ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2739

Immunochip Analysis Identifies New Susceptibility Loci For Systemic Sclerosis: Implications For Pathogenesis

Maureen D. Mayes for the US Scleroderma GWAS Group1, Lara Bossini-Castillo for the Spanish Scleroderma Group2, Olga Gorlova3, Jose Ezequiel Martin4, Xiaodong Zhou1, Wei Chen5, Shervin Assassi1, Jun Ying5, John D. Reveille1, Peter K. Gregersen6, Annette T. Lee7, Maria Teruel8, Francisco David Carmona4, Bobby P.C. Koeleman9, Matthew A. Brown and the Immunochip Consortium10, Christopher P. Denton11, Murray Baron for the Canadian Scleroderma Research Group12, Jasper Broen13, T.R.D.J. Radstake13 and Javier Martin4, 1Rheumatology, University of Texas Health Science Center at Houston, Houston, TX, 2Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain, 3Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 4Immunology, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Armilla (Granada), Spain, 5Department of Epidemiology, UT M.D. Anderson Cancer Center, Houston, TX, 6Genomics and Human Genetics, Feinstein Institute for Medical Research, Manhasset, NY, 7Genomics & Human Genetics, Feinstein Institute for Medical Research, Manhasset, NY, 8Immunology, Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Granada, Spain, 9Department of Medical Genetics, University Medical Center Utrecht, Utrecht, Netherlands, 10Translational Research Institute, University of Queensland Diamantina Institute, Brisbane, Australia, 11Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom, 12Rheumatology, Jewish General Hospital, Montreal, QC, Canada, 13Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Title: Genetics and Genomics of Rheumatic Disease II

Session Type: Abstract Submissions (ACR)

Background/Purpose : The purpose of this study was to identify SSc risk loci shared with other autoimmune diseases on the Immunochip and to fine-map previously associated loci. 

Methods : We genotyped 1,959 SSc cases and 3,582 controls of European ancestry from the United States and Spain using the Immunochip custom array containing 196,524 SNP variants within 186 known autoimmune risk loci. Ten SNPs were then chosen for replication in 4,017 SSc cases and 5,935 controls from 6 additional populations of European ancestry from the US, Canada, Europe and the UK for a combined population of 5,876 SSc cases and 9,517 controls.

Results : As noted in the Table below, we identified and validated 4 novel SSc risk loci including DNASE1L3 at 3p14, SCHIP1 | IL12A at 3q25, ATG5 at 6q21 and TREH/DDX6 at 11q23. Remarkably, the association of the rs35677470 missense variant in the DNASE1L3 locus with the ACA+ subset of patients is the most significant non-HLA association with SSc revealed to date (p = 2.70×10-32 OR=2.00).  In addition, we further refined the area of association for the STAT4, IRF5/TNPO3 loci and related an observed peak of association in the PXK gene to the novel DNASE1L3 locus.

Conclusion : The DNASE1L3 association suggests that failure to clear apoptotic debris plays a role in SSc; that the IL12 pathway is key to SSc susceptibility; that autophagy (ATG5), previously unreported in SSc, may be an important mechanism; and that DDX6, which has been shown to regulate VEGF under hypoxic conditions may provide a clue to SSc vasculopathy.

Novel non-HLA loci associated with SSc and its subsets (p < 5x10-8) identified through Immunochip analysis.

Locus

SNP

Chr

Minor Allele

Comments

Phenotype

MAF

Cases/CTRLs

p-value

OR

DNASE1L3

rs35677470

3p14

A

Missense Arg>Cys

All SSc

0.088/0.062

1.20×10-15

1.43

lcSSc

0.099/0.062

5.82×10-21

1.6

ACA+

0.133/0.062

2.70×10-32

1.99

SCHIP1 | IL12A

rs77583790

 

3q25

A

Intergenic

All SSc

0.015/0.005

2.25×10-12

2.54

lcSSc

0.016/0.005

3.60×10-12

2.74

ACA+

0.016/0.005

2.24×10-8

2.61

ATG5

rs9373839

6q25

G

Intronic

All SSc

0.241/0.185

2.16×10-8

1.18

TREH/DDX6

rs7130875

11q23

G

Intergenic

All SSc

0.27/0.24

4.03×10-8

1.17

 

Disclosure:

M. D. Mayes for the US Scleroderma GWAS Group,
None;

L. Bossini-Castillo for the Spanish Scleroderma Group,
None;

O. Gorlova,
None;

J. E. Martin,
None;

X. Zhou,
None;

W. Chen,
None;

S. Assassi,
None;

J. Ying,
None;

J. D. Reveille,
None;

P. K. Gregersen,
None;

A. T. Lee,
None;

M. Teruel,
None;

F. D. Carmona,
None;

B. P. C. Koeleman,
None;

M. A. Brown and the Immunochip Consortium,
None;

C. P. Denton,
None;

M. Baron for the Canadian Scleroderma Research Group,
None;

J. Broen,
None;

T. R. D. J. Radstake,
None;

J. Martin,
None.

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