A common genetic factor underlies hypertension and other cardiovascular disorders

A number of conditions characterised by blood vessel occlusion and/or vascular spasm have been found to be associated in both clinical and epidemiological studies. These include hypertension (HPT), Raynaud's phenomenon (RP), migraine (MIG) and coronary artery disease (CAD) [1‐5]. Whether these associations are the consequences of a shared environmental risk factor or represent an underlying propensity to develop the conditions through a common biological mechanism remains controversial. The exploration of the genetic and environmental relationships underlying these conditions is one approach to resolving the biological basis for the association. We have examined the association between these phenotypes in a classical twin study conducted in a large sample. This approach allows us to assess whether the association between HPT, RP, MIG and CAD is explained by a common genetic or environmental aetiology.

Complete data for analysis were available from 1,102 pairs of female twins, comprising 525 MZ and 577 DZ pairs. The mean (± SD) age of the twins was 48.5 (± 8.2) years. The prevalence of each trait is shown in Table 1.

Four of the six combinations of traits showed significant phenotypic association after adjusting for age, smoking and BMI (odds ratios, Table 2). HPT was clearly not associated with RP but there was a suggestion of association of HPT with migraine (significantly so if adjusted for age and smoking only, data not shown). Since smoking status, age and BMI did not influence the size of the odds ratios, these variables were not included in the multivariate modeling. Concordance data and the results of univariate modeling confirmed a significant heritable component to all 4 traits (Table 3). Multivariate model fitting showed that for each of the three models tested, a model containing genetic (A) and unique environmental (E) factors provided the best explanation of the data (Table 4, in bold): incorporation of a shared environmental factor (C) offered no significant improvement in the fit of any model. The independent AE pathway model (Figure 2) offered the best explanation of the data, suggesting that a single common genetic factor loads on the four traits HPT, RP, migraine and CAD. A unique environmental factor loads similarly on the traits. Using this model, genetic and unique environmental correlations between the four traits were calculated (Table 5). Overall, the genetic correlations were greater than the environmental correlations, suggesting a greater role for the genetic factor than the unique environmental factor.

This is the first study to examine the role of genetic and environmental factors in explaining the association between HPT, RP, migraine and CAD. The results suggest that all four variables share a heritable basis. These conditions have been shown to be associated with one another and individually each is known to have a genetic basis. The data presented here confirm these previous findings and suggest that shared environmental factors such as diet and lifestyle do not contribute to their expression. In view of the nature of these phenotypes, we speculate that the shared genetic component leads to a predisposition to vasospasm. Indeed, a 'vasospastic phenotype' to account for their co-occurrence has been postulated by others [14]. The demonstration of a single genetic component lends weight to such a theory.

A number of considerations should to be taken into account when interpreting these results. Self administered questionnaires were used for trait ascertainment, introducing the possibility of recall bias. In the present study efforts were taken to minimise recall bias: when surveyed, the twins were unaware of the hypothesis being tested; the questions relating to vascular phenotypes were included non-sequentially and were amongst many other questions in two questionnaires mailed at different times; and the twins completed questionnaires separately with no knowledge of their co-twin's responses. Furthermore there is no reason to suspect differential rates of recall in MZ when compared to DZ twins, hence any effects of recall should not have biased our estimates of genetic influence. Some conditions, such as RP, are notoriously difficult to diagnose regardless of the method employed [15] and it is possible that some subjects have cardiac valve rather than coronary artery disease. No attempt was made to differentiate primary RP and essential HPT from their secondary forms. However, questionnaire diagnoses were based on standard methods [8‐10]. Despite these limitations, the traits' prevalences are in keeping with the findings of others for RP (9.6%[3], 5% and 16.8% according to geographical area sampled [16]), migraine (20% [17]) and CAD (8% [18]). In addition, heritability estimates are consistent with published findings for MIG (49–58% [19]), blood pressure (40–70% [20], 57% [21]) and CAD (15–30% [18]). Taken together, these observations suggest that our twins are representative of the adult female population and do not simply reflect a 'healthy volunteer' sample.

The assumptions underpinning twin studies themselves may be questioned. Unequal sharing of the family environment by MZ and DZ twins has been raised as a concern, but this has been shown not to be the case [22]. In addition, twins from this cohort have been shown to be similar to singletons with respect to anti-hypertensive drug use, blood pressure and other phenotypes [23]. The proposed inverse relationship between birth weight and HPT [24] and CAD [25] could potentially bias a study of twins and cardiovascular disease. The explanation for this relationship is still debated, but maternal environment has been suggested to be the main influence on adult blood pressure [26]. As we have demonstrated that the shared environment makes no significant contribution to the vasospastic phenotype, this is not a likely source of error.

It is clear that genetic factors play an important role in all four conditions. The demonstration that they are heritable is consistent with numerous reports of clustering in twin and family studies conducted in a range of settings, including a Dutch kindred with an autosomal dominant condition characterised by vascular retinopathy, migraine and Raynaud's phenomenon [27]. The detection of a common, genetically determined mechanism that contributes to these conditions is important because it points to an intermediate phenotype, vasospasm, and provides a possible focus for future studies. As with all chronic diseases and traits, the difficulty is in establishing which genes are responsible. Vascular tone is controlled at many levels, including local soluble mediators and neurotransmitters. Genes proposed through the study of the individual phenotypes include the beta2-adrenergic receptor gene in hypertension [28]; the muscle acetylcholine- and serotonin receptor genes in RP [29]; and a G protein subunit polymorphism and endothelial nitric oxide gene polymorphism in CAD [30]. A gain of function mutation in a vasoconstrictor or a loss of function mutation in a vasodilator may predispose to vasospasm: many of these genes deserve further consideration with the identification of a common genetic factor underlying HPT, migraine, RP and CAD.

In summary, this twin study has identified phenotypic associations between four vascular conditions and shown that the association is explained by a single common genetic factor. These findings are consistent with the proposed 'vasospastic phenotype' and suggest that studies of genes controlling vascular tone will help to define the genetic basis of these conditions.