Linkage to the FOXC2 region of chromosome 16 for varicose veins in otherwise healthy, unselected sibling pairs
- 1Twin Research and Genetic Epidemiology Unit, St. Thomas’ Hospital, London SE1 7EH
- 2Medical Genetics Unit, St George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE
- Correspondence to: Professor S Jeffery Medical Genetics Unit, St George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE;
- Received 15 June 2004
- Accepted 12 September 2004
Background: The FOXC2 gene on 16q24 is mutated in lymphoedema distichiasis (LD), in which varicose veins (VV) are a common feature. We hypothesised that this gene might be implicated in the development of VV in the normal population, therefore, after performing a classical twin study, we tested for linkage and association in white women. We also tested for linkage with haemorrhoids (H), as a separate venous anomaly at the same locus.
Methods: A total of 2060 complete female twin pairs aged 18–80 years from the St Thomas’ Adult UK Twin registry replied to questions on VV and H as part of a broader postal survey of 6600 twins (62% response rate). Dizygotic female twin pairs were tested for linkage and association to the candidate marker D16S520 (1903 individuals genotyped), which is located about 80 kb from FOXC2.
Results: Casewise concordance rates were significantly higher for monozygotic than dizygotic twins for both phenotypes (VV 67% v 45%; p = 2.2×10−6; H 68% v 59%; p = 0.01; H including during pregnancy 73% v 64%; p = 2.1×10−4), corresponding to additive genetic heritabilities in liability of 86% (95% confidence interval (CI) 73% to 99%) for VV and 56–61% for H (95% CI 43% to 73%). The presence of VV and H were significantly correlated. We found significant evidence of linkage to the marker for VV (MLSASP = 1.37, p = 0.01; GLMASP/DSP Z = 3.17 p = 0.002), but no association. Both linkage and association tests were negative for H. The combined phenotype of having VV and H did not show any evidence of linkage or association.
Conclusion: These results demonstrate VV and H to be heritable, related conditions, and the data strongly suggest FOXC2 to be implicated in the development of VV in the general population.
- ASP, affected sibling pairs
- DSP, discordant sibling pairs
- DZ, dizygotic
- H, haemorrhoids
- LD, lymphoedema distichiasis
- MZ, monozygotic
- PIC, polymorphism information content
- VV, varicose veins
The first two authors contributed equally to this work.