title: Genetic linkage and association of Fcgamma receptor IIIA (CD16A) on chromosome 1q23 with human systemic lupus erythematosus.
abstract: OBJECTIVE
  Although low-affinity alleles of human Fcgamma receptor types IIA and IIIA (FcgammaRIIA and FcgammaRIIIA, respectively) polymorphisms have been associated with systemic lupus erythematosus (SLE) in case-control studies, the relative contribution of these genes to SLE susceptibility has not been resolved.
  
  
  METHODS
  We analyzed the distribution of alleles of FcgammaRIIA, FcgammaRIIIA, and FcgammaRIIIB in 126 multiplex-SLE pedigrees and FcgammaRIIA and FcgammaRIIIA in a case-control replication study, using allele-specific polymerase chain reaction and direct sequencing of genomic DNA. Statistical tests of association were performed to detect evidence of linkage between the single nucleotide polymorphisms and SLE.
  
  
  RESULTS
  We found evidence for linkage at both the FcgammaRIIIA (single-point nonparametric linkage [NPL] 1.8, P = 0.038; multipoint NPL 2.7, P = 0.004) and the FcgammaRIIA (single-point NPL 2.0, P = 0.021; multipoint NPL 2.6, P = 0.006) loci, but not the FcgammaRIIIB locus. Family-based tests of association demonstrated increased transmission of the low-affinity F176 allele at the FcgammaRIIIA locus (odds ratio [OR] 2.18, P = 0.0005 by transmission disequilibrium test and P = 0.002, by pedigree disequilibrium test [PDT]), but little evidence of preferential transmission of alleles at FcgammaRIIA (P = 0.089 by PDT). Stratification by ethnicity showed preferential transmission of the associated FcgammaRIIIA allele both in families of African American ancestry and in those of European American ancestry. Despite significant linkage disequilibrium between these genes, 2- and 3-locus haplotype analysis of the extended Fcgamma receptor cluster did not reveal any significant association beyond that observed with FcgammaRIIIA alone. In a large case-control replication study of 438 patients with SLE and 219 controls, FcgammaRIIIA provided the strongest evidence of an FcgammaR-SLE association (additive model: V/V 176 versus V/F 176 OR 1.51, V/V 176 versus F/F 176 OR 1.98, P = 0.007).
  
  
  CONCLUSIONS
  To our knowledge, these data are the first to demonstrate linkage and both family-based and case-control-based association of FcgammaRIIIA with SLE. These data provide genetic evidence supporting a role for the physiologically relevant single nucleotide polymorphism of the FcgammaRIIIA gene in the pathophysiology of this complex genetic disease.
authors.affiliation: University of Alabama at Birmingham, Birmingham, Alabama 35294-0006, USA. JEdberg@uab.edu
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Edberg
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Jianming
authors.initials: J
authors.lastname: Wu
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Moser
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Kaufman
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kelly
authors.forename: Vipin
authors.initials: V
authors.lastname: Bansal
authors.forename: W Mark
authors.initials: WM
authors.lastname: Brown
authors.forename: Jane E
authors.initials: JE
authors.lastname: Salmon
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.forename: Robert P
authors.initials: RP
authors.lastname: Kimberly
mesh_terms: D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1; D004247:DNA / Q000032:analysis; D017931:DNA Primers / Q000737:chemistry; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D017452:Receptors, IgG / Q000235:genetics*
chemical_list: D017931:DNA Primers; D017452:Receptors, IgG; D004247:DNA