Trp64Arg polymorphisms of the Beta3-adrenergic receptor gene and systemic disorders of metabolism: a close association

I read with great interest the recent article by Kotani et al. ¹ about the relationship between polymorphisms of Trp64Arg in the beta3-adrenergic receptor (B3AR) gene and serum low density lipoprotein (LDL) cholesterol concentrations levels. Interestingly, Trp64Arg polymorphisms of the B3AR gene are associated with a number of systemic disorders besides influencing serum LDL concentrations.

The frequency of the Trp64Arg polymorphism varies widely with race, culture and geography. For instance, the frequency of the Arg/Arg allele varies from 0.8% in the Spanish population ² to 6% in the Japanese population. ³ Similarly, the prevalence of the Trp/Arg allele varies from 11.7% in the Spanish population ² to 36% in the Japanese population. ³ Interestingly, an enhanced risk for developing diabetes mellitus is conferred by the presence of the Arg64 allele. ⁴ A similar association with Type II diabetes mellitus has been seen in populations that carry the Arg64 allele along with −75G/A polymorphism of the APOA1 gene. ² Of note, presence of the Trp64Arg genotype, especially increases the risk of developing gestational diabetes in pregnant females. ⁵ A higher prevalence of hypertension is also characteristically seen in individuals who display the Trp64Arg mutation. This genetic predisposition for hypertension is most likely secondary to a combination of insulin resistance, increased obesity as well as increased vascular sensitivity to noradrenaline. ⁶

Similarly, higher fat mass as well as body mass indexes (BMI) are characteristically seen in populations that display the Trp64/Arg64 genotype. ⁷ In fact, the BMI is 0.24 kg/m² higher in individuals who carry the Arg64 allele in comparison with those who do not carry the Arg64 allele. ⁸ The BMI difference is especially more pronounced in Asian populations. Presence of the Arg64 allele also decreases the resting metabolic rate and subsequently energy expenditure in women thereby further contributing to obesity. ⁹ Interestingly, individuals with obstructive sleep apnoea who express the Arg64 allele are more likely to develop obesity. ¹⁰ Simultaneously, lower concentrations of HDL lipoprotein as well as higher concentrations of C-reactive protein are seen in individuals who express the Trp64/Arg64 genotype. ^7,11

Individuals with the Trp64Arg genotype are also more likely to develop hyperuricaemia. ¹² Similarly, obese individuals who express the Trp64Arg genotype are 2.63 times more likely to develop colon carcinoma in comparison with patients who express the Trp64 genotype. ¹³

Clearly, the Trp64Arg polymorphisms of the B3AR gene are associated with a myriad of pathological effects ranging from obesity to colon cancer. Further, trans-continental studies involving different races and populations are needed to confirm these observations. By modulating Trp64Arg expression we may one day very well be able to control diseases such as hypertension.