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PMID: 17997607 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Identification of two independent risk factors for lupus within the MHC in United Kingdom families.

PLoS genetics ·Vol. 3 ·No. 11 ·2007-11-00 ·Pages e192

Fernando MM, Stevens CR, Sabeti PC, Walsh EC, McWhinnie AJ, Shah A, Green T, Rioux JD, Vyse TJ

Abstract

The association of the major histocompatibility complex (MHC) with SLE is well established yet the causal variants arising from this region remain to be identified, largely due to inadequate study design and the strong linkage disequilibrium demonstrated by genes across this locus. The majority of studies thus far have identified strong association with classical class II alleles, in particular HLA-DRB1*0301 and HLA-DRB1*1501. Additional associations have been reported with class III alleles; specifically, complement C4 null alleles and a tumor necrosis factor promoter SNP (TNF-308G/A). However, the relative effects of these class II and class III variants have not been determined. We have thus used a family-based approach to map association signals across the MHC class II and class III regions in a cohort of 314 complete United Kingdom Caucasian SLE trios by typing tagging SNPs together with classical typing of the HLA-DRB1 locus. Using TDT and conditional regression analyses, we have demonstrated the presence of two distinct and independent association signals in SLE: HLA-DRB1*0301 (nominal p = 4.9 x 10(-8), permuted p < 0.0001, OR = 2.3) and the T allele of SNP rs419788 (nominal p = 4.3 x 10(-8), permuted p < 0.0001, OR = 2.0) in intron 6 of the class III region gene SKIV2L. Assessment of genotypic risk demonstrates a likely dominant model of inheritance for HLA-DRB1*0301, while rs419788-T confers susceptibility in an additive manner. Furthermore, by comparing transmitted and untransmitted parental chromosomes, we have delimited our class II signal to a 180 kb region encompassing the alleles HLA-DRB1*0301-HLA-DQA1*0501-HLA-DQB1*0201 alone. Our class III signal importantly excludes independent association at the TNF promoter polymorphism, TNF-308G/A, in our SLE cohort and provides a potentially novel locus for future genetic and functional studies.

MeSH Terms
Alleles Blacks/genetics Case-Control Studies Cohort Studies Family Female Gene Frequency Genetic Markers Genetic Predisposition to Disease HLA-DR Antigens/genetics HLA-DRB1 Chains Haplotypes Histocompatibility Antigens Class II/genetics Humans Linkage Disequilibrium/genetics Lupus Erythematosus, Systemic/epidemiology,genetics Major Histocompatibility Complex/genetics Male Pedigree Phenotype Polymorphism, Single Nucleotide/genetics Regression Analysis United Kingdom/epidemiology United States
Chemicals
Genetic Markers HLA-DR Antigens HLA-DRB1 Chains HLA-DRB1*03:01 antigen Histocompatibility Antigens Class II
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Fernando Michelle M A
Section of Molecular Genetics and Rheumatology, Imperial College London, London, United Kingdom.
Stevens Christine R
Sabeti Pardis C
Walsh Emily C
McWhinnie Alasdair J M
Shah Anila
Green Todd
Rioux John D
Vyse Timothy J
Conflict of Interest

Competing interests. The authors have declared that no competing interests exist.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.0030192
Published
2007-11-00
Pages
e192
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC2065882
Subset
IM
Grants
NIDDK NIH HHS · R01 DK064869 · United States
NIAID NIH HHS · AI065687 · United States
NIDDK NIH HHS · (DK064869 · United States
NIAID NIH HHS · P01 AI065687 · United States
NIDDK NIH HHS · DK062432 · United States
NCRR NIH HHS · U54 RR020278 · United States
NIAID NIH HHS · U19 AI067152 · United States
Arthritis Research UK · 16211 · United Kingdom
NIAID NIH HHS · AI067152 · United States
NIDDK NIH HHS · U01 DK062432 · United States
NCRR NIH HHS · U54 RR020278-01 · United States
Wellcome Trust · United Kingdom
Databases
OMIM
120290, 120810, 120820, 138470, 142590, 142830, 142857, 142860, 146880, 154040, 164951, 191160, 600169, 600214, 600478, 600985, 604305, 604599, 604977, 605996, 606107, 610990
External Links
PubMed source DOI: 10.1371/journal.pgen.0030192 PMC Full Text View journal details
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