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Cardiovascular Diseases and G-Protein B3 Subunit Gene (GNB3) in the Era of Genomewide Scans

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Cardiovascular Diseases and G-Protein B3 Subunit Gene (GNB3) in the Era of Genomewide Scans Journal of Human Hypertension (2003) 17, 379–380 & 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00 www.nature.com/jhh COMMENTARY Cardiovascular diseases and G-protein b3 subunit gene (GNB3) in the era of genomewide scans M Tomaszewski1,2, FJ Charchar1, S Padmanabhan1, E Zukowska-Szczechowska2, W Grzeszczak2 and AF Dominiczak1 1BHF Glasgow Cardiovascular Research Centre, Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK; 2Department of Internal Medicine, Diabetology and Nephrology, Medical University of Silesia, Zabrze, Poland Journal of Human Hypertension (2003) 17, 379–380. doi:10.1038/sj.jhh.1001559 The last 4 years were the era of genomewide scans The ability of angiotensin-converting enzyme (ACE) in cardiovascular genetics. Since 1999, after pub- inhibitors to induce the regression of hypertensive lication of the first comprehensive genome linkage LVH and prevent ventricular remodelling after analysis of systolic blood pressure in humans,1 more myocardial infarction provides a clinical correlate than 20 genomewide searches for hypertension to these observations. Thus, insertion/deletion (I/D) genes have been reported. The number of detected polymorphism of the ACE gene has been tested as a cardiovascular quantitative trait loci (QTLs) has potential risk factor of hypertensive LVH in numer- increased rapidly, forming a new dense QTL-map ous studies, and the proportion of negative and within the human genome. At present, a QTL for positive results appears to be roughly equal.2 blood pressure or hypertension exists almost on Studies on association between hypertensive LVH every human chromosome. However, most of the and polymorphisms within the genes encoding detected QTLs do not overlap, even within popula- angiotensinogen and angiotensin II receptors have tions of the same ethnic origin. Much remains to be also provided conflicting results.2 done in further dissection of these regions in order Single nucleotide polymorphisms (SNPs) within to identify new, consistent positional genetic candi- genes encoding G-protein subunits belong to the dates of human hypertension. The use of such most promising candidates in investigations on identified positional markers is needed in associa- genetic determinants of LVH and essential hyperten- tion studies following genomewide searches and sion, since the most important receptors in cardio- remains a promising strategy in cardiovascular vascular system have been linked to these genetics. However, most of the genes tested cur- intracellular signal messengers.3 A SNP in exon 10 rently for association with essential hypertension (C825T) of the G-protein b3 subunit gene is and related phenotypes are not identified based on associated with alternative splicing.4 The splice their positional relation to a detected QTL but on variant (Gb3s) occurring with T allele has been their pathophysiological potential to affect cardio- shown to enhance intracellular signal transmission vascular functions. Approximately 100 genes have with a potential to affect vascular reactivity, and been tested as candidates in association studies with cell growth.5 These functional consequences of cardiovascular traits including left ventricular hy- C825T polymorphism demonstrated at a molecular pertrophy (LVH) and essential hypertension. level as well as ubiquitous expression of this gene The expression of genes encoding components in cardiovascular system make the GNB3 an of the renin–angiotensin system is upregulated in optimal target in pursuit of genes for human vascular and cardiac hypertrophy and remodelling. hypertension and its cardiac complications. In addition, the early studies in Caucasian populations have demonstrated that a distribution of the C825T Correspondence: Dr M Tomaszewski, Division of Cardiovascular genotypes among subjects of European origin en- and Medical Sciences, University of Glasgow, Western Infirmary, Glasgow G11 6NT, UK. E-mails: [email protected], sures appropriate epidemiological representation of [email protected] each variant in population samples of different Received and accepted 10 February 2003 size.6–8 Cardiovascular diseases and GNB3 M Tomaszewski et al 380 In light of these findings, a selection of this environment interactions to fulfil our expectation candidate by Olszanecka et al9 in their study on of coming closer to the dissection of major genes genetic determinants of cardiovascular phenotypes