High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions

Lisa F. Barcellos, Suzanne L. May, Patricia P. Ramsay, Hong L. Quach, Julie A. Lane, Joanne Nititham, Janelle A. Noble, Kimberly E. Taylor, Diana L. Quach, Sharon A. Chung, Jennifer A. Kelly, Kathy L. Moser, Timothy W. Behrens, Michael F Seldin, Glenys Thomson, John B. Harley, Patrick M. Gaffney, Lindsey A. Criswell

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Abstract

A substantial genetic contribution to systemic lupus erythematosus (SLE) risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6p21. Previous studies in SLE have lacked statistical power and genetic resolution to fully define MHC influences. We characterized 1,610 Caucasian SLE cases and 1,470 parents for 1,974 MHC SNPs, the highly polymorphic HLA-DRB1 locus, and a panel of ancestry informative markers. Single-marker analyses revealed strong signals for SNPs within several MHC regions, as well as with HLA-DRB1 (global p = 9.99×10-16). The most strongly associated DRB1 alleles were: *0301 (odds ratio, OR = 2.21, p = 2.53×10-12), *1401 (OR = 0.50, p = 0.0002), and *1501 (OR = 1.39, p = 0.0032). The MHC region SNP demonstrating the strongest evidence of association with SLE was rs3117103, with OR = 2.44 and p = 2.80×10-13. Conditional haplotype and stepwise logistic regression analyses identified strong evidence for association between SLE and the extended class I, class I, class III, class II, and the extended class II MHC regions. Sequential removal of SLE - associated DRB1 haplotypes revealed independent effects due to variation within OR2H2 (extended class I, rs362521, p = 0.006), CREBL1 (class III, rs8283, p = 0.01), and DQB2 (class II, rs7769979, p = 0.003, and rs10947345, p = 0.0004). Further, conditional haplotype analyses demonstrated that variation within MICB (class I, rs3828903, p = 0.006) also contributes to SLE risk independent of HLA-DRB1*0301. Our results for the first time delineate with high resolution several MHC regions with independent contributions to SLE risk. We provide a list of candidate variants based on biologic and functional considerations that may be causally related to SLE risk and warrant further investigation.

Original languageEnglish (US)
Article numbere1000696
JournalPLoS Genetics
Volume5
Issue number10
DOIs
StatePublished - Oct 2009

Fingerprint

major histocompatibility complex
lupus erythematosus
Major Histocompatibility Complex
Systemic Lupus Erythematosus
Single Nucleotide Polymorphism
screening
Haplotypes
HLA-DRB1 Chains
haplotypes
ancestry
chromosome
logistics
allele
odds ratio
Chromosomes
Logistic Models
Alleles
Odds Ratio
gene
Regression Analysis

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions. / Barcellos, Lisa F.; May, Suzanne L.; Ramsay, Patricia P.; Quach, Hong L.; Lane, Julie A.; Nititham, Joanne; Noble, Janelle A.; Taylor, Kimberly E.; Quach, Diana L.; Chung, Sharon A.; Kelly, Jennifer A.; Moser, Kathy L.; Behrens, Timothy W.; Seldin, Michael F; Thomson, Glenys; Harley, John B.; Gaffney, Patrick M.; Criswell, Lindsey A.

In: PLoS Genetics, Vol. 5, No. 10, e1000696, 10.2009.

