ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 745

Genetic Susceptibility Loci of Idiopathic Interstitial Pneumonitis Do Not Represent Risk for Systemic Sclerosis

Minghua Wu1, Shervin Assassi1, Gloria Salazar1, Olga Y Gorlova2, Wei V Chen3, Julio Charles4, Fredrick M. Wigley5, Laura K. Hummers5, Ami A. Shah5, Monique Hinchcliff6, Dinesh Khanna7, Elena Schiopu8, Kristine Phillips7, Daniel E. Furst9, Virginia D. Steen10, Murray Baron11, Marie Hudson11, Xiaodong Zhou1, Janet E. Pope12, Niall Jones13, Peter Docherty14, Nader A. Khalidi15, David B. Robinson16, Robert W. Simms17, Richard Silver18, Tracy Frech19, Barri J. Fessler20, Marvin J. Fritzler21, Jerry A. Molitor22, Barbara M. Segal22, Javier Martín23, John Varga24 and Maureen D Mayes1, 1Rheumatology, University of Texas Health Science Center at Houston, Houston, TX, 2Department of Community and Family Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH, 3Geisel School of Medicine at Dartmouth, Hanover, NH, 4Internal Medicine/Rheumatology, University of Texas Health Science Center at Houston, Houston, TX, 5Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, 6Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL, 7Division of Rheumatology, University of Michigan, Ann Arbor, MI, 8Rheumatology, University of Michigan, Ann Arbor, MI, 9University of California, Los Angeles, Department of Medicine, Los Angeles, CA, 10Department of Rheumatology, Georgetown University Medical Center, Washington, DC, 11Division of Rheumatology, McGill University, Montreal, QC, Canada, 12Medicine/Rheumatology, St. Joseph's Health Care, University of Western Ontario, London, ON, Canada, 13Division of Rheumatology, University of Alberta, Edmonton, AB, Canada, 14Internal Medicine, The Moncton Hospital, Moncton, NB, Canada, 15Division of Rheumatology, St. Joseph’s Hospital, McMaster University, Hamilton, ON, Canada, 16Arthritis Centre, University of Manitoba, Winnipeg, MB, Canada, 17Rheumatology, Boston University School of Medicine, Boston, MA, 18Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, SC, 19Div of Rheumatology, University of Utah, Salt Lake City, UT, 20Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 21Mitogen Advanced Diagnostics Laboratory, Faculty of Medicine, University of Calgary, Calgary, AB, Canada, 22Rheumatology, University of Minnesota, Minneapolis, MN, 23Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Granada, Spain, 24Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose: Systemic sclerosis (SSc) related interstitial lung disease (ILD) has phenotypic similarities to idiopathic interstitial pneumonia (IIP). The objective of this study was to assess whether genetic susceptibility loci which were recently identified in a large idiopathic interstitial pneumonia (IIP) genome-wide association study (GWAS) were also risk loci for SSc overall, for SSc-autoantibody subgroups or for severity of SSc-ILD.

Methods: A total of 2571 North-American Caucasian SSc patients and 4500 unaffected control subjects were investigated in two independent cohorts. The discovery cohort consisted of 1486 SSc cases and 3477 unaffected controls while the confirmation cohort consisted of 1085 additional SSc cases and 1023 unaffected controls. All patients were enrolled in the National Scleroderma Family Registry and DNA Repository and fulfilled the 1980 American College of Rheumatology classification criteria for SSc or had at least three of the five CREST features. Forced vital capacity % predicted (%FVC) as continuous outcome was used as a validated outcome measure for severity of ILD. Single nucleotide polymorphisms (SNPs) rs2736100 (TERT), rs2076295 (DSP), rs4727443 (AZGP1), rs7934606 (MUC2), rs2034650 (IVD), rs1981997 (MAPT), rs12610495 (DPP9), rs6793295 (LRRC34), rs2609255 (FAM13A), rs11191865 (OBFC1), rs1278769 (ATP11A) and rs1379326 (CSMD1), which were identified/confirmed to be associated with IIP in a recently published GWAS (Fingerlin et al. Nat Genetics 2013) were genotyped and analyzed for its association with SSc and severity of SSc-ILD.

Results:  In the discovery cohort, we observed nominally significant associations with SSc overall for LRRC34 rs6793295 (MAF=0.29, OR=1.14, CI 95% 1.03 to 1.25, p value=0.009) and OBFC1 rs11191865 (MAF=0.52, OR=1.09, CI 95% 1.00 to 1.19, p value=0.043). There were no significant associations in the anti-topoisomerase I (ATA) or anti-centromere (ACA) positive patient subgroups. However, DSP rs2076295 (β=-2.29, CI 95% -3.85 to -0.74, p value=0.004) and MAPT rs1981997 (β=2.26, CI 95% 0.35 to 4.17, p value=0.02) were associated with forced vital capacity % predicted (% FVC) even after adjusting for ATA status. All SNPs observed to reach nominal significance levels in the discovery cohort were genotyped in the replication cohort.  However, none of the above observed associations were confirmed in the replication cohort.   

Conclusion: Herein, we add new evidence that SSc and SSc related ILD are genetically distinct from IIP, although they share phenotypic similarities. This finding might have important implications for follow-up mechanistic studies and identification of therapeutic targets. Genetic background of SSc seems to be mainly related to innate and adaptive immunity while IIP genetic susceptibility relates to epithelial cell injury and dysfunction, mucin production, and telomere length. Interstitial lung involvement in SSc-ILD and IIP might be the common end-product of two different pathological backgrounds.

Disclosure:

M. Wu,
None;

S. Assassi,
None;

G. Salazar,
None;

O. Y. Gorlova,
None;

W. V. Chen,
None;

J. Charles,
None;

F. M. Wigley,
None;

L. K. Hummers,
None;

A. A. Shah,
None;

M. Hinchcliff,
None;

D. Khanna,
None;

E. Schiopu,
None;

K. Phillips,
None;

D. E. Furst,
None;

V. D. Steen,
None;

M. Baron,
None;

M. Hudson,
None;

X. Zhou,
None;

J. E. Pope,
None;

N. Jones,
None;

P. Docherty,
None;

N. A. Khalidi,
None;

D. B. Robinson,
None;

R. W. Simms,
None;

R. Silver,
None;

T. Frech,
None;

B. J. Fessler,
None;

M. J. Fritzler,
None;

J. A. Molitor,
None;

B. M. Segal,
None;

J. Martín,
None;

J. Varga,
None;

M. D. Mayes,
None.

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