Through a combination of genotyping and resequencing we have identified 3 SNPs (rs17564430, rs3802858 and rs6589488) in a venous thrombosis (VT) susceptibility gene encoding Immunoglobulin Superfamily 4 (IGSF4), that interacts with protein C (PC) deficiency (3363InsC) in a large thrombophilic kindred (n=516). The IGSF4 gene is located on chromosome 11q23. To verify the association with VT and to estimate the joint effect with PC deficiency, we genotyped the 3 SNPs in the 450 available kindred members, of whom 40 (32 PC deficient) had experienced VT. For each SNP we estimated the odds ratio (OR) and 95% confidence interval (CI95) for VT, adjusting for age and sex. Because earlier linkage analyses and SNP genotyping had suggested a dominant effect of the gene, we calculated the OR for carriers compared to non-carriers. Two of 3 SNPs in IGSF4 remained associated with VT. Carriers of the rs6589488 minor allele had a more than 10-fold increased risk of VT (OR 10.2, CI95 7.8–13.4), compared to those homozygous for the major allele. The effect was more pronounced in PC deficient family members (OR 17.0, CI95 13.5–21.4). PC deficient carriers of the rs3802858 minor allele had about 5-fold increased risk of VT (OR 4.7 CI95 2.2–10.0). We designed a replication study of these findings in the Leiden Thrombophilia Study (LETS) comprised of 471 VT patients and 471 control subjects. The 2 original and 11 additional SNPs were selected based on linkage disequilibrium (LD) in the locus surrounding the 2 SNPs associated with VT in the family. None of the SNPs was associated with VT across the whole LETS population. However, we observed a potential synergistic effect between some of these SNPs and the factor V Leiden (FVL) mutation, suggesting interaction with the PC system. For example, rs658948 major allele homozygotes who carry FVL have an 11–fold increased risk of VT (OR 11.2, CI95 5.1–24.3) compared to minor allele carriers who do not carry FVL. This is a 3-fold increase (CI95 0.9–9.9) over the VT risk associated with FVL alone. In LETS we took rs6589488 minor allele carriers as reference since the major allele was the higher risk allele. This is opposite of what we observed in the family. Apart from refuting associations, reverse associations in different populations might be true but caused by variation in LD patterns between the rs6589488 and other or true causal variants (
Disclosures: Bovill:Haematologic Technolgies Inc.: Equity Ownership.