chronic venous disease ( cvd ) is one of the most common disorders in northern and western europe . according to the ceap classification , cvd comprises those clinical entities that are characterized by visible venous ecstasies but which are not associated with an identifiable mechanism of venous dysfunction ( porter and moneta 1995 ; kistner et al . the clinical presentation of cvd ranges from complication - free telangiectasias or reticular veins , via varicose veins ( vv ) without oedema and skin changes , to venous ulceration . varicose veins requiring medical care but lacking signs of oedema or skin changes are sometimes referred to as if skin changes or ulcerations occur , patients are defined as having  chronic vein insufficiency ( cvi ) , classified as ceap c3 to c6 ( ruckley et al . defined in this way , cvd represents a summary term comprising patients with either simple vv or cvi ( eklof et al . epidemiological studies of cvd have revealed that vv affects 1646% of females and 1240% of males ( evans et al . the prevalence of cvi ranges from 5 to 18% in females , and from 7 to 15% in males ( evans et al . although cvd is relatively common , the aetiologic factors predisposing individuals to the dilatation , elongation and tortuosity of the saphenous vein and its tributaries are still poorly understood . the clinically observed thickening of the vessel wall appears to be associated with an increase of thick and disorganized collagen bundles ( sansilvestri - morel et al . in addition to age , sex and obesity , family history was also found to be a major risk factor for cvd ( coon et al . however , family data were often inconsistent and confounded by selection bias ( meissner 2004 ) . a cvd twin study reported 84% phenotypic concordance between monozygotic twins , compared to only 39% between dizygotic twins ( niermann 1964 ) . in view of these ambiguities , we set out to formally assess the heritability of cvd in a large sample of affected nuclear families from all over germany . between october 2005 and july 2008 , a total of 2,701 index patients with cvd were recruited at the capio mosel - eifel - clinic ( capio mec , bad bertrich , germany ) , which is specialized in the treatment of severe forms of cvd . the ethics committee of the kiel medical faculty and the local data protection authorities both approved the study . exclusion criteria were clinically overt debility , any signs of acute deep vein thrombosis and congenital causes of cvd . all patients suffered from severe injury of their great saphenous vein and had stayed in the clinic for at least 4  days . a questionnaire was administered to each index patient by capio mec staff to obtain information on their demographic and personal characteristics ( sex , date and place of birth , parental origin ) as well as their medical history ( medical treatment , pain , severe operations , age at cvd onset , presence of deep vein thrombosis , phlebitis ) . duration of disease ( in years ) was calculated from these data as the difference between age at ascertainment and age at onset . a 30-ml blood sample for further genetic analysis , including candidate gene and genome wide association studies , was taken by capio mec staff and immediately frozen at 20c . genomic dna was prepared from defrosted blood samples using the invisorb blood giga kit ( invitec , berlin , germany ) . patients were also interviewed about the cvd status of all living first degree relatives ( parents and siblings ) . family information was provided by all 2,701 index patients , which generated 4,033 nuclear families comprising 16,434 individuals for heritability analysis ( table  1).table  1data base for the estimation of narrow - sense heritability hceap gradeno . individualsany ( cvd)2,7014,03316,434c2 ( vv)4486622,706c31,6982,53910,317c44416562,702c5&c6114174701c3 to c6 ( cvi)2,2533,36913,720c2 to c42,5873,85715,725 data base for the estimation of narrow - sense heritability h all index patients were classified according to the severity , cause , site and specific abnormalities of their disease , using the ceap classification . the ceap