MCRC Project 4, Some of Our Advances...
Under the auspices of the MCRC award, we genotyped 15 TGFBR1 haplotype tagging SNPs in 212 clinic-based patients with a diagnosis of SSc and 426 clinic-based individuals without a diagnosis of SSc or cancer. SNPs associated with risk for SSc were validated in 1373 SSc cases and 744 controls. One of the three TGFBR1 SNPs associated with risk for SSc in the discovery cohort was also associated with risk for SSc in the validation cohort. Combined analysis of the two cohorts shows OR 1.67, 95% CI 1.16-2.41 for rs2026811 and OR 0.62, 95% CI 0.45-0.86 for rs334348. Disease subset analysis shows that rs10733710 is associated with diffuse disease, rs2026811 is associated with limited disease, and rs334348 with both limited and diffuse disease, Functional analysis shows that lymphoblastoid cell lines that carry the two-SNP TGFBR1 haplotype associated with risk for SSc in the combined analysis have significantly reduced TGF-ß signaling. These findings provide the first evidence that the TGFBR1 locus is associated with risk for SSc and suggest that constitutively altered TGFBR1 signaling contributes to the pathogenesis of this disease. The work has been prepared as a manuscript that is under review for publication. Additional analyses will be pursued in the laboratories of Boris Pasche (now at University of Alabama) and John Varga (Northwestern University), with clinical phenotype correlations analyzed by Drs. Monique Hinchcliff and Spencer Huang at Northwestern. Additionally, we have leveraged these resources into further genetic studies including GWAS as part of large multicenter international research consortia, and the results from these studies were recently published in Nature Genetics and in PLOS One).
Gorlova O, Martin JE, Rueda B, Koeleman BP, Ying J, Teruel M, Diaz-Gallo LM, Broen JC, Vonk MC, Simeon CP, Alizadeh BZ, Coenen MJ, Voskuyl AE, Schuerwegh AJ, van Riel PL, Vanthuyne M, van 't Slot R, Italiaander A, Ophoff RA, Hunzelmann N, Fonollosa V, Ortego-Centeno N, González-Gay MA, García-Hernández FJ, González-Escribano MF, Airo P, van Laar J, Worthington J, Hesselstrand R, Smith V, de Keyser F, Houssiau F, Chee MM, Madhok R, Shiels PG, Westhovens R, Kreuter A, de Baere E, Witte T, Padyukov L, Nordin A, Scorza R, Lunardi C, Lie BA, Hoffmann-Vold AM, Palm O, García de la Peña P, Carreira P; Spanish Scleroderma Group, Varga J, Hinchcliff M, Lee AT, Gourh P, Amos CI, Wigley FM, Hummers LK, Hummers J, Nelson JL, Riemekasten G, Herrick A, Beretta L, Fonseca C, Denton CP, Gregersen PK, Agarwal S, Assassi S, Tan FK, Arnett FC, Radstake TR, Mayes MD, Martin J. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. PLoS Genet. 2011 Jul;7(7):e1002178. Epub 2011 Jul 14.
Radstake TR, Gorlova O, Rueda B, Martin JE, Alizadeh BZ, Palomino-Morales R, Coenen MJ, Vonk MC, Voskuyl AE, Schuerwegh AJ, Broen JC, van Riel PL, van 't Slot R, Italiaander A, Ophoff RA, Riemekasten G, Hunzelmann N, Simeon CP, Ortego-Centeno N, González-Gay MA, González-Escribano MF; Spanish Scleroderma Group, Airo P, van Laar J, Herrick A, Worthington J, Hesselstrand R, Smith V, de Keyser F, Houssiau F, Chee MM, Madhok R, Shiels P, Westhovens R, Kreuter A, Kiener H, de Baere E, Witte T, Padykov L, Klareskog L, Beretta L, Scorza R, Lie BA, Hoffmann-Vold AM, Carreira P, Varga J, Hinchcliff M, Gregersen PK, Lee AT, Ying J, Han Y, Weng SF, Amos CI, Wigley FM, Hummers L, Nelson JL, Agarwal SK, Assassi S, Gourh P, Tan FK, Koeleman BP, Arnett FC, Martin J, Mayes MD. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet. 2010 May;42(5):426-9. Epub 2010 Apr 11. http://www.ncbi.nlm.nih.gov/pubmed/20383147