Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Association of VEGF, NOS2, IL6, CCL2 and IL1RN Polymorphisms and Haplotypes with Susceptibility to Giant Cell Arteritis. A Simultaneous Study of 130 Potentially Functional SNPs in 14 Candiadte Genes.
Enjuanes4, Anna, Benavente8, Yolanda, Hernandez-Rodriguez6, Jose, Queralt6, Carme, Yague1, Jordi, Jares5, Pedro, de Sanjose7, Silvia
Department of Immunology, Barcelona, Spain
Departmentof Systemic Autoimmune Diseases, Hospital Clinic, Barcelona, Spain
Hematopathology Section, Department of Anatomic Pathology, Barcelona, Spain
Hematopathology Section, Department of Anatomic Pathology, Hospital Clinic, Barcelona, Spain
Hematopatholoy Section, Department of Anatomic Pathology, Barcelona, Spain
Systemic Autoimmune Diseases, Barcelona, Spain
Unit of Infection and Cancer, Cancer Epidemiology Research, Catalan Institute of Oncology, Barcelona, Spain
Unit of Infection and Cancer. Cancer Epidemiology Research. Catalan Institute of Oncology
Giant cell arteritis (GCA) is an immune-mediated vasculitis involving large and medium-sized arteries, especially the aorta and its cervico-cranial branches. GCA is probably a polygenic disease and it seems plausible that frequent genetic variants with modest effects may be related to GCA susceptibility. To date, existing studies assessing genetic risk for GCA have only analyzed limited number of candidate genes and restricted number of genetic variants.
To investigate the genetic susceptibility to GCA, we performed a case-control study genotyping 130 SNPs in 82 biopsy-proven GCA patients and 166 healthy controls from the Spanish population. The study evaluates SNPs in potentially functional regions (coding and regulatory gene regions) and some tag SNPs in 14 candidate genes related to the inflammatory response (CCL2, CCR7, IL10, IL12A, IL-1A, IL-1B, IL-1RN, IL6, IL8, INFG, LTA, NOS2, TNF and VEGF).
Genomic DNA was isolated from peripheral blood mononuclear cells and genotyping was carried out at the Spanish National Genotyping Centre (CeGen) using an Illumina Bead Array System. Hardy-Weinberg equilibrium (HWE) for each SNP was evaluated in control subjects. To test the hypothesis of association we used multivariate methods based on logistic regression analyses under four inheritance models (codominant, dominant, recessive and log-additive) and adjusted for age and sex.
We found than 9 SNPs located in five genes had a significant statistical association with disease risk (P < 0.05) for any of the inheritance models. These SNPs were located in NOS2 (rs2779251), VEGF (rs1885657, rs2010963, rs699946 and rs699947), IL1RN (rs17207494), IL6 (rs7805828 and rs1546766), and CCL2 (rs1860190) genes. The strongest associations were provided by rs2779251, rs1885657 and rs2010963 (P = 2.3 10-5, P= 0.0078 and P= 0.0097, respectively). The association of rs2779251 and GCA risk was statistically significant after strong adjustment for multiple testing (P corr= 0.0024). The presence of the minor allele of NOS2 variant rs2779251 had a protective effect for the risk of GCA (OR=0.27, 95% CI:0.140.52). Risk alleles for three of the four SNPs located in VEGF gene (rs2010963, rs699946 and rs699947), in homozygosis, showed an increase in the GCA risk (OR=4.22, 95% CI:1.3812.87; OR=9.04, 95% CI:1.5851.81; and OR=2.38, 95% CI:1.055.38; respectively). Minor allele for the other SNP in VEGF gene, the rs1885657, had a protective effect for GCA (OR=0.46, 95% CI:0.260.84). Moreover, we defined linkage disequilibrium blocks for each candidate gene included in this study and we explored the effect of haplotypes on disease risk. We found four haplotypes that showed significant association with susceptibility to GCA (IL6, OR=0.51, 95% CI:0.280.94; VEGF, OR=2.92, 95% CI:1.038.34; VEGF, OR=0.42, 95% CI:0.210.85; and IL1B, OR=2.94, 95% CI:1.296.67).
In summary, our results show that common genetic variants in NOS2, VEGF, IL6, ILRN1 and CCL2 genes are associated with risk for GCA, reinforcing a polygenic influence in susceptibility to this vasculitis.
Suported by Fundacion Genoma España, SAF 08/04328 and Marato TV3 (06/0710).
To cite this abstract, please use the following information:
Enjuanes, Anna, Benavente, Yolanda, Hernandez-Rodriguez, Jose, Queralt, Carme, Yague, Jordi, Jares, Pedro, et al; Association of VEGF, NOS2, IL6, CCL2 and IL1RN Polymorphisms and Haplotypes with Susceptibility to Giant Cell Arteritis. A Simultaneous Study of 130 Potentially Functional SNPs in 14 Candiadte Genes. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1280