classification was developed in 1994 by an international ad hoc committee of the american venous forum , endorsed by the society for vascular surgery and incorporated into the  reporting standards in venous disease in 1995 ( porter and moneta 1995 ; kistner et al . the ceap classification underwent its first official review and revision by an international panel under the auspices of the american venous forum in 2004 by eklof et al . clinical severity was the most important criterion for the initial assessment of index patients in our study . there are seven grades of increasing clinical severity of cvd : c0 , no evidence for venous disease ; c1 , superficial spider veins ; c2 , simple vv ; c3 , oedema of venous origin ; c4 , skin changes ascribed to venous disease ( e.g. pigmentation , venous eczema and lipodermatosclerosis ) ; c5 , skin changes as defined above , with healed ulceration ; c6 , skin changes , as defined above , with active ulceration . groups c5 and c6 were combined in our study (  c5&c6 ) because of the limited number ( n  =  114 ) of samples available ( table  1 ) . patients of grades c3 to c6 show an increasing severity of cvi , and all suffer from a functional abnormality of the venous system . for estimating heritability ( fisher 1918 ) cvd status (  affected ,  non - affected ) , current age and sex it should be noted that , so far , only a few prevalence studies have used the ceap classification as a phenotypic measure ( rabe et al . preoperative diagnostic tests entering into the ceap grading of index patients included handheld doppler evaluation of the great and small saphenous veins as well as venous duplex ultrasonography . in combining b mode imaging with pulsed doppler , duplex is capable of accurately localizing both the venous obstruction and the valvular reflux to specify venous segments . colour duplex imaging was performed with a hewlett packard image point hx , employing a 7.5  mhz probe . examinations were undertaken with the patient in a standing position , using the valsalva manoeuvre and manual calf compression . for estimating the actual length of clinically significant reflux , the handheld doppler and the colour duplex imagine were combined with photoplethysmography to gauge the venous hemodynamics . repeating the test while firmly compressing a particular vein allows assessment of the degree of hemodynamic disturbance contributed by that vein . specifically , if the venous refilling time increases from 10  s ( 15 ) to > 25  s when the vein is compressed , this vein can be assumed to contribute sizeably to the patients health problem ( meissner 2004 ) . the genetic contribution to cvd was assessed by estimating the heritability of the disease using a pedigree - based likelihood approach as implemented in the solar software package ( almasy and blangero 1998 ) . a total of 2,701 pedigrees comprising the index patient and the self - reported disease status of their first degree relatives ( parents and siblings ) were used for analysis . the narrow - sense heritability , h , is defined as the proportion va of the phenotypic variance vp in a population that is attributable to additive genetic causes , i.e. , h  =  va / vp ( visscher et al . a 95% confidence interval for h was derived as 2 standard errors of the estimate . the statistical significance of h was assessed by means of a likelihood ratio test ( guerra et al . the influence of the two main cvd risk factors , namely sex and age , upon ceap grade was estimated using the kullback leibler deviance r. the h values of individual ceap grades or grade ranges ( tables  1 , 2 ) were estimated grouping index patients into six subgroups , namely c2 , c3 , c4 , c5&c6 , c3 to c6 ( cvi ) and c2 to c4 ( samples without any past or acute venous ulcer ) . sex differences in terms of ascertainment age , age at cvd onset , disease duration or bmi were assessed for statistical significance using a welch t test for unpaired samples . two - factor analysis of variance was carried out to evaluate the joint influence of sex and ceap grades on bmi . all statistical analyses were done by using r version 2.8.1 ( http://www.r-project.org).table  2estimates of the narrow - sense heritability ( h ) for different ceap gradesceap gradeh ( % ) standard error ( % ) p valuekullback  leibler deviance r ( % ) any ( cvd)17.32.51.4    1010.7c2 ( vv)18.56.07.3    1012.2c318.32.11.5    1011.8c416.76.01.2    108.5c5&c69.211.30.1923.5c3 to c6 ( cvi)17.12.22.0    1010.4c2 to c417.62.32.2 1011.0likelihood ratio test for h  =  0 , adjusted for age and sex estimates of the narrow - sense heritability ( h ) for different ceap grades likelihood ratio test for h  =  0 , adjusted for age and sex we recruited 2,701 patients ( 1,904 females , 797 males ) , which represented approximately 90% of the total number of patients treated at capio mec between october 2005 and july 2008 ( table  3 ) . simple vv ( ceap grade c2 ) was diagnosed in 448 ( 16.6% ) of the patients ( 13.0% of males , 18.1% of females ) . in total , 2,253 ( 83.4% ) of the index patients were affected by cvi ( ceap grade c3 to c6 ) , the majority having either grade c3 ( 62.8% ) or grade c4 ( 16.3% ) . males were more severely affected ( c4 27.4% , c5&c6 5.5% ) than females ( c4 11.7% , c5&c6 3.7% ) . heritability estimation was carried out in 4,033 nuclear families from 2,701 pedigrees , comprising a total of 16,434 individuals ( table  1 ) , with family sizes varying between 3 and 14 individuals . the h estimate for overall cvd was 17.3    2.5% ( p  =  1.4    10 ; table2 ) . for grade c2 alone , h was 18.5    6.0% ( p  =  7.3    10 ) whereas h equalled 17.1    2.2% ( p  =  2.0    10 ) for the cvi phenotype ( grades c3 to c6 ) . the grade - specific estimates of h were as follows : 9.2    11.3% for c5&c6 ( p  =  0.192 , not significant ) , 18.3    2.1% for c3 ( p  =  1.5    10 ) and 16.7    6.0% for c4 ( p  =  1.2    10 ) . using age ( at blood donation ) and sex as covariates , the kullback leibler deviance r was estimated to be 10.7% ( p  =  4.6    10 . leibler r was only observed for c5&c6 grades ( 3.5%).table  3prevalence of different ceap grades in the study populationceap gradetotal ( n  =  2,701)males ( n  =  797 , 29.5%)females ( n  =  1,904 , 70.5%)c2 ( vv)448 ( 16.6%)104 ( 13%)344 ( 18.1%)c31,698 ( 62.8%)431 ( 54.1%)1,267 ( 66.5%)c4441 ( 16.3%)218 ( 27.4%)223 ( 11.7%)c5&c6114 ( 4.2%)44 ( 5.5%)70 ( 3.7)c3 to c6 ( cvi)2,253 ( 83.4%)693 ( 87%)1,560 ( 81.9)c2 to c42,587 ( 95.7%)753 ( 94.5%)1,834 ( 96.3%)vv varicose veins , cvi chronic venous insufficiency prevalence of different ceap grades in the study population vv varicose veins , cvi chronic venous insufficiency the mean ascertainment age of our patients was 56.2  years [ standard deviation ( sd ) 11.1  years , range 1883  years ; table  4 ] . the overall mean age at cvd onset was 32.6  years ( sd 12.2 , range 572 ) , with 36.8  years ( sd 12.8 , range 572 ) for males and 30.8  years ( sd 11.3 , range 672 ) for females ( table  4 ) . the grade - specific mean age of onset ranged from 30.7  years ( sd 10.8 ) for c5&c6 to 35.8  years ( sd 11.6 ) for c2 whereas the grade - specific mean age at ascertainment of our patients ranged from 52.0  years ( sd 12.3 ) for c2 to 60.9  years ( sd 10.4 ) for c5&c6 ( table  5 ) . the mean disease duration was 23.4  years ( sd 12.9 , range 063 ) for all index patients combined , 19.3  years ( sd 12.7 , range 055 ) for males , and 25.1  years ( sd 12.9 , range 063 ) for females ( table  4 ) . the grade - specific mean of the disease duration ranged from 20.1  years ( sd 12.8  years ) for grade c2 to 29.8  years ( sd 13.0  years ) for grade c5&c6 ( table  5 ) . the mean bmi was 26.8 ( sd 4.7 , range 1466 ) for all index patients combined , and equalled 27.5 ( sd 3.7 , range 2053 ) for males and 26.6 ( sd 5.0 , range 1466 ) for females ( table  4 ) . the grade - specific bmi ranged from 25.6 ( sd 4.5 ) for c2 to 29.6 ( sd 5.2 ) for c5&c6 ( table  5).table  4characteristics of cvd patientsall patients ( n  =  2,701)sd ( range)males ( n  =  797)sd ( range)females ( n  =  1,904)sd ( range)p valueage at ascertainment56.2  years11.1  years ( 1883)56.2  years11.6  years ( 1881)56.1  years11.9  years ( 2183)0.95 ( not significant)age at onset32.6  years12.2  