We read with great interest the review article by Zakai and McClure  regarding racial differences in venous thromboembolism (VTE). While racial differences in the incidence of VTE have been reported, the race-specific genetic risk factors for VTE have remained obscure until recently. Factor V Leiden mutation and prothrombin G20210A mutation are commonly found in populations of European origin as modest genetic risk factors for VTE , and Asians have neither mutation. Although the incidence of VTE in African-Americans is more than 5-fold greater than that in Asian-ancestry populations, and European and Hispanic populations are at intermediate risk of VTE, Asian populations may have race-specific mutations for VTE. Recently, we identified a protein S K196E mutation as a genetic risk factor for VTE in a Japanese population [2–4]. As Zakai and McClure have described a high prevalence of protein C and protein S deficiency in Japanese, Taiwanese and Thai populations with VTE, the protein S K196E mutation can account for the high prevalence of protein S deficiency in Japanese subjects. An in vitro study showed that the recombinant protein S with the K196E mutation lost activated protein C-dependent anticoagulant activity .
So far, three independent case–control studies, all performed in Japan, have reached the same conclusion – that the protein S K196E mutation is a risk factor for VTE, with odds ratios between 3.74 and 8.56 [2–4]. The prevalence of this mutation has been examined in four cohorts, and 77 heterozygous carriers have been identified in 4319 Japanese subjects [2–4,6], indicating a mutant allele frequency of 0.0089. None were homozygotes. The total population of Japan is now 127 million. Therefore, approximately 10 000 Japanese may be homozygotes. Three VTE patients homozygous for protein S K196E mutation have been identified with a prevalence of one homozygote out of approximately 85 VTE patients [2,3]. One homozygote showed 78% total protein S antigen, 94% free protein S antigen, and 35% protein S anticoagulant activity . Another homozygote showed 39% protein S anticoagulant activity but no data on antigen levels. The third homozygote did not have any antigen or activity data . The protein S K196E mutation can be found in VTE patients with congenital protein C deficiency, facilitating the development of VTE [4,7], and is frequently present in VTE patients with pregnancy . The genotype-phenotype study of the Japanese general population showed that the individuals heterozygous for the mutant E-allele had 16% lower protein S anticoagulant activity than wild-type subjects .
The protein S K196E mutation seems to be race specific, because so far this mutation has not been identified in a Caucasian population. We believe that the protein S K196E mutation should be present in other east Asian populations, including the Chinese and Koreans; however, so far there are no reports on those populations. Some genetic mutations specific to eastern Asian populations, in particular the plasminogen A610 T mutation with an allele frequency of 0.020 in Japanese subjects and the ADAMTS13 P475S mutation with an allele frequency of 0.050 in Japanese subjects, have been reported in other east Asian populations . These mutations are low-frequency variations, with allele frequencies between 0.05% and 0.5% . Factor V Leiden mutation and prothrombin G20210A mutation in Caucasian populations are also regarded as low-frequency variations. Thus, as previously described , the low-frequency genetic variations would be important for specific phenotypes such as VTE, and the protein S K196E mutation is a race-specific genetic risk factor for VTE. Recent genomewide genetic analysis in Asian populations revealed the southern migration route to eastern Asia . The low-frequency genetic variation should have occurred recently and should be fixed within a specific population. This accumulating body of evidence strongly suggests that genetic studies should be carried out in each ethnic population and that studies of common variations as well as low-frequency variations would be valuable.