Genetic and environmental nature of the insulin resistance syndrome in Indo-Mauritian subjects with premature coronary heart disease: contribution of β3-adrenoreceptor gene polymorphism and beta blockers on triglyceride and HDL concentrations

Abstract

Several studies have documented high rates of coronary heart disease (CHD) among migrants from the Indian subcontinent [1]. The common risk factors shared by these communities are increased plasma triglyceride concentrations, decreased high density lipoprotein (HDL) cholesterol, high fasting and post-glucose insulin concentrations, central obesity and a high prevalence of Type II (non-insulin-dependent) diabetes mellitus. These features, found consistently in Indian communities settled overseas, reflect an underlying state of insulin resistance [2]. The majority of the Mauritian population, 70 %, are descen- Diabetologia (2001) Abstract Aims/hypothesis. Insulin resistance syndrome is an important risk factor for developing premature coronary heart disease. It is a complex syndrome which could arise from the interaction of several genes modulated by environmental factors. The Trp64Arg polymorphism in the b3-adrenoreceptor gene has been found to be associated with insulin resistance, obesity or with earlier onset of Type II (non-insulin-dependent) diabetes mellitus in different populations. We aimed to study whether features of the insulin resistance syndrome are associated with this polymorphism in Indo-Mauritian patients with premature coronary heart disease. Methods. We carried out a case control study using PCR-RFLP techniques, of consecutive Indo-Mauritian patients (n = 338) with premature coronary heart disease (onset below age of 60 years) and unrelated control subjects (n = 148) of the same ethnicity.Results. In Indo-Mauritian patients with premature coronary heart disease who were not treated by beta blockers, triglyceride concentrations were lower (median: 1.44 vs 1.93 mmol/l, p < 0.008) and HDL cholesterol concentrations higher (mean: 0.98 vs 0.85 mmol/l, p < 0.015) in those carrying the wild type of the b3-adrenoreceptor gene than in those carrying the Trp64Arg variant. The latter genotype specific effect on HDL was inverse in patients treated with beta blockers. Conclusion/interpretation. The b3-adrenoreceptor gene variant seems to modulate the effects of beta blockers on triglyceride and HDL cholesterol concentrations in this group of Indo-Mauritian population. Dyslipidaemia, a key component of the metabolic syndrome has a heterogeneous nature in IndoMauritian subjects. This potent risk factor for earlyonset coronary heart disease is influenced by the interaction between genetic and environmental effects.[Diabetologia (2001)

The Trp64Arg β3-adrenergic receptor amino acid variant confers increased sensitivity to the pressor effects of noradrenaline in Sardinian subjects

“…Our new data, as well as confirming a link between the Trp64Arg amino acid variant of the β $ AR and essential hypertension and hypertriglyceridaemia, as described previously [11], are in keeping with the observations of Manraj et al [14] on the modulatory effects of the Trp64Arg β $ AR gene on triacylglycerol levels during β-blocker treatment in Indo-Mauritian subjects. These observations indicate that this polymorphism may influence the response to environmental factors (both drug therapy with β-blockers, and stress mediated by circulating catecholamines) of the lipolytic process in both of these populations (Indo-Mauritians and Sardinians), which have very different genetic backgrounds.…”

“…Despite this, our data suggest an altered phenotypic function due to the described β $ AR polymorphism, and are in keeping with other data suggesting an association of this polymorphism with blood pressure and plasma triacylglycerol levels [11,14,32].…”

“…We previously investigated the role of the Trp64Arg amino acid variant of the β $ AR in the metabolic syndrome in Sardinia, taking advantage of the population enrolled by ' The Study Group for the Genetics of Diabetes in Sardinia (SGGDS) ' [15,20,21]. In the period 1994-2001, a total of 2451 subjects were enrolled with different phenotypes for parameters related to blood pressure, diabetes and lipids ; the inclusion\exclusion criteria have been detailed previously [14]. We previously reported, in this population, a significant association of the Trp64Arg β $ AR with essential hypertension [11], but we were not able to find an association with Type II diabetes or obesity (G. Tonolo, unpublished work ; presented at the 37th EADSD Meeting, Glasgow, 9-13 September 2001).…”

“…The association with Type II diabetes has been replicated in some, but not in all, studies [12,13]. Recently the Trp64Arg amino acid variant of the β $ AR has been shown to modulate the effects of β-blockers on levels of triacylglycerols and high-density lipoprotein (HDL) cholesterol in a group of Indo-Mauritian subjects with premature coronary heart disease [14], suggesting a key role for the β $ AR in the regulation of lipid metabolism by endogenous catecholamines.…”

β-Blockade and increased dyslipidemia in patients bearing Glu27 variant of β2 adrenergic receptor gene

“…This result is corroborated by a previous observation conducted in an Indian population of young patients affected by coronary artery disease, where the b 3 AR Trp64 polymorphism associates with higher serum triglycerides. 21 These observations suggest the possibility that b 2 and b 3 AR interfere with metabolism through different mechanisms. Such a hypothesis can find support in the different tissue localizations of the two bAR subtypes, with a larger component of b 3 AR at the fat cells, while b 2 AR are more localized in skeletal muscle.…”