An Arab selective gradient in the distribution of factor V G1691A (Leiden), prothrombin G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T

Abstract

Venous thrombosis (VTE) is a multi-factorial disease resulting from the interaction of genetic and environmental risk factors. Among the inherited factors are factor V (FV) G1691A (FV Leiden) [1], prothrombin (PRT) G20210A [2], and methylenetetrahydrofolate reductase (MTHFR) C677T [3] single nucleotide polymorphisms (SNPs). In FV Leiden, an arginine is substituted by glutamine at amino acid residue 506, which renders FVa resistant to degradation by activated protein C [1]. The PRTG20210A SNP, a G to A transition in the 3¢ untranslated region of the PRT gene, is associated with increased PRT levels [2].WhilebothFVLeidenandG20210ASNPsarepresent at varying rates in Caucasians [4], and are virtually absent from Africans and Asians [5], the MTHFR C677T is found in many populations with a marked heterogeneity in its distribution, exemplified by its low incidence in Africa and Indian subcontinent [6], and higher rates in North America, Europe [7], and Japan. Insofar as the incidence of FV Leiden, PRT G20210A, andMTHFRC677T SNPs among Arabs is poorly defined, we assessed the incidence of these three SNPs in four distinct Arab communities: Lebanon, Tunisia, Bahrain, and Saudi Arabia. Study subjects comprised 698 Lebanese (288 males and 410 females), 313 Tunisian (129 males and 184 females), 193 Bahraini (150 males and 43 females), and 149 Saudi (69 males and 80 females) healthy subjects. Genotyping was carried out by PCR-RFLP analysis using MnlI, HindIII, and HinfI digestion for detecting FV Leiden, PRT G20210A and MTHFR C677T, respectively. Allele frequencies were determined using the gene counting method, and Wright’s FST calculations were made using GENALEX software. Additional statistical was performed with SPSS version 12.0.1. The distribution of the three SNPs genotypes was in Hardy– Weinberg equilibrium. The frequencies of FV Leiden (A) and PRT G20210A mutant (A) alleles, together with the G/A and A/A genotypes of FV Leiden, were highest among Lebanese, while Tunisians, Bahraini and Saudi Arabian participants had lower frequencies (Table 1).Higher incidence of FVLeidenwas seen among Lebanese compared with other populations (P < 0.001), while the difference between Tunisians and Bahraini (P 1⁄4 0.157) or Saudi (P 1⁄4 0.073) subjects was not different. All PRT G20210A SNP carriers were in the heterozygous state (G/A); no PRT G20210A SNP carrier was found among Saudi participants (Table 1). With the exception of Lebanese–Saudi (P 1⁄4 0.038), thedistributionofPRTG20210A was similar among study communities. The distribution of the C677T alleles varied; high incidence of the T allele and the T/T genotype was found in Lebanon and Tunisia, and lower rates among Saudi and Bahraini subjects (Table 1). While the incidence of T/T genotype was similar between Lebanese and Tunisian (P 1⁄4 0.542), and Saudi and Bahraini (P 1⁄4 0.470) subjects, higher incidence of T/T genotype was seen among Lebanese vs. Bahraini (P < 0.001) and Saudi (P 1⁄4 0.014), and between Tunisian and Bahraini (P 1⁄4 0.005) subjects.