Linkage to the FOXC2 region of chromosome 16 for varicose veins in otherwise healthy, unselected sibling pairs.
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 = 2.2x10(-6); H 68% v 59%; p = 0.01; H including during pregnancy 73% v 64%; p = 2.1x10(-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 (MLS(ASP) = 1.37, p = 0.01; GLM(ASP/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.


CONCLUSIONS
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.
Ng
M Y M
MY
Twin Research and Genetic Epidemiology Unit, St. Thomas' Hospital, London SE1 7EH.
Andrew
T
T
Spector
T D
TD
Jeffery
S
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D008040:Genetic Linkage; D005820:Genetic Testing; D005838:Genotype; D006484:Hemorrhoids / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D018433:Twin Studies as Topic; D014648:Varicose Veins / Q000235:genetics*
D051858:Forkhead Transcription Factors; C082078:mesenchyme fork head 1 protein
Genes Dev. 1997 Apr 1;11(7):926-40
9106663
Am J Hum Genet. 1996 Jun;58(6):1347-63
8651312
Dev Biol. 1999 Sep 15;213(2):418-31
10479458
Br J Dermatol. 2000 Jan;142(1):148-52
10651712
Am J Hum Genet. 2000 Apr;66(4):1273-86
10729111
Am J Hum Genet. 2000 May;66(5):1616-30
10762547
Am J Hum Genet. 2000 Dec;67(6):1382-8
11078474
Hum Mol Genet. 2001 May 15;10(11):1185-9
11371511
Cancer Epidemiol Biomarkers Prev. 2001 Jul;10(7):733-41
11440958
Hum Genet. 2001 Jun;108(6):546-51
11499682
Genes Dev. 2001 Sep 15;15(18):2470-82
11562355
J Med Genet. 2001 Nov;38(11):761-6
11694548
Twin Res. 2001 Dec;4(6):464-77
11780939
J Med Genet. 2002 Jul;39(7):478-83
12114478
Nat Genet. 2002 Sep;32(1):135-42
12161752
Bioinformatics. 2003 Jan;19(1):149-50
12499305
Twin Res. 2002 Oct;5(5):440-3
12537873
Hum Mol Genet. 2003 May 15;12(10):1179-85
12719382
Invest Ophthalmol Vis Sci. 2003 Jun;44(6):2627-33
12766066
Genet Epidemiol. 2004 Feb;26(2):97-107
14748009
Hum Hered. 1969;19(5):573-80
5365895
Hum Hered. 1974;24(3):225-35
4435791
Behav Genet. 1985 Sep;15(5):467-73
4074272
Nat Genet. 1994 Jul;7(3):390-5
7920657
Behav Genet. 1994 May;24(3):229-38
7945153
Hum Mol Genet. 1995 Feb;4(2):197-202
7757067
Ann Hum Genet. 1995 Jan;59(Pt 1):97-105
7762987
Am J Hum Genet. 1995 Aug;57(2):439-54
7668271
Am J Hum Genet. 1999 Aug;65(2):427-32
10417285