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.
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.