Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


HLA DQB103:02 Is a Marker for Severity of Interstitial Lung Disease in Systemic Sclerosis.

Assassi1,  Shervin, Tan1,  Filemon K., Ying2,  Jun, Gorlova2,  Olga Y., Harper3,  Brock E., Draeger4,  Hilda T., Gonzalez3,  Emilio B.

University of Texas Health Science Center at Houston, Houston, TX
UT M. D. Anderson Cancer Center, Houston, TX
University of Texas Medical Branch, Galveston, TX
University of Texas Health Science Center, San Antonio, TX

Background/Purpose:

Interstitial lung disease (ILD) is associated with significant morbidity and mortality in systemic sclerosis (SSc). The major histocompatibility region (MHC) showed the strongest association with SSc in the first genome-wide association study, making it the prime genetic locus for studying the pathogenesis of SSc and biomarker development. The goal of the current study was to examine the association of MHC genetic markers with severity of ILD in SSc.

Methods:

Patients with SSc were recruited from two US cohorts, GENISOS and the Scleroderma Family Registry. HLA Class II genotyping (DRB1, DQA1, DQB1, DPB1) was performed on extracted and purified genomic DNA. Furthermore, anti-centromere (ACA), anti-topoisomerase (ATA), and RNA Polymerase III were detected utilizing commercially available kits. The primary outcome was forced vital capacity (FVC)% predicted at enrollment. A two-step approach was used for the analysis in order to limit the number of performed comparisons. Initially, the top 10 most discriminating, independent clinical and genetic variables were identified in a random forest analysis. Subsequently, these variables were analyzed by linear regression following a forward variable selection strategy. A final multivariable model was constructed with independent variables, significantly associated with the outcome.

Results:

A total of 793 patients with SSc were examined, from which 38 % had moderate (FVC=50%–80%) and 6% severe (FVC<50%) restrictive lung disease. Diffuse cutaneous involvement was present in 47% of patients. The mean disease duration was 6.2 years.

HLA DQB1*03:02 (p=0.0001, b= 6.9, 95% C.I.: 3.4–10.4), disease duration, as well as presence of ACA and ATA were significantly associated with FVC in the multivariable model (adjusted for ethnicity). Addition of disease type (limited versus diffuse) did not significantly change the overall fit of the model. No other HLA Class II allele was associated with FVC.

In our multiethnic sample, 19.6% of patients had at least one HLA DQB1*03:02 allele. In the multivariable model, patients with this HLA allele had on average 6.9% higher FVC levels, indicating that this HLA allele was a predictor of milder ILD, independent of autoantibody profile and disease duration (Table 1).

We also repeated the entire analysis with only Caucasian patients (n=553). HLA DQB1*03:02 was again the only HLA Class II allele, significantly associated with FVC. HLA DQB1*03:02 was present in 19% of Caucasian patients. The same clinical variables were the independent predictors of FVC among these patients in the final model (Table 1).

Table 1. Final Multivariable Model

 Caucasian PatientsAll Patients*
Variableb, 95% (C.I.)p-valueb, 95% (C.I.)p-value
DQB1*03:026 (2.2,9.8)0.0026.9 (3.4,10.4)<0.001
ATA-4.1 (-7.7,-0.4)0.031-4.3 (-7.7,-0.9)0.013
ACA11.3 (7.6, 15)<0.00112.3 (8.6, 15.9)<0.001
Disease Duration, yrs-0.4 (-0.6,-0.2)<0.001-0.4 (-0.6,-0.2)<0.001
* Adjusted for ethnicity

Conclusion:

This is the first study linking an MHC locus/allele to severity of SSc-ILD. HLA DQB1*03:02 is an independent predictor of milder ILD in SSc. Because of its high frequency, this allele can be used for risk stratification in patients with SSc beyond the known clinical predictors.

To cite this abstract, please use the following information:
Assassi, Shervin, Tan, Filemon K., Ying, Jun, Gorlova, Olga Y., Harper, Brock E., Draeger, Hilda T., et al; HLA DQB103:02 Is a Marker for Severity of Interstitial Lung Disease in Systemic Sclerosis. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1452
DOI:

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