1494 - Immunochip Genotyping of 1,884 Systemic Sclerosis Cases and 4,325 Controls Reveals Novel Associations

Monday, November 7, 2011: 9:00 AM-6:00 PM
Hall F2 - Poster Hall (McCormick Place West)
Maureen D. Mayes1, Olga Y. Gorlova2, Lara Bossini-Castillo3, Jose Ezequiel Martin4, Jun Ying2, Peter K. Gregersen5, Annette T. Lee6, Shervin Assassi1, Sandeep K. Agarwal1, Filemon K. Tan1, John D. Reveille1, Xiaodong Zhou1, Frank C. Arnett1, Fredrick M. Wigley7, Laura K. Hummers7, Marilyn Perry1, Carmen Pilar Simeon8, Patricia Carriera9, Norberto Ortego-Centeno10, Miguel Gonzalez-Gay11, the Spanish Scleroderma Group12 and Javier Martin13, 1University of Texas Health Science Center at Houston, Houston, TX, 2UT M. D. Anderson Cancer Center, Houston, TX, 3Consejo Superior de Investigaciones Científicas (CSIC), Armilla (Granada), Spain, 4Instituto de Parasitología y Biomedicina López-Neyra, IPBLN-CSIC, Armilla (Granada), Spain, 5Feinstein Institute Medical Reschearch, Manhasset, NY, 6Feinstein Institute Med Rsch, Manhasset, NY, 7Johns Hopkins University, Baltimore, MD, 8Hospital Valle de Hebron, Barcelona, Spain, 9Madrid, Spain, 10Hospital Clínico San Cecilio, Granada, Spain, 11Hospital Marques De Valdecilla, Santander, Spain, 12Granada, Spain, 13Instituto de Parasitologia y Biomedicina Lopez-Neyra (CSIC), Granada, Spain
Presentation Number: 1494

Background/Purpose: The goal of this study was to identify which single nucleotide polymorphisms (SNPs) were truly associated with systemic sclerosis (SSc) and to identify shared susceptibility loci between SSc and other diseases represented on the Immunochip.


Genotyping: Genotyping was performed using the Immunochip, which is a custom chip developed by the Immunochip Consortium and which contains 196,524 polymorphisms that provide deep coverage of loci previously reported from genome-wide association studies (GWAS) and candidate gene studies of major autoimmune and inflammatory diseases.

Cases and Controls: SSc was diagnosed on the basis of fulfillment of the 1980 criteria for the classfiication of systemic sclerosis or if 3 of 5 CREST features (Calcinosis, Raynaud's phenomenon, Esophageal dysfunction, Sclerodactyly, Telangiectasia) were present. Data on healthy controls were obtained from the Immunochip Consortium.

Data Analysis: After quality control measures were applied, a total of 1,884 SSc cases and 4,325 controls were included in the analysis. Case samples included white European-American subjects from the U.S. Scleroderma Registry (n=981, 88.6% female) and from the Spanish Scleroderma group (903 cases, 89.3% female). Control data on 3,993 race-matched U.S. subjects and 332 Spanish subjects were obtained from the Immunochip Consortium.  P-values reported are adjusted for multiple comparisons by FDR-BH (False Discovery Rate using the step-up procedure of Benjamini and Hochberg).

Result:  After quality control measures, the genotyping rate was 99.8% and 124,001 SNPs were included in the analysis.

As expected and previously reported in the SSc GWAS, the most highly associated loci (adjusted p-values ranging from 8.9x10-12 to 7.38x10-5) included the major histocompatibility complex region (MHC) region on chromosome 6, STAT4 on chromosome 2, TNPO3/IRF5 on chromosome 7, and BLK on chromosome 8.

Aside from the regions noted above, 16 SNPs in 8 additional genes/intergenic gene regions were significantly associated with SSc with adjusted p-values ranging from 5.34x10-9 to 3.24x10-5. These include FAM69A at 1p22 (p=6.05x10-7 for the most significant SNP), IL12RB2 at 1p31 (p=3.24x10-5), PARK7 at 1p36 (p=6.73x10-7), DENND1B at 1q31 (p=1.75x10-6), the intergenic region LOC100121216/CXCR4 at 2q21 (p=5.96x10-7), KIAA1109 at 4p27 (p=5.34x10-9), the intergenic region LOC286016/LOC407835 at 7q32 (p=2.32x10-7) and DDC at 7p11 (p=4.30x10-6)

In addition, significant associations were seen with rare variants in 3 genes (PER3, CD6, and IKZF4) and 2 intergenic areas (FCGR3A/FCGR2Cand SMARCC2/RNF41) but the numbers of subjects with these was quite small making estimates unreliable.

Conclusion:  The Immunochip analysis has provided confirmation of previously reported genetic loci in SSc. In addition 8 genes/gene regions have been identified as potential susceptibility regions. The identification of rare variants, although affecting only a small number of subjects, deserves additional studies.

Keywords: genomics, polymorphism and systemic sclerosis

Disclosure: M. D. Mayes, Research Grant: United Therapeutics, 2, Actelion Pharmaceuticals US, 8, Gilead Sciences, 8, Novartis Pharmaceutical Corporation, Actelion Pharmaceuticals US ; O. Y. Gorlova, None; L. Bossini-Castillo, None; J. E. Martin, None; J. Ying, None; P. K. Gregersen, None; A. T. Lee, None; S. Assassi, None; S. K. Agarwal, None; F. K. Tan, None; J. D. Reveille, None; X. Zhou, None; F. C. Arnett, None; F. M. Wigley, none, 2 ; L. K. Hummers, None; M. Perry, None; C. P. Simeon, None; P. Carriera, None; N. Ortego-Centeno, None; M. Gonzalez-Gay, None; J. Martin, None.