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 bet a3 subunit of heterotrimeric G proteins. The 825T allele is associated with alternative splicing of the gene and the formation of a truncated but func tionally active P3 subunit which is referred to as G beta 3s. Expression of the splice variant results in an enhanced G protein activation on stimulat ion of G protein-coupled receptors. Carriers of the 825T allele show an inc reased risk for hypertension and left ventricular hypertrophy. Homo- and he terozygous 825T allele carriers respond with a stronger decrease in blood p ressure to therapy with a thiazide diuretic than homozygous 825C allele car riers. Moreover, 825T allele carriers appear to have an increased risk for obesity which appears sensible given the established role of G protein sign aling 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 fulfil ls the criteria of a thrifty genotype.