Smoking is bad for you

The renin–angiotensin system has been at the centre of attention in the control of blood pressure for over a century. Indeed, it was just over 100 years ago that Tigersted observed that an aqueous extract of the kidney when injected intravenously into rabbits caused a prolonged increase in blood pressure [1]. Since that time, a wealth of knowledge has been gained not only in terms of understanding the physiological role of the renin–angiotensin system in blood pressure control, but also in the development of pharmacological agents to modify its impact. It is now evident that the angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptor antagonists are becoming the most widely used therapeutic drugs in the treatment of hypertension, and increasingly for a wide range of cardiovascular diseases. Over recent decades, with the unravelling of knowledge of genes and the recent elucidation of the human genome, interest in the role and significance of the renin–angiotensin system has again been subject to scrutiny, but this time from a genomic perspective. It has become evident from a range of association studies that the genes making up the components of the renin–angiotensin system (i.e. the genes for angiotensinogen, renin, ACE and the angiotensin II receptor) can, to a greater or lesser degree, play a role in determining genetic susceptibility to hypertension and cardiovascular disease. The level of association may be modified by polymorphisms within each of these genes. For example, a variant of the angiotensinogen gene has been associated with hypertension in European and African populations but not in African-Americans [2,3]. By contrast, there is relatively limited evidence that variants in the renin gene can be associated with hypertension and cardiovascular disease [4,5]. Somewhat more is known of the significance of the ACE gene and its association with hypertension. It has been reported that the level of ACE, found both extracellularly and intracellularly is dependent upon an insertion/deletion (I/D) polymorphism within the gene with the D allele giving rise to increased ACE activity. Moreover, associations have been drawn between these polymorphisms and the level of blood pressure in different populations, although again, this has not been a consistent finding [6,7]. Finally, polymorphisms of the angiotensin II receptor 1 have been reported but relating these to the level of blood pressure or cardiovascular pathologies have yet to be firmly established [8]. The uncertainty in the outcomes of these various association studies have been due partly to the size of the population studied and partly to the heterogeneity of the population investigated, but it is likely that other factors may come into play. There is an increasing recognition that environmental factors may also exert an important influence on the degree of association linking the different gene polymorphisms and cardiovascular diseases. In the current issue of the journal, this particular aspect is elegantly illustrated by Schut et al. [9]. The Dutch group investigated how smoking influenced the level of association of the insertion/deletion polymorphisms of the ACE gene with a range of cardiovascular variables and metabolic indicators. Importantly, this group had access to a large population cohort, comprising almost seven thousand non-smokers, smokers and former smokers between the age of 60–70 years. The different groups were accurately matched except that of the non-smoking population (a total of 2414 subjects, only 10% were male). They evaluated the relationship between the ACE insertion/deletion polymorphisms and systolic and diastolic blood pressure and the risk of hypertension development. Interestingly, in the non-smokers and former smokers, there was no difference between genotypes and the risk of hypertension development. However, in the smokers, although their blood pressures were lower than non-smokers, systolic blood pressure was higher in the individuals carrying the DD compared to the II alleles, although there was no interaction with diastolic blood pressure. Perhaps more intriguingly in the smoking cohort, systolic blood pressure was higher in DD compared to the II genotypes. Moreover, the risk of hypertension development was significantly enhanced in smokers who had the D allele, whether it was a single or a double copy. Importantly, these relationships were not evident in either non-smokers or former smokers. Of further note, in those individuals who carry the D allele but who stop smoking, the risk of the development of hypertension falls to a level comparable to non-smokers. Thus, Schut et al. [9] demonstrate that an environmental factor, in this case smoking, appears to interact with gene polymorphisms to uncover the sensitivity of a particular allele to the environmental factor leading to an association with a disease process. This is an important concept in terms of understanding the influences which may impact on alleles and thereby determine whether they are associated with a disease state. Indeed, the question arises as to whether the previous conflicting conclusions arising from association studies could have been due, in part, to a failure to appreciate an interaction between gene polymorphisms and exposure to particular environmental conditions. The study by Schut et al. [9] to some extent leads the way in alerting investigators who are carrying out such association studies to the idea that there may be other underlying features of the environment that determine the degree of association revealed. It will be of great importance to see whether this influence of smoking can be demonstrated in a younger population cohort, where the genotype–environment interaction may be of greater significance in determining the risk of hypertension, and all the subsequent consequences for health care resources.