Factor V Leiden and Natural Selection

Factor V Leiden ([FVL] 1691G-A) is a thrombophilic single-point mutation (G1691A), leading to an amino acid substitution of Arg⁵⁰⁶ with Gln that causes activated protein C (APC) resistance, thus, yielding to a hypercoagulation disorder. ^1,2 The mutation shows an uneven geographic distribution, ranging from nonexistence in natives of Africa, America, Asia, and Australia, to high existence reaching at 15% in some areas of Europe. ^3,4

High prevalence of the mutation among all whites makes it plausible to ask whether FVL had caused selective advantages during evolution, some of which are assumed to be the reduction in the risk of hemorrhage after delivery and also for fighter ancestors living in a period when no satisfactory medical care was offered. It should also be noted that reduction in the mortality rate might be related to severe sepsis. ^5-7 The disadvantageous impact of the mutation, resulting in a higher risk of thrombosis, might not have been as damaging because the risk factors associated with the lifestyle such as arteriosclerosis were rare. ⁸ A supporting data were obtained from a contemporary study in which the participants were centenarians, suggesting that FVL does not contradict extreme longevity and successful ageing. ⁹

There exists limited information about why some mutations causing susceptibility to diseases are present in a high frequency rather than not being eliminated by natural selection. ¹⁰ Most probably, the answer lies in the survival advantage caused by the mutation. Even a small increase in the frequency of FVL for 1 generation would have yielded a significant difference through hundreds of generations. ⁶

Turkey, lying between 2 continents, Europe and Asia, connecting East and West, played a major role in the world history. Turkish population seems to be a very good resource to study the possible selective disadvantages of FVL with its significantly high frequency. Furthermore, historically Turkish population experienced neither war nor famine during the last 85 years, with decreasing newborn and childhood deaths along the last century.

Review on the distribution of FVL in Turkish population revealed FVL frequency as 7.9% among normal healthy Turkish adults, whereas it was 12% among newborns. ¹¹ The difference between adults and newborns needed further attention. There should be a reason for the difference between newborns and adults. This review was undertaken in order to clarify the difference.

A marked difference between adult and newborn frequency may have importance (8.0% vs 11.5%; Table 1 ). This calls to mind the question, “Did some of the infants with FVL mutation die of clinical conditions related to thromboembolism before reaching adult age and without receiving a specific diagnosis?” This may explain the difference between the frequencies in newborns and adults. ¹⁴ The difference between the 2 groups was statistically significant (P = .015). If this hypothesis is verified by other studies, it will be a very important finding from an evolutionary point of view.

Figure 1.

Kaplan-Meier data of pediatric patients with and without FVL. FVL indicates factor V Leiden.

Table 1.

Distribution of FVL in Newborns, Adults, and Elderly Individuals (Compiled Data)

	N	FVL Heterozygous	FVL Homozygous	%	References
Newborns	494	56	1	11.5	Atasay et al 12 and Baytan et al 13
Adults	4431	357	—	8.0	Akar 11
Elderly individuals 70 and over	266	29	—	11.0	Unpublished data

Abbreviations: FVL, factor V Leiden.

The data revealed us to study the question whether carrying FVL affects the morbidity of children with thrombosis. We compared the effect of FVL in children with thrombosis with and without FVL. Kaplan-Meier analysis revealed that in the control group the 5-year survival rate was 76%; in the FVL carrier group, it was 56%. In the control group, average age of survival was 9.33 (8.79-9.88) and it was 7.13 (6.56-7.71) in the FVL carrier group. Log-rank test was statistically significant (P = 0.00). ¹⁵ Further carrying FVL increases the risk of pediatric stroke significantly. ¹⁶

Another interesting point was that FVL increased among the elderly (older than 70 years) to 11.5%. The difference between elderly group and the other 2 groups is insignificant, respectively (P = .8 and P = .13). Our data are similar to the previous report on centenarians. ⁹ There should be several possible reasons for this increase. First, a specific factor V haplotype may have a protective effect or vice versa. Other gene combinations may have protective or causative effect on the risk possibility of FVL.

A population scale Genomewide Association Study (GWAS) might be instrumental in order to identify these possible gene combinations.

Further, if this difference would be verified by large number of controls, this might be a clue for the advantageous role of FVL in natural selection.