years ( 572)36.8  years12.8  years ( 672)30.8  years11.3  years ( 572)2.2    10disease age23.412.9  years ( 063)19.3  years12.7  years ( 055)25.1  years12.9  years ( 063)2.2    10bmi26.84.7 ( 1466)27.53.7 ( 2053)26.65.0 ( 1466)9.2    10given are the overall and sex - specific means , standard deviations ( sd ) and rangestable  5ceap grade - specific characteristics of cvd patientsceap gradeage at onsetage at ascertainmentdisease agebmic2 ( vv)35.8 ( 11.6 , 572)52.0 ( 12.3 , 1882)20.1 ( 12.8 , 054)25.6 ( 4.5 , 2042)c332.9 ( 12.1 , 672)56.4 ( 10.6 , 2382)23.4 ( 12.6 , 063)26.5 ( 4.5 , 1466)c433.2 ( 12.7 , 1072)58.3 ( 10.5 , 2481)25.3 ( 13.0 , 156)28.3 ( 4.8 , 1846)c5&c630.7 ( 10.8 , 1471)60.9 ( 10.4 , 3383)29.8 ( 13.0 , 661)29.6 ( 5.2 , 2145)c3 to c6 ( cvi)32.8 ( 12 , 672)57 ( 10.6 , 2383)24.1 ( 12.8 , 063)27.1 ( 4.7 , 1466)c2 to c432.8 ( 12.1 , 572)55.9 ( 11.1 , 1882)23.2 ( 12.8 , 063)26.7 ( 4.6 , 1466)given are the means and , in brackets , standard deviations and ranges characteristics of cvd patients given are the overall and sex - specific means , standard deviations ( sd ) and ranges ceap grade - specific characteristics of cvd patients given are the means and , in brackets , standard deviations and ranges the major aim of the present study was to determine the heritability of cvd and to assess the relative impact of genetic ( familial background , sex ) and non - genetic factors ( age , bmi ) upon cvd risk . data from a large number of individual index patients and the disease status , age and sex of their first degree relatives led us to conclude that the additive genetic component of cvd is approximately 17% . two recently published , population - based studies of cvd also used the ceap classification to define the disease phenotype ( rabe et al . 2004 ) . however , these studies employed a substantially different recruitment scheme than ours . the bonn vein study for example , included all ceap grades thereby addressing a much lower proportion of severe cvi cases than we did ( rabe et al . 2003 ) , however , males in our study were found to be more often affected by the severe ceap grades c4 to c6 phenotypes than females . interestingly , h was found to vary only little with disease severity ( from 18.5% for c2 to 16.7% for c4 ; table  5 ) . although not formally statistically significant ( p  =  0.192 , table  2 ) , the substantially lower h estimate obtained for grades c5&c6 ( 9.2% ) may indicate a smaller genetic impact upon the severe cvd phenotype , since the number of samples in this category was comparatively small ( n  =  114 ) , however , small h estimate obtained may also reflect higher sampling variance . the main cvd risk factors identified so far have been age ( at ascertainment ) , female sex and familial history ( rabe et al . 2003 ) , and our study was the first to include age at disease onset and the disease duration disease as well . index patients with simple vv ( c2 ) were ascertained at a mean age of 52  years whereas those with a more severe form of cvi were ascertained at a mean age of 60.9  years . these results corroborate an earlier multicenter study by carpentier ( 2004 ) , which also revealed a statistically significant association between a higher ceap grade and an older current age of patients . however , an inverse relationship was observed in our study between disease severity and the age at disease onset . patients affected by simple vv ( c2 ) were first affected at 35.8  years compared to 30.7  years for patients with cvi ( c3 to c5&c6 ) . this discrepancy may be explicable in terms of the cvi phenotype requiring a longer time period for its etiopathology than vv . indeed , cvd is a progressive disease where those with longer disease duration ( i.e. , earlier onset and/or older current age ) can be expected to show the worst phenotype . consequently , a remarkable increase in disease duration with disease severity was observed in our study , ranging from 20.1  years for c2 , via 23.4  years and 25.3  years for c3 and c4 , respectively , to 29.8  years for c5&c6 . in most studies undertaken so far , cvd has been found to be more prevalent among women than among men ( rabe et al . 