Gender-specific association of the factor V Leiden mutation with fertility and fecundity in a historic cohort. The Leiden 85-Plus Study

Dunné, Frederique M. van; Craen, Anton J. M. de; Heijmans, B.T.; Helmerhorst, Frans M.; Westendorp, Rudi G.J.

doi:10.1093/humrep/dei422

Cited by 16 publications

(13 citation statements)

References 21 publications

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“…Our results provide an explanation for the increased fecundity found in men with FVL as described in a previous study [12]. In this large case–control study among 1176 subjects, the relative risk of conception within 3 months after marriage was 3.5 (95% CI 2.1–5.7) for men with FVL as compared with men without FVL.…”

Section: Discussionsupporting

confidence: 84%

“…It has long been thought that the high population frequency of FVL reflects some sort of evolutionary benefit for carriers [7–11]. Interestingly, male, but not female, FVL carriers display a higher fecundity rate (the time between marriage and first pregnancy) than non‐carriers [12]. We hypothesized that men with FVL have high sperm counts, thereby increasing their chance to establish a pregnancy and spreading their genotype.…”

Section: Introductionmentioning

confidence: 99%

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Increased sperm count may account for high population frequency of factor V Leiden

Cohn

Repping

Büller

et al. 2010

Journal of Thrombosis and Haemostasis

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To cite this article: Cohn DM, Repping S, Bü ller HR, Meijers JCM, Middeldorp S. Increased sperm count may account for high population frequency of factor V Leiden. J Thromb Haemost 2010; 8: 513-6. Summary. Background: Factor V Leiden (FVL) increases the risk of venous thrombosis and pregnancy loss in carriers. Nevertheless, this relatively old mutation is prevalent in Caucasion populations, which could be explained by positive selection pressure. Men with FVL have previously been found to have higher fecundity (the time between marriage and first pregnancy). Whether this is caused by increased sperm counts in men with FVL is unknown. Objectives: To assess whether men with factor V Leiden have increased sperm counts. Patients/ methods: We performed a prospective cohort study among 1139 consecutively included male partners of subfertile couples presenting at our university hospital for fertility workup between January 2000 and July 2007. All potential candidates who gave informed consent were included, irrespective of their fertility workup. In this retrospective analysis, we excluded participants with known causes of spermatogenic function or azoospermia. Subsequently, we genotyped all participants and compared sperm counts between FVL carriers and noncarriers. Results: We identified 37 FVL carriers and 921 noncarriers. FVL carriers had higher total sperm counts and total motile sperm counts than non-carriers: 236 · 10 6 (95% CI 158-292 · 10 ), respectively. Conclusions: To our knowledge, this is the first study that indicates that an increased incidence of a genotype may be controlled by increased sperm counts. However, the finding that men with FVL had higher total (motile) sperm counts was not statistically significant and needs confirmation in other studies.

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Section: Discussionsupporting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Increased sperm count may account for high population frequency of factor V Leiden

Cohn

Repping

Büller

et al. 2010

Journal of Thrombosis and Haemostasis

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“…1 Flow diagram of study selection was no association between recurrent miscarriage and frequency of homozygous mutations for factor V (G1691A; Leiden), factor V [H1299R (R2)], factor V (Y1702C), factor II prothrombin (G20210A), factor XIII (V34L), b-fibrinogen ()455G > A), plasminogen activator inhibitor-1 (PAI-1) (4G/5G), human platelet antigen 1 (HPA1) (a/b9L33P), methylenetetrahydrofolate reductase (MTHFR) (C677T) or MTHFR (A1298C). A previous small case-control study has demonstrated that FVL could significantly increase the risk of infertility [25], but this association has not been observed in another study [26]. A role of thrombophilia has also been advised in recurrent IVF failure.…”

Section: Discussionmentioning

confidence: 93%

Association between in vitro fertilization outcomes and inherited thrombophilias: a meta-analysis

