VEGF Gene Haplotypes Are Associated With Sarcoidosis

Abstract

The cause of sarcoidosis is unclear. Evidence suggests that there is a genetic susceptibility toward the disease. In this study, we examined whether haplotypes of vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2 are associated with the onset or the course of sarcoidosis. Three hundred white patients with sarcoidosis and 381 matched controls were included. Sixty-three haplotype-tagging single nucleotide polymorphisms (SNPs) in the VEGF and VEGFR-1 and VEGFR-2 genes were selected from the HapMap Project phase 2. Mass spectrometry-based SNP genotyping was performed. Sarcoidosis, in general, was significantly associated with three SNPs in the VEGFR-1 gene: rs7337610 (P = .041), rs2296283 (P = .034), and rs12858139 (P = .027). In an acute course (defined as less than two episodes in a lifetime or a course lasting less than 2 years), an association of three SNPs in the VEGF gene was observed: rs833060 (P = .004), rs833068 (P = .008), and rs3025000 (P = .012). In the VEGFR-2 gene, one SNP was associated with an acute course of sarcoidosis (rs7667298, P = .023), whereas two SNPs were associated with a chronic course of sarcoidosis: rs7691507 (P = .029) and rs2125489 (P = .024). We then performed a haplotype analysis. After permutation-based correction, no significant haplotype association for the VEGF receptors was observed. However, we found two haplotypes associated with the onset of sarcoidosis in the VEGF gene. Even after correction for multiple testing, we obtained a P value of .0388. Moreover, patients with a chronic course of the disease showed a P value of .0103 for the same haplotype. There is strong evidence that VEGF and its receptors are involved in the onset of sarcoidosis and influence its course.