Molecular genetics of G proteins and atherosclerosis risk.
Using a classical candidate gene approach, we have described a common C825T polymorphism in the gene GNB3 which encodes the ubiquitously expressed beta3 subunit of heterotrimeric G proteins. The 825T allele is associated with alternative splicing of the gene and the formation of a truncated but functionally active beta3 subunit which is referred to as Gbeta3s. Expression of the splice variant results in an enhanced G protein activation on stimulation of G protein-coupled receptors. Carriers of the 825T allele show an increased risk for hypertension and left ventricular hypertrophy. Homo- and heterozygous 825T allele carriers respond with a stronger decrease in blood pressure to therapy with a thiazide diuretic than homozygous 825C allele carriers. Moreover, 825T allele carriers appear to have an increased risk for obesity which appears sensible given the established role of G protein signaling in adipogenesis. The highest frequencies of the 825T allele are found in ethnicities with the highest lifestyle-dependent risk for obesity, e.g., black Africans and East Asians. This suggests that the 825T allele fulfills the criteria of a thrifty genotype.
Siffert
W
W
Institut für Pharmakologie, Universitätsklinikum Essen, Germany. winfried.siffert@uni-essen.de
D001161:Arteriosclerosis / Q000453:epidemiology* / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics; D009765:Obesity / Q000453:epidemiology / Q000235:genetics; D012307:Risk Factors
D019204:GTP-Binding Proteins