Association of the C8orf13-BLK region with systemic sclerosis in North-American and European populations.
OBJECTIVE
Genetic studies in the systemic sclerosis (SSc), an autoimmune disease that clinically manifests with dermal and internal organ fibrosis and small vessel vasculopathy, have identified multiple susceptibility genes including HLA-class II, PTPN22, IRF5, and STAT4 which have also been associated with other autoimmune diseases, such as systemic lupus erythematosus (SLE). These data suggest that there are common autoimmune disease susceptibility genes. The current report sought to determine if polymorphisms in the C8orf13-BLK region (chromosome 8p23.1-B lymphoid tyrosine kinase), which is associated with SLE, are associated also with SSc.


METHODS
Two variants in the C8orf13-BLK region (rs13277113 & rs2736340) were tested for association with 1050 SSc cases and 694 controls of North Americans of European descent and replicated in a second series 589 SSc cases and 722 controls from Spain.


RESULTS
The "T" allele at rs2736340 variant was associated with SSc in both the U.S. and Spanish case-control series (P = 6.8 x 10(-5), OR 1.27, 95% CI 1.1-1.4). The "A" allele at rs13277113 variant was associated with SSc in the U.S. series only (P = 3.6 x 10(-4), OR 1.32, 95% CI 1.1-1.6) and was significant in the combined analyses of the two series (P = 2.0 x 10(-3); OR 1.20, 95% CI 1.1-1.3). Both variants demonstrated an association with the anti-centromere antibody (P = 2.2 x 10(-6) and P = 5.5 x 10(-4), respectively) and limited SSc (P = 3.3 x 10(-5) and P = 2.9 x 10(-3), respectively) in the combined analysis. Peripheral blood gene expression profiles suggest that B-cell receptor and NFkappaB signaling are dysregulated based on the risk haplotype of these variants.


CONCLUSIONS
We identify and replicate the association of the C8orf13-BLK region as a novel susceptibility factor for SSc, placing it in the category of common autoimmune disease susceptibility genes.
Division of Rheumatology and Clinical Immunogenetics, Department of Internal Medicine, University of Texas Health Science Center at Houston (UTHSC-H), Houston, TX 77030, USA.
Pravitt
P
Gourh
Sandeep K
SK
Agarwal
Ezequiel
E
Martin
Dipal
D
Divecha
Blanca
B
Rueda
Haley
H
Bunting
Shervin
S
Assassi
Gene
G
Paz
Sanjay
S
Shete
Terry
T
McNearney
Hilda
H
Draeger
John D
JD
Reveille
T R D J
TR
Radstake
Carmen P
CP
Simeon
Luis
L
Rodriguez
Esther
E
Vicente
Miguel A
MA
Gonzalez-Gay
Maureen D
MD
Mayes
Filemon K
FK
Tan
Javier
J
Martin
Frank C
FC
Arnett
D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D016022:Case-Control Studies; D002503:Centromere / Q000276:immunology*; D002898:Chromosomes, Human, Pair 8; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013030:Spain; D014481:United States; D044465:White People; D019061:src-Family Kinases / Q000235:genetics* / Q000276:immunology
D001323:Autoantibodies; D016328:NF-kappa B; D011947:Receptors, Antigen, B-Cell; C082599:protein-tyrosine kinase p55(blk); D019061:src-Family Kinases