Genes and environment behind ethnical differences in variations in left ventricular mass

Left ventricular hypertrophy (LVH) is an important predictor of cardiovascular morbidity and mortality in hypertensives. Consequently, a better understanding of the underlying causal mechanisms for variations in left ventricular mass (LVM) is a prerequisite for the development of better treatment modalities in the future. Quantitative genetic studies based on twins and families suggest that genetic factors could explain a considerable proportion of the variability in both electrocardiographic (ECG) and echocardiographic measures of left ventricular components [1–3]. In a recent family study, heritability estimates ranged from 23 to 41%, based upon either Sokolow–Lyon ECG voltage or echocardiographic LVM calculations [3]. Therefore, the search for susceptibility genes that contribute to LVM is highly merited. However, the identification of alleles that are relevant to cardiovascular disease (CVD) has proven to be a more difficult task than was anticipated some years ago, shortly after the launch of the Human Genome Project. In a rapid review published in the Lancet [4], Stephen Harrap asks ‘Where are all the blood-pressure genes?', referring to the scant results obtained in the BRIGHT study [5], based upon genotyping of 3599 hypertensive patients. In that study, only a single locus on chromosome 6 achieved genome-wide significance. Even a large NHLBI-funded family blood-pressure program was unable to reveal statistically suggestive evidence of polygenes [6]. It was further speculated by Harrap that the lack of agreement between genetic studies might arise from population differences in allele distributions, raising the issue of race and ethnicity [4]. With regard to LVH and changes in LVM, induced by hypertension, the pathophysiological mechanisms may be more interesting to study than the development of hypertension per se. It might therefore be even more rewarding to focus on distinct hypertension-related phenotypes, such as LVH, in the search for important susceptibility genes. As the renin–angiotensin system (RAS) is an important player in the regulation of blood pressure and volume homeostasis, extensive research has been directed towards the gene encoding angiotensin-converting enzyme (ACE). The vast majority of studies have examined a single Alu insertion/deletion (I/D) polymorphism in intron 16, which is strongly associated with variation in plasma and tissue ACE levels [7,8]. However, one of the major caveats of studying the Alu indel is that it might not itself be pathogenic, and may only sporadically capture effects of functionally relevant alleles by virtue of linkage disequilibrium depending on which population is studied [9,10]. The ACE locus may in fact harbor multiple functional variants [10]. There are a number of challenges that must be overcome to achieve success in identifying CVD susceptibility genes. The examination of large-scale population samples is essential, but also requires extensive and well-documented clinical and epidemiological data to be useful, including details about ethnicity. Relevant phenotypes including, when possible, quantitative traits perhaps more proximally related to disease pathways should be studied, in addition to clinically defined discrete traits. An understanding of the genetic architecture of a locus is also important, although the study of single gene variants can be an excellent guide and starting point. Finally, where possible, gene–gene and gene–environment interactions should be explored. In this issue of the journal, Kuznetsova et al. [11] report an investigation of the genes encoding two key enzymes in the RAS, ACE and the gene encoding aldosterone synthase (CYP11B2), given their potential biological relevance to LVM. As part of the European Project on Genes in Hypertension (EPOGH), a careful investigation was undertaken in three countries to assess to what extent LVM might be influenced by the ACE I/D and CYP11B2–344C/T polymorphisms and their relation to urinary sodium excretion as an index of salt intake. Nuclear families of European descent, consisting of at least one parent and two siblings, were recruited from Poland, Russia and Italy. Interestingly, significant differences were found between the Slavic participants and Italians in LVM index (LVMI), sodium excretion and the prevalence of the ACE D allele. In addition, ACE I/I homozygosity was significantly associated with higher LVMI in Slavic participants whereas, in Italians, LVMI was only slightly higher in D/D homozygotes. To search for a possible interaction between LVMI and sodium excretion, the authors analysed untreated offsprings, and noted that there was a positive relationship between LVMI and urinary sodium excretion in Slavic offsprings, but not in Italians. Furthermore, in both Slavics and Italians, LVMI increased significantly with higher sodium excretion in ACE I/I homozygotes, but LVMI increased as well with higher sodium excretion in Slavic offsprings who were carrying the ACE D allele. They also noted an interaction between the ACE I/D genotype and urinary sodium excretion in Italian offsprings. These findings, although novel and intriguing, should be interpreted with caution due to the relatively low numbers of participants and families. The power needed to reliably assess the importance of genetic variants in association and linkage studies is typically underestimated [12]. Furthermore, sample sizes needed to detect significant gene–environment interactions likely will be substantially higher than those necessary to detect genetic or environmental effects alone [13,14]. The results from the study by Kuznetsova et al. [11] suggest that there are ethnic differences with regard to sodium intake and sodium excretion. Similarly, the results indicate significant differences in LVMI, suggesting that a higher sodium intake might be related to a higher LVMI in the Slavic population compared to Italians. It is also possible that gene–environmental interactions may operate differently regarding ACE genotype and urinary sodium excretion in different ethnic groups and societies. Based upon the genetic evidence, it is possible that ACE influences LVH, although its contribution to variations in LVM remains unresolved. Gene– environment interactions may also be of importance, as suggested by previous studies indicating a relationship between the ACE I/D polymorphism and exercise-induced LVH [15,16]. Another example of a potentially important gene–environmental interaction with regard to LVM relates to ACE genotype and sodium intake [17,18]. Patients with high angiotensin II concentrations in relation to sodium excretion appear to have greater LVM, posterior wall thickness, and septum wall thickness than those with relatively low angiotensin II levels in relation to sodium excretion [18]. Epistatic interactions between the ACE I/D polymorphism, alpha adductin, Gly406Trp and 344C/T also contribute to the risk of developing hypertension in Europeans [19]. Future studies will require diverse approaches to delineate the genetic basis of LVH, and probably involve genome-wide linkage studies and association analyses. These will benefit from the inclusion of aspects of ethnicity and gene–environment interactions, as outlined in the study by Kusnetsova et al. [11]. Many more genes of functional importance in addition to those of the RAS system remain to be explored.