Tan

Sao

et al. 2016

J Assist Reprod Genet

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Purpose The aim of this study was to determine whether in vitro fertilization (IVF) outcomes are associated with inherited thrombophilias. Methods Several databases including PubMed, Embase, and Cochrane Library were retrieved up to 12 January 2016. The quality of the included studies was assessed by two authors. The associations of the following mutations in inherited thrombophilias and IVF outcomes were explored: factor V Leiden (FVL), prothrombin gene G20210A mutation (PGM), 5,10-methylentetrahydrofolate reductase (MTHFR) C677T, MTHFR (A1298C) and activated protein C resistance (APCR). The main outcome measures included CPR and implantation rate (IR). The relative risk (RR) and its 95 % confidence interval (CI) were calculated for effect index. Heterogeneity test was evaluated by Chi-square based on Q statistic and I 2 statistics. Results A total of seven articles published between 2007 and 2015 with the ages of subjects between 30.9 and 36.2 were included. For subgroups analysis of CPR or IR, there were no significant differences in MTHFR (C377T), MTHFR (A1298C), FVL, PGM, and FVL/PGM mutation were found between the mutation group and control group (P > 0. 05). Conclusions IVF outcomes are not associated with FVL, PGM, MTHFR (C677T), MTHFR (A1298C), and APCR mutation in inherited thrombophilias.

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“…In contrast, we found no evidence for the Foxo1a involvement in female fertility and fecundity, which were respectively defined as the ability to have children, and the probability to conceive within a specific period of time. 25 The other FOXO transcription factor, Foxo3a, has been implicated in a variety of biological processes, including metabolism, fertility, stress response and ageing. In this study, we found no associations between Foxo3a haplotypes, human fertility and fecundity.…”

Section: Discussionmentioning

confidence: 99%

Haplotypes in the human Foxo1a and Foxo3a genes; impact on disease and mortality at old age

et al. 2007

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Recently, the Daf-16 gene has been shown to regulate the lifespan of nematodes and flies. In mammals, the Daf-16 homologues are forkhead (FOXO) transcription factors, of which specific functions have been identified for Foxo1a and Foxo3a. Despite that, their influence on human age-related trajectories and lifespan is unknown. Here, we analysed the effect of genetic variance in Foxo1a and Foxo3a on metabolic profile, age-related diseases, fertility, fecundity and mortality. This study was carried out in the prospective population-based Leiden 85-plus Study, which includes 1245 participants, aged 85 years or more. The mean follow-up time was 4.4 years. Haplotype analyses of Foxo1a revealed that carriers of haplotype 3 'TCA' have higher HbA1c levels (P ¼ 0.025) and a 1.14-fold higher all-cause mortality risk (P ¼ 0.021). This increase in mortality was attributable to death from diabetes, for which a 2.43-fold increase was observed (P ¼ 0.025). The analyses with Foxo3a haplotypes revealed no differences in metabolic profile, fertility or fecundity. However, increased risks of stroke were observed for Foxo3a block-A haplotype 2 'GAGC' (P ¼ 0.007) and haplotype 4 'AAAT' (P ¼ 0.014) carriers. In addition, the haplotype 2 'GAGC' carriers had a 1.13-fold increased risk for all-cause mortality (P ¼ 0.036) and 1.19-fold increased risk for cardiovascular mortality (P ¼ 0.052). In conclusion, this study shows that genetic variation in evolutionarily conserved Foxo1a and Foxo3a genes influences lifespan in our study population.

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Gender-specific association of the factor V Leiden mutation with fertility and fecundity in a historic cohort. The Leiden 85-Plus Study

Abstract: Fecundity is increased in male FVL carriers; in female subjects, no such association was observed.

Cited by 16 publications

References 21 publications

Increased sperm count may account for high population frequency of factor V Leiden

Increased sperm count may account for high population frequency of factor V Leiden

Association between in vitro fertilization outcomes and inherited thrombophilias: a meta-analysis

Haplotypes in the human Foxo1a and Foxo3a genes; impact on disease and mortality at old age

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