-391 C to G substitution in the regulator of G-protein signalling-2 promoter increases susceptibility to the metabolic syndrome in white European men: consistency between molecular and epidemiological studies.

ABSTRACT

BACKGROUND: The regulator of G-protein signalling-2 (RGS2) is a key factor in adipogenesis. We hypothesized that the metabolic syndrome, of which obesity is an important component, might be related to genetic variation in RGS2. METHODS AND RESULTS: We screened the human RGS2 gene. We tested the functionality of a common genetic variant in vitro, ex vivo, and in epidemiological study involving six European populations. The C to G substitution at position -391 in the RGS2 promoter was associated with enhanced RGS2 expression in vitro in transfected 3T3-L1 adipocytes and Chinese hamster cells and ex vivo in adipocytes from male, but not female, volunteers. In 2732 relatives from 512 families and 348 unrelated individuals, randomly recruited from six European populations, the prevalence of GG homozygosity was 54.1%. The metabolic syndrome score, a composite of six continuous traits making up this clinical entity, was 0.27 standardized units higher (P < 0.001) in 795 GG homozygous men compared with 683 men carrying the C allele. Transmission of the -391 G allele to male offspring was associated with a 0.20 unit increase in the score (P=0.039). These epidemiological relations were not significant in 1602 women. CONCLUSIONS: The C to G substitution at position -391 in the RGS2 promoter increases RGS2 expression in adipocytes and is associated with the metabolic syndrome in white European men. Further experimental and clinical research should establish whether this common polymorphism might be a target for preventive or therapeutic intervention.