Candidate Gene Polymorphisms and the Risk for Pregnancy Related Venous Thrombosis

Abstract 4203 Background: Venous thrombosis (VT) is the leading cause of maternal death in the western world. Genetic causes of pregnancy related VT are insufficiently understood. Objectives: To investigate if recently discovered associations between single nucleotide polymorphisms (SNPs) and thrombotic disease influenced the risk for pregnancy related VT. To investigate candidate genes for new associations between SNPs and pregnancy related VT. Methods: A hospital based case control study. Cases were women with objectively verified VT during pregnancy or puerperium, controls were women giving birth without having VT. We selected 49 candidate genes involved in coagulation (35 genes), inflammation (4 genes), and hormonal metabolism (10 genes). In these genes, 463 tag-SNPs were selected from the CEU population in Hapmap and analyzed in 313 cases and 353 controls. Odds ratios for VT were calculated with the most common genotype as the reference genotype for each SNP. P-values were adjusted for multiple testing to false discovery rates. Results: Of the SNPs previously shown by others to be associated to thrombotic disease, rs2289252 in the FXI gene (F11), rs3917643 in the tissue factor gene (F3), rs1613662 in the glycoprotein VI gene, rs2001490 in NAT8B, rs4524 in the FV gene (F5), and rs3087505 in the prekallikrein gene were associated to pregnancy related VT. After analyzing all 463 tag-SNPs, 13 SNPs were associated to total pregnancy related VT with a false discovery rate ≤ 0.20. These SNPs belonged to F5, SELP (coding for P-selectin), F3, F8 (coding for factor VIII), and F11. When we studied antenatal and postnatal VT separately, 17 SNPs were associated with antenatal VT, while only 1 SNP was associated with postnatal VT. Thirteen SNPs in F5, SELP, or the gene for E-selectin were associated with thrombosis. After excluding carriers of factor V Leiden, 4 of these SNPs remained associated. Two SNPs in the gene for epidermal growth factor receptor (EGFR) were associated to antenatal thrombosis. Conclusion: Genetic variation seems more important for antenatal than for postnatal VT. We confirmed the importance of some SNPs for the risk for pregnancy related VT, in particular rs2289252 in F11. The EGFR-gene appears to be a new genetic locus associated with pregnancy related VT. Table 1 SNPs associated with total pregnancy related VT, antenatal VT, or postnatal VT with false discovery rate ≤ 0.20. No (%) alleles Gene SNP Controls Cases OR (CI95) p Total pregnancy related VT F5 rs6427202 274 (39) 311 (50) 1.6 (1.3–2.0) <0.001 SELP rs2205895 285 (41) 191 (31) 0.6 (0.5–0.8) <0.001 SELP rs3917744 202 (29) 236 (38) 1.5 (1.2–2.0) <0.001 SELP rs2076074 177 (25) 112 (18) 0.6 (0.5–0.8) 0.001 SELP rs2142760 346 (49) 362 (58) 1.5 (1.2–1.8) 0.001 SELP rs2244529 196 (28) 227 (36) 0.7 (0.5–0.9) 0.001 F5 rs9332640 247 (35) 332 (53) 1.5 (1.2–1.8) <0.001 F11 rs22892521–3 278 (39) 281 (45) 1.4 (1.1–1.7) 0.003 F3 rs39176434 54 (8) 23 (4) 0.5 (0.3–0.8) 0.002 SELP rs3917854 231 (33) 160 (26) 0.7 (0.5–0.9) 0.003 F5 rs6427199 291 (41) 201 (32) 0.7 (0.6–0.9) 0.002 F5 rs9332542 237 (34) 163 (26) 0.7 (0.5–0.9) 0.002 F8 rs1472977 153 (22) 98 (16) 0.7 (0.5–0.9) 0.003 Antenatal VT SELP rs2244529 253 (36) 187 (60) 0.6 (0.4–0.8) <0.001 F5 rs6427202 137 (39) 79 (1) 1.7 (1.3–2.3) <0.001 F8 rs1472977 153 (22) 43 (14) 0.6 (0.4–0.8) 0.004 NAT8B rs20014902 240 (34) 136 (44) 1.5 (1.1–2.0) 0.003 SELP rs2205895 285 (41) 95 (31) 0.6 (0.5–0.9) 0.002 SELE rs3917410 77 (11) 56 (18) 1.8 (1.2–2.6) 0.002 SELP rs3917744 202 (29) 119 (38) 1.6 (1.2–2.2) 0.002 F5 rs45241 181 (29) 53 (38) 0.6 (0.4–0.8) 0.003 EGFR rs4947491 252 (36) 144 (46) 1.5 (1.2–2.0) 0.002 SELP rs6131 139 (20) 88 (28) 1.6 (1.2–2.1) 0.004 F5 rs6427199 291 (41) 97 (28) 0.7 (0.5–0.9) 0.003 SELP rs2142760 346 (49) 181 (58) 1.5 (1.1–2.0) 0.005 EGFR rs2330951 170 (24) 101 (33) 1.5 (1.1–2.0) 0.006 NR1I2 rs2461825 228 (32) 74 (24) 0.6 (0.5–0.9) 0.006 F3 rs39176434 54 (8) 9 (3) 0.4 (0.2–0.7) 0.005 PROS1 rs8178607 201 (29) 64 (21) 0.6 (0.5–0.9) 0.007 GP6 rs16136622 130 (18) 36 (12) 0.6 (0.4–0.9) 0.007 Postnatal VT SELP rs2076074 177 (25) 48 (15) 0.5 (0.4–0.7) <0.001 Disclosures: No relevant conflicts of interest to declare.