Abstract
BackgroundThe C825T polymorphism (rs5443) of the Guanine Nucleotide-Binding protein subunit β3 (GNB3) gene has been associated with obesity, essential hypertension, atherosclerosis, coronary diseases, and cerebrovascular events, but with some sex-specific effects. Its association with inflammatory mediators such as cell adhesion molecules has not been studied, although they are heavily involved in cardiovascular diseases’ (CVDs) processes. The aim of our study was then to investigate a possible sex-specific effect of the GNB3 C825T polymorphism on serum soluble cell adhesion molecules such as E, P and L-selectins (sE, sP and sL-selectins).ResultsParticipants were from the STANISLAS Family Study and were free of chronic disease as CVDs or cancer. We included in total 771 subjects aged 6 to 58 years (391 males (50.71%) and 380 females (49.29%)). No significant association of rs5443 was observed in the whole population with serum sE, sP and sL-selectins after adjusting for age, sex, body mass index, systolic blood pressure, anti-inflammatory drugs and hormonal drugs consumption. A significant interaction of rs5443 was observed with sex for sE-selectin (p < 0.001), but not for sP and sL-selectins. After adjusting for covariables, the T allele was significantly associated with an additive increase effect on serum sE-selectin levels in males (β = 5.03 ± 2.18; p = 0.020), while a significant additive decrease effect was observed in females (β =−4.46 ± 2.06; p = 0.030). These associations stayed significant after correction for multiple tests (p = 0.045 in males and in females). The additive phenotypic variance was 21.54% in males versus 1.91% in females.ConclusionsIn our Caucasian population, the GNB3 C825T polymorphism showed a significant sex-specific effect on serum sE-selectin levels, with a disadvantage for males, as increased sE-selectin levels has been associated with CVDs outcomes. The T allele has been previously associated with the same CVDs as increased sE-selectin, but more often in males. The link we observed between this polymorphism and E-selectin is then consistent with previous findings, and helps to better understand the deleterious effect of the GNB3 825 T allele on CVDs outcomes in males. We revealed in this study an important pathway through which the GNB3 gene induces CVDs’ outcomes.
Highlights
The C825T polymorphism of the Guanine Nucleotide-Binding protein subunit β3 (GNB3) gene has been associated with obesity, essential hypertension, atherosclerosis, coronary diseases, and cerebrovascular events, but with some sex-specific effects
* Correspondence: ndeye-coumba.ndiaye@univ-lorraine.fr; sophie.visvikissiest@inserm.fr UMR INSERM U1122; Interactions Gène-Environnement en Physiopathologie CardioVasculaire” (IGE-PCV) “Interaction Gène-Environnement en Physiopathologie CardioVasculaire”, Faculté de Pharmacie, Université de Lorraine, Nancy F-54000, France. This polymorphism is involved in cardiovascular pathophysiological processes and cardiovascular diseases (CVDs). It has been associated with obesity [2], higher blood pressure [3], hypertension [1, 4, 5], carotid atherosclerosis [6], incident cerebrovascular events [7] and coronary diseases [8], even though these effects have been controverted in the literature [9, 10]
We suggest that the link between the GNB3 C825T polymorphism and E-selectin found in this study is possible through G proteins’ effect within endothelial cells, by a mechanotransduction process
Summary
The C825T polymorphism (rs5443) of the Guanine Nucleotide-Binding protein subunit β3 (GNB3) gene has been associated with obesity, essential hypertension, atherosclerosis, coronary diseases, and cerebrovascular events, but with some sex-specific effects. The Guanine Nucleotide-Binding protein subunit β3 (GNB3) gene is present on chromosome 12 at the location 12p13 and presents a polymorphism called rs5443, resulting from a cytosine (C) to a thymine (T) substitution at position 825 (C825T) located in exon 10 of the gene [1] This polymorphism is involved in cardiovascular pathophysiological processes and cardiovascular diseases (CVDs). Frey et al observed that the TT genotype was a significant risk factor for fatal and non-fatal myocardial infarction, independently of other established cardiovascular risk factors at a population level, but only in males, while in females no significant association was observed [8] All these elements encourage further investigations of a sex-specific effect of this polymorphism
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