2003 ) , although this difference was only small in a recent study by labropoulos ( 2003 ) . among our samples , twice as many patients were female ( n  =  1,904 , 70.5% ) than male ( n  =  797 , 29.5% ) thereby highlighting the cvd - predisposing role of the female sex ( table  3 ) clearly , women are more likely to seek medical attention for varicose veins and are about three times more likely to undergo treatment ( madar et al . however , a remarkable sex difference was also observed in our data in terms of the mean age at disease onset , with females showing first symptoms of cvd at 30.8  years of age , compared to 36.8  years for males ( table  4 ) , and in terms of disease duration ( 19.3  years for males , 25.1  years for females ) . the higher proportion of female cvd patients consistently noted in previous reports , may thus be at least partially explicable by a different timing of disease in the two sexes . obesity has been noted to be an additional risk factor for cvd ( de backer 1997 ; fowkes et al . 1999 ) . indeed , the mean bmi of the index patients in our study was 26.8 ( table  4 ) . many studies considered bmi to be more important in females than in males ( de backer 1997 ; fowkes et al . however , only a small yet significant difference ( p  =  9.210 ) difference was observed between the mean bmi of males ( 27.5 , sd 3.7 ) and females ( 26.6 , sd 5.0 ; table  4 ) . however , obesity seems to play a more important role for the development of severe forms of cvd ( 26.5 for c3 , via 28.3 for c4 , to 29.6 for c5&c6 ; table  5 ) . indeed , in a two - factor analysis of variance , sex and ceap grade both had a significant effect upon bmi ( p  =  7.810 and p  =  2.210 ) . two major strengths of our study have been ( 1 ) the use of a high - risk population , thereby resulting in a higher prevalence of both simple vv and cvi than , for example , the bonn vein study ( rabe et al . 2003 ) , and ( 2 ) a large number of nuclear families available for heritability analysis . however , we do not regard this as a major source of upward bias for our heritability estimates because , if anything , a less than perfect patient recall will have introduced additional variance into the analysis , thereby leading to an underestimate of the true level of familiarity of cvd . another possible drawback may have been that , by definition , h is population - dependent , i.e. h , estimates from one population do not necessarily reflect the heritability of the same trait in another population ( visscher et al . therefore , future studies are required to clarify whether our heritability estimate is indeed representative of cvd in general . these limitations notwithstanding , our results strongly encourage efforts to identify susceptibility genes predisposing for severe forms of cvd .
varicose veins without skin changes have a prevalence of approximately 20% in northern and western europe whereas advanced chronic venous insufficiency affects about 3% of the population . 
 genetic risk factors are thought to play an important role in the aetiology of both these chronic venous diseases ( cvd ) . 
 we evaluated the relative genetic and environmental impact upon cvd risk by estimating the heritability of the disease in 4,033 nuclear families , comprising 16,434 individuals from all over germany . upon clinical examination 
 , patients were classified according to the ceap guidelines as either c2 ( simple varicose veins ) , c3 ( oedema ) , c4 ( skin changes without ulceration ) , c5 ( healed ulceration ) , or c6 ( active ulcers ) . 
 the narrow - sense heritability ( h2 ) of cvd equals 17.3% ( standard error 2.5% , likelihood ratio test p  =  1.4    1013 ) . 
 the proportion of disease risk attributable to age ( at ascertainment ) and sex , the two main risk factors for cvd , was estimated as 10.7% ( kullback  leibler deviance r2 ) . 
 the heritability of cvd is high , thereby suggesting a notable genetic component in the aetiology of the disease . 
 systematic population - based searches for cvd susceptibility genes are therefore warranted .