High Frequency of Factor V Leiden in a Population of Israeli Arabs

Since the discovery of increased incidence of vascular disease in people bearing common mutations in the genes for coagulation factor V (”factor V Leiden“) and methylenetetrahydrofolate reductase (MTHFR) (677C T), investigators have sampled the frequencies of these mutations in local ethnic populations. Few studies have been undertaken in the Middle East. While Rees (1) found no cases of factor V Leiden among 55 Saudi Arabians, Dzimiri (2) reported a 2.5% frequency of the heterozygous mutant among 200 healthy Saudi men. We have screened 443 employees of our medical center for these two mutations (175 males, 268 females, ages 19-68). None of the subjects were first degree relatives of each other. DNA samples were obtained using buccal cells from mouthwash, and DNA was extracted using a standard salting out procedure (3). Mutation analyses for factor V Leiden and the MTHFR polymorphism were performed according to published methods (4, 5), using PCR amplification with the appropriate primers, followed by restriction digestion with MnlI and HinfI, respectively. Digested fragments were electrophoretically separated on 3% agarose gels. The ethnic distribution of mutation frequencies for factor V is shown in Table 1. Statistical significance was determined using the two-tailed student’s t test. We found a strikingly high percentage of factor V Leiden heterozygotes (24.3%) among Israeli Arabs. It is almost five times that of the Israeli Jewish population (5.1%, p <0.0001), and is the highest frequency of factor V Leiden heterozygotes of any ethnic group reported to date. Haplotype analysis has implied that the factor V Leiden mutation arose from a single founder (6), and the finding of higher mutation frequencies in Greece, Azerbaijan, Turkey, and Dagestan compared to central Europe led to the suggestion that this mutation originated in the Middle East (7). Our results support this hypothesis and suggest that this population may be the closest to the original founding population. The generally high consanguinity rate in the Arab population in Israel is another factor which may have driven the carrier frequency even higher, and this may be reflected in our results, even though the subjects tested were unrelated. The high percentage of factor V Leiden carriers identified in Israeli Arabs raises the possibility that venous thromboembolism (VTE), a disease known to be increased in factor V Leiden carriers (8), may be especially common in this population. Nevertheless, a preliminary review of VTE prevalence using Israel Health Ministry statistics for hospitalizations for 1994 has not shown an increase in this group. This could be due to possible underreporting of VTE in the Arab sector or, if substantiated, may imply the existence of protective factors (genetic and/or environmental) which negate the expected rise in VTE contributed by the factor V Leiden allele. A possible genetic modifier of VTE is the MTHFR 677C T mutation, which is associated with hyperhomocysteinemia and vascular disease in homozygotes (5, 9). Nevertheless, no difference was found in the frequency of MTHFR homozygotes between the Arab (12.9%) and combined Jewish (12.9%) populations. These results point to a need for an in-depth investigation of the relative prevalence of VTE and factor V Leiden among Arab populations, both in Israel and in neighboring Arab countries.