contributing to cardiovascular disease perceived as is fully justified. They examined associations of the polygenic or at least oligogenic trait. C825T polymorphism with blood pressures as well as indicators of left ventricular structure and 9 function in two generations of Caucasian families. References The most important finding from their study is an association between TT genotype and a reduced 1 Krushkal J et al. Genome-wide linkage analyses of early peak diastolic inflow velocityFa marker of systolic blood pressure using highly discordant sib- impairment of left ventricular relaxation. Interest- lings. Circulation 1999; 19: 1407–1410. ingly, the relation was apparent in both parents and 2 Charchar FJ, Tomaszewski M, Carr F, Dominiczak AF. offspring analysed separately. This observation, in Hypertension geneticsFan update in the post- agreement with most of the studies evaluating the genomic era. Curr Med Lit Cardiol 2001; 20: 73–78. influence of the GNB3 on parameters of left 3 Dzimiri N. Receptor crosstalk. Implications for cardio- ventricular function and structure,8,10,11 has pro- vascular function, disease and therapy. Eur J Biochem 2002; 269: 4713–4730. vided evidence for early onset and stability of this 4 Siffert W et al. Association of a human G-protein beta3 association over generations. Ageing is associated subunit variant with hypertension. Nat Genet 1998; 18: with alterations in functions of cardiac and vascular 45–48. G-protein receptors with a potential to impair 5 Rosskopf D, Busch S, Manthey I, Siffert W. G protein b3 intracellular signalling and the ultimate cardio- gene. Structure, promoter, and additional polymorph- vascular phenotype.12 Consequently, an associa- isms. Hypertension 2000; 36: 33–41. tion between a polymorphism within a G-protein 6 Beige J, Hohenbleicher H, Distler A, Sharma AM. G-protein b3 subunit C825T variant and ambulatory receptor gene (b2-adrenergic receptor gene – ADRB2) seen in young subjects may not be evident among blood pressure in essential hypertension. Hyper- the older individuals as the recent study by tension 1999; 33: 1049–1051. 12 9 7 Brand E et al. The 825C/T polymorphism of the G- Castellano et al has shown. Olszanecka et al protein subunit b3 is not related to hypertension. have demonstrated that the effect of C825T poly- Hypertension 1999; 33: 1175–1178. morphism on left ventricular relaxation is age- 8 Poch E et al. G-protein b3 subunit gene variant and left independent. ventricular hypertrophy in essential hypertension. This study provokes also a question regarding the Hypertension 2000; 35: 214–218. nature of the detected association between the 9 Olszanecka A et al. Ambulatory blood pressure and left C825T SNP and left ventricular function. Despite a ventricular structure and function in relation to the molecular functionality of this particular poly- G-protein b3-subunit polymorphism C825T in white morphism and consistent findings suggesting the Europeans. J Hum Hypertens 2003; 17(5): 325–332. b negative effect of T allele on cardiovascular pheno- 10 Jacobi J et al. 825T allele of the G-protein 3 subunit gene (GNB3) is associated with impaired left ventri- types, a causative role of the C825T SNP remains 5 cular diastolic filling in essential hypertension. uncertain. The GNB3 is rich in other SNPs whose J Hypertens 1999; 17: 1457–1462. associations with hypertension and left ventricular 11 Semplicini A et al. G protein b3 subunit gene 825T function have not been tested. In addition, the allele is associated with increased left ventricular mass recent data tightly link the C825T to the GNB3 SNPs in young subjects with mild hypertension. Am J in haplotype combinations.12 The haplotype ap- Hypertens 2001; 14: 1191–1195. proach is an ultimate goal in genetic association 12 Castellano M et al. b2-Adrenergic receptor gene analysis and has been successfully used in investi- polymorphism, age and cardiovascular phenotypes. gations on relations between G-protein receptor Hypertension 2003; 41: 361–367. genes (such as ADRB2) and essential hyper- 13 Rosskopf D, Manthey I, Siffert W. Identification and 14 ethnic distribution of major haplotypes in the gene tension. This strategy will help to understand the GNB3 encoding the G-protein b3 subunit. Pharmaco- complex associations of the GNB3 with blood genetics 2002; 12: 209–220. pressure as well as left ventricular structure and 14 Tomaszewski M et al. Essential hypertension and b2- function. Future studies should use a combination adrenergic receptor geneFlinkage and association of haplotype analyses, gene–gene and gene– analysis. Hypertension 2002; 40: 286–291. Journal of Human Hypertension.
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