title: Linkage and interaction of loci on 1q23 and 16q12 may contribute to susceptibility to systemic lupus erythematosus.
abstract: OBJECTIVE
  Six recent genome scans of different systemic lupus erythematosus (SLE) multiplex family cohorts showed multiple putative susceptibility loci. In the present study, we examined 4 previously identified loci to replicate findings of significant linkage to 1q23 and 16q12, and to support findings of suggestive linkage to 14q21-23 and 20p12 in a cohort of 115 multiethnic nuclear families containing 145 SLE-affected sibpairs.
  
  
  METHODS
  Model-free, multipoint linkage analyses (SIBPAL2, SAGE version 4.0) and exclusion mapping (GeneHunter) were performed.
  
  
  RESULTS
  Linkages to 1q23 (peak at D1S2675, mean allele sharing [MAS] 0.56; P = 0.003) and to 16q12 (peaks between D16S753 and D16S757, MAS 0.57; P = 0.003) were confirmed, but linkage evidence at 20p12 was weak and inconsistent (MAS 0.52-0.56; from P = 0.005 to P not significant). Evidence for linkage to 1q23 and 16q12 was stronger in 68 non-Caucasian affected sibpairs than in 77 Caucasian affected sibpairs. Exclusion mapping ruled out linkage at 14q21-23 (lambda(s) [sib recurrence risk or genotypic risk ratio] = 1.8). Because the pericentromeric region of chromosome 16 has been identified by genome scans in several autoimmune diseases, we postulated that it might harbor an autoimmune modifier gene. To explore this possibility, we tested for an interaction between 16q12 and 1q23, and between 16q12 and 20p12. Haplotype sharing at 1q23 increased concomitantly with increased haplotype sharing at 16q12 (P = 0.008 by nonparametric Jonckheere-Terpstra exact statistical test). No evidence supporting an interaction between 16q12 and 20p12 was observed. Analysis of sibpairs sharing 2 alleles at 16q12 also showed increased allele sharing at 1q23 (MAS from 0.56 to 0.65).
  
  
  CONCLUSIONS
  These data support the presence of SLE susceptibility genes at 1q23 and 16q12, particularly in non-Caucasians. The skewed distribution of haplotypes suggests that genetic interaction of these two loci may affect SLE susceptibility.
authors.affiliation: Department of Medicine, Rehabilitation Center, Room 32-59, 1000 Veteran Avenue, UCLA School of Medicine, Los Angeles, CA 90095-1670, USA. BTsao@mednet.ucla.edu
authors.forename: Betty P
authors.initials: BP
authors.lastname: Tsao
authors.forename: Rita M
authors.initials: RM
authors.lastname: Cantor
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Grossman
authors.forename: Sung K
authors.initials: SK
authors.lastname: Kim
authors.forename: Noel
authors.initials: N
authors.lastname: Strong
authors.forename: Chak S
authors.initials: CS
authors.lastname: Lau
authors.forename: Chung-Jen
authors.initials: CJ
authors.lastname: Chen
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Ginzler
authors.forename: Rose
authors.initials: R
authors.lastname: Goldstein
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Kalunian
authors.forename: Frank C
authors.initials: FC
authors.lastname: Arnett
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wallace
authors.forename: Bevra H
authors.initials: BH
authors.lastname: Hahn
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D005260:Female; D008040:Genetic Linkage / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D008875:Middle Aged