Linkage and interaction of loci on 1q23 and 16q12 may contribute to susceptibility to systemic lupus erythematosus
Open Access
- 8 November 2002
- journal article
- research article
- Published by Wiley in Arthritis & Rheumatism
- Vol. 46 (11), 2928-2936
- https://doi.org/10.1002/art.10590
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 (λs [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). Conclusion 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.Keywords
This publication has 43 references indexed in Scilit:
- Baseline characteristics of a multiethnic lupus cohort: PROFILELupus, 2002
- Genome Scan of Human Systemic Lupus Erythematosus by Regression Modeling: Evidence of Linkage and Epistasis at 4p16-15.2American Journal of Human Genetics, 2000
- Haseman and Elston revisitedGenetic Epidemiology, 2000
- A Susceptibility Locus for Human Systemic Lupus Erythematosus (hSLE1) on Chromosome 2qJournal of Autoimmunity, 2000
- Lupus Susceptibility Genes on Human Chromosome 1International Reviews of Immunology, 2000
- Replication of Linkage Studies of Complex Traits: An Examination of Variation in Location EstimatesAmerican Journal of Human Genetics, 1999
- Isolation and radiation hybrid mapping of dinucleotide repeat polymorphism at the human estrogen receptor β locusJournal of Human Genetics, 1998
- Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus.JCI Insight, 1997
- Genetic basis of systemic lupus erythematosusCurrent Opinion in Immunology, 1996
- Genetic dissection of complex traits: guidelines for interpreting and reporting linkage resultsNature Genetics, 1995