB5, DRB1 and DQA1/DRA genes in the major histocompatibility complex (MHC) region (chromosome 6p21.3) were moderately associated with elevated early antibody response (β = 0.14, p = 1.78×10(-3)) among European Americans, and the strongest association was observed between peak antibody response and a segmental insertion on chromosome 1, containing NBPF4, NBPF5, STXMP3, CLCC1, and GPSM2 genes (β = 1.66, p = 6.06×10(-5)). For African-Americans, segmental deletions spanning PRR20, PCDH17 and PCH68 genes on chromosome 13 were associated with elevated early antibody production (β = 0.18, p = 4.47×10(-5)). Population-specific findings aside, one genomic insertion on chromosome 17 (containing NSF, ARL17 and LRRC37A genes) was associated with elevated peak antibody response in both populations.
  
  
  CONCLUSIONS
  Multiple CNV regions, including the one consisting of MHC genes that is consistent with earlier research, can be important to humoral immune responses to anthrax vaccine adsorbed.
authors.affiliation: Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Falola
authors.forename: Howard W
authors.initials: HW
authors.lastname: Wiener
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Wineinger
authors.forename: Gary R
authors.initials: GR
authors.lastname: Cutter
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.forename: Donna K
authors.initials: DK
authors.lastname: Arnett
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kaslow
authors.forename: Jianming
authors.initials: J
authors.lastname: Tang
authors.forename: Sadeep
authors.initials: S
authors.lastname: Shrestha
mesh_terms: D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics; D000881:Anthrax / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D022122:Anthrax Vaccines / Q000276:immunology*; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology; D000917:Antibody Formation / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D056915:DNA Copy Number Variations; D017353:Gene Deletion; D055106:Genome-Wide Association Study; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D013997:Time Factors; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D022122:Anthrax Vaccines; D000907:Antibodies, Bacterial; D007074:Immunoglobulin G