Impact of Genetic Variations on Thrombotic Risk in Saudis with Sickle Cell Disease

Abstract

Background Sickle cell disease (SCD) is a Mendelian disease characterised by multigenic phenotypes. Previous reports indicated a higher rate of venous thromboembolism (VTE) in SCD patients. A number of candidate polymorphisms in certain genes (e.g. FVL, PRT, and MTHFR) were previously reported as risk factors for VTE in different clinical conditions. This study aimed to genotype these genes and other loci predicted to underlay VTE in SCD patients. Methodology A genome-wide association study involving Saudi SCD adult patients with a history of VTE (n=65) and control patients without VTE history (n=285) was performed. Genotyping used the 10x Affymetrix Axiom array which includes 683,030 markers. Results No associations were identified between the targeted single nucleotide polymorphisms (SNPs) [FVL (rs6025), PRT (rs1799963), and MTHFR (rs1801133)] and VTE episodes in SCD patients. In contrast, GWAS analysis showed two genome-wide significant signals (P<5×10 -8) on chromosome (Chr) 11. These SNPs, rs35390334 and rs331532, are in strong linkage equilibrium (LD, r 2=0.97). A total of 35 other markers had an association threshold of P<5×10 -6. Four of these variants are located in olfactory receptor genes [OR51B5 (rs147062602), OR51V1 (rs7933549), OR51A1P (rs80034548), and OR52A5 (rs2472530)]. Conclusion No association between FVL, PRT, and MTHFR genes and VTE episodes was seen in Saudis with SCD. In contrast, two markers (rs35390334 and rs331532) showed significant genome-wide associations and less significant associations (P<5×10 -6) were identified for 35 other variants (24 of them are located on Chr 11). Further replication of these findings is needed.