Association of NOS2 and potential effect of VEGF, IL6, CCL2 and IL1RN polymorphisms and haplotypes on susceptibility to GCA-a simultaneous study of 130 potentially functional SNPs in 14 candidate genes

Objective. Frequent genetic variants may be associated with GCA. Existing studies have analysed a limited number of candidate genes and genetic variants. To expand this information, we performed a case-control study genotyping 130 single nucleotide polymorphisms (SNPs) in 82 biopsy-proven GCA patients and 166 healthy controls from the Spanish population. Methods. SNPs in coding and regulatory gene regions of 14 candidate genes (CCL2, CCR7, IL10, IL12A, IL1A, IL1B, IL1RN, IL6, IL8, INFG, LTA, NOS2, TNF and VEGF) were explored using the Illumina Bead Array System. Multivariate methods based on logistic regression were used for statistical analysis. Results. Nine SNPs located in five genes had significant association with GCA risk (P < 0.05). These SNPs were located in the NOS2 (rs2779251), VEGF (rs1885657, rs2010963, rs699946 and rs699947), IL1RN (rs17207494), IL6 (rs7805828 and rs1546766) and CCL2 (rs1860190) genes. The strongest associations were seen for rs2779251, rs1885657 and rs2010963 (P = 2.3 x 10(-5), P = 0.0078 and P = 0.0097, respectively). The presence of the minor allele of NOS2 variant rs2779251 had a protective effect on the risk for GCA [odds ratio (OR) = 0.27, 95% CI 0.14, 0.52]. Risk alleles for three of the four SNPs in the VEGF gene (rs2010963, rs699946 and rs699947) were associated in homozygosis with increased risk (OR = 4.22, 95% CI 1.38, 12.87; OR = 9.04, 95% CI 1.58, 51.81; and OR = 2.38, 95% CI 1.05, 5.38, respectively), whereas a minor allele for the other SNP (rs1885657) had a protective effect (OR = 0.46, 95% CI 0.26, 0.84). Conclusion. Common genetic variants in NOS2, VEGF, IL6, ILRN1 and CCL2 genes are associated with GCA, indicating a polygenic influence on disease susceptibility.