Research output: Contribution to journalArticle

Barcellos, LF, May, SL, Ramsay, PP, Quach, HL, Lane, JA, Nititham, J, Noble, JA, Taylor, KE, Quach, DL, Chung, SA, Kelly, JA, Moser, KL, Behrens, TW, Seldin, MF, Thomson, G, Harley, JB, Gaffney, PM & Criswell, LA 2009, 'High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions', PLoS Genetics, vol. 5, no. 10, e1000696. https://doi.org/10.1371/journal.pgen.1000696
Barcellos, Lisa F. ; May, Suzanne L. ; Ramsay, Patricia P. ; Quach, Hong L. ; Lane, Julie A. ; Nititham, Joanne ; Noble, Janelle A. ; Taylor, Kimberly E. ; Quach, Diana L. ; Chung, Sharon A. ; Kelly, Jennifer A. ; Moser, Kathy L. ; Behrens, Timothy W. ; Seldin, Michael F ; Thomson, Glenys ; Harley, John B. ; Gaffney, Patrick M. ; Criswell, Lindsey A. / High-density SNP screening of the major histocompatibility complex in systemic lupus erythematosus demonstrates strong evidence for independent susceptibility regions. In: PLoS Genetics. 2009 ; Vol. 5, No. 10.
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abstract = "A substantial genetic contribution to systemic lupus erythematosus (SLE) risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6p21. Previous studies in SLE have lacked statistical power and genetic resolution to fully define MHC influences. We characterized 1,610 Caucasian SLE cases and 1,470 parents for 1,974 MHC SNPs, the highly polymorphic HLA-DRB1 locus, and a panel of ancestry informative markers. Single-marker analyses revealed strong signals for SNPs within several MHC regions, as well as with HLA-DRB1 (global p = 9.99×10-16). The most strongly associated DRB1 alleles were: *0301 (odds ratio, OR = 2.21, p = 2.53×10-12), *1401 (OR = 0.50, p = 0.0002), and *1501 (OR = 1.39, p = 0.0032). The MHC region SNP demonstrating the strongest evidence of association with SLE was rs3117103, with OR = 2.44 and p = 2.80×10-13. Conditional haplotype and stepwise logistic regression analyses identified strong evidence for association between SLE and the extended class I, class I, class III, class II, and the extended class II MHC regions. Sequential removal of SLE - associated DRB1 haplotypes revealed independent effects due to variation within OR2H2 (extended class I, rs362521, p = 0.006), CREBL1 (class III, rs8283, p = 0.01), and DQB2 (class II, rs7769979, p = 0.003, and rs10947345, p = 0.0004). Further, conditional haplotype analyses demonstrated that variation within MICB (class I, rs3828903, p = 0.006) also contributes to SLE risk independent of HLA-DRB1*0301. Our results for the first time delineate with high resolution several MHC regions with independent contributions to SLE risk. We provide a list of candidate variants based on biologic and functional considerations that may be causally related to SLE risk and warrant further investigation.",
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AU - Barcellos, Lisa F.

AU - May, Suzanne L.

AU - Ramsay, Patricia P.

AU - Quach, Hong L.

AU - Lane, Julie A.

AU - Nititham, Joanne

AU - Noble, Janelle A.

AU - Taylor, Kimberly E.

AU - Quach, Diana L.

AU - Chung, Sharon A.

AU - Kelly, Jennifer A.

AU - Moser, Kathy L.

AU - Behrens, Timothy W.

AU - Seldin, Michael F

AU - Thomson, Glenys

AU - Harley, John B.

AU - Gaffney, Patrick M.

AU - Criswell, Lindsey A.

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N2 - A substantial genetic contribution to systemic lupus erythematosus (SLE) risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6p21. Previous studies in SLE have lacked statistical power and genetic resolution to fully define MHC influences. We characterized 1,610 Caucasian SLE cases and 1,470 parents for 1,974 MHC SNPs, the highly polymorphic HLA-DRB1 locus, and a panel of ancestry informative markers. Single-marker analyses revealed strong signals for SNPs within several MHC regions, as well as with HLA-DRB1 (global p = 9.99×10-16). The most strongly associated DRB1 alleles were: *0301 (odds ratio, OR = 2.21, p = 2.53×10-12), *1401 (OR = 0.50, p = 0.0002), and *1501 (OR = 1.39, p = 0.0032). The MHC region SNP demonstrating the strongest evidence of association with SLE was rs3117103, with OR = 2.44 and p = 2.80×10-13. Conditional haplotype and stepwise logistic regression analyses identified strong evidence for association between SLE and the extended class I, class I, class III, class II, and the extended class II MHC regions. Sequential removal of SLE - associated DRB1 haplotypes revealed independent effects due to variation within OR2H2 (extended class I, rs362521, p = 0.006), CREBL1 (class III, rs8283, p = 0.01), and DQB2 (class II, rs7769979, p = 0.003, and rs10947345, p = 0.0004). Further, conditional haplotype analyses demonstrated that variation within MICB (class I, rs3828903, p = 0.006) also contributes to SLE risk independent of HLA-DRB1*0301. Our results for the first time delineate with high resolution several MHC regions with independent contributions to SLE risk. We provide a list of candidate variants based on biologic and functional considerations that may be causally related to SLE risk and warrant further investigation.

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