RESEARCH - MHC class II alleles, haplotypes, and epitopes which confer susceptibility or protection in the fibrosing autoimmune disease systemic sclerosis

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Ann Rheum Dis. Published Online First: 12 July 2009.

doi:10.1136/ard.2009.111906

BMJ Publishing Group Ltd & European League Against Rheumatism.

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Extended Report

Major Histocompatibility Complex (MHC) class II alleles, haplotypes,

and epitopes which confer susceptibility or protection in the

fibrosing autoimmune disease systemic sclerosis: analyses in 1300

Caucasian, African-American and Hispanic cases and 1000 controls

C Arnett 1*, Pravitt Gourh 1, Sanjay Shete 1, Chul W Ahn 1,

Honey 1, Sandeep K Agarwal 1, Filemon K Tan 1, Terry McNearney

2, Fischbach 3, Marvin J Fritzler 4, Maureen D Mayes 1 and

D Reveille 1

1 University of Texas at Houston, United States

2 University of Texas Medical Branch (UTMB) Galveston, United States

3 University of Texas at San , United States

4 University of Calgary, Canada

Abstract

Objective: A case-control association study was conducted to determine

HLA-class II (DRB1, DQB1, DQA1, and DPB1) alleles, haplotypes and

shared epitopes associated with scleroderma (systemic sclerosis or

SSc) and its sub-phenotypes in a large multi-ethnic US cohort.

Patients and methods: 1300 SSc cases (961 whites, 178 blacks and 161

Hispanics) characterized for clinical skin forms (limited vs diffuse),

SSc- specific autoantibodies (anti-centromere (ACA),

anti-topoisomerase I (ATA), anti-RNA polymerase III (ARA), anti-U3 RNP

(fibrillarin), and others were studied using molecular genotyping.

Statistical analyses in SSc itself by ethnicity, gender, skin type and

autoantibodies were performed using exact logistic regression modeling

for dominant (D), additive (A) and recessive ® effects from HLA.

Results: The strongest positive class II associations with SSc in

whites and Hispanics were the DRB1*1104, DQA1*0501, DQB1*0301

haplotype, and DQB1 alleles encoding a non-leucine residue at position

26 (DQB1 26 epi), while the DRB1*0701, DQA1*0201, DQB1*0202 haplotype

and DRB1*1501 haplotype were negatively correlated and possibly

protective in dominant and recessive models, respectively. These

associations did not discriminate limited SSc from diffuse SSc. SSc in

blacks was associated with DRB1*0804, DQA1*0501, DQB1*0301 alleles.

DPB1*1301 showed the highest odds ratio for ATA (OR=14). Moreover, it

showed no LD or gene interaction with DR/DQ. ACA was best explainable

by DQB1*0501 and DQB1*26 epi alleles and ARA by DRB1*0404, DRB1*11 and

DQB1*03 alleles in whites and Hispanics but DRB1*08 in blacks. These

data indicate unique and multiple HLA class II effects in SSc,

especially on autoantibody markers of different sub-phenotypes.

http://ard.bmj.com/cgi/content/abstract/ard.2009.111906v1?papetoc

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