Adrenergic Receptor β2
ADRB2 Arg16Gly G>A
The 1000 Genomes Project Database and the genome Aggregation Database (gnomAD) reports global frequencies of 47.6% and 42.74% respectively (NIH) for the ADRB2 Arg16 (A) allele. A recent study comparing allele frequencies of various β-adrenergic receptors (ARs) in a Southeastern European Caucasian population versus other populations reported a global frequency of 47.56% for the β-2 AR variant allele (Arg16).
ADRB2 Gln27Glu C>G
A recent study comparing allele frequencies of various β-adrenergic receptors (ARs) in a Southeastern European Caucasian population versus other populations reported a global frequency of 20.43% for the variant G allele (Glu27).
ADBR2 Gene Detail
The β-ARs are considered essential components of the sympathetic nervous system. The β-2 AR is found in human adipose tissue and is said to moderate energy expenditure by stimulating lipid mobilisation through the binding of catecholamines.
The Arg16Gly polymorphism is one of the most common SNPs occurring in the ADBR2 gene and it has been conflictingly associated with obesity, insulin resistance, type 2 diabetes mellitus, hypertension, dyslipidemia, as well as more convincingly, with the occurrence of respiratory disorders. Although G (Arg16) is considered the wild type allele, there is conflicting evidence as to which allele (A or G) is associated with a higher risk for developing negative health outcomes. The gene-environment thus may be the influencing factor for determining negative health outcomes, where responsiveness to the environment is based on the individual genotype.
The Glu27-allele (CG or GG genotypes) has been associated with obesity and weight loss resistance in some populations, although the research does present some conflicting results. It is also suggested that a high carbohydrate intake (>49% of total energy) may result in a greater obesity risk in Glu27-allele female carriers.
ADBR2 Arg16Gly G>A and Gln27Glu C>G
ADRB2 Arg16Gly G>A
The β-ARs are widely distributed transmembrane receptors, belonging to the G protein-coupled receptor superfamily and their signalling pathway is stimulated by endogenous catecholamines, epinephrine and norepinephrine. Other than lipolysis in adipose and muscle tissue, these receptors are reported to regulate thermogenesis, resting metabolic rate and energy balance; these roles imply its ability to potentially control body weight over time. Insulin is a noteworthy inhibitor of catecholamine-stimulated lipolysis as it reduces the β-2 AR effects of epinephrine. The distribution and affinity of ARs on human adipocytes are speculated to influence the differences in lipid metabolism and fat distribution between men and women.
The ADRB2 gene, located on chromosome 5q31-q32 and encoding for the β-2 AR with 413 amino acids, has more than 80 SNPs identified within its coding region. The mutation that results in the amino acid change at codon 16, where neutral glycine is substituted for basic arginine, is located within the N-terminus of the β-2 AR. This polymorphism is said to alter the receptor function and may influence receptor affinity and signal transduction.
Ellsworth et al. (2002) suggests that carriers of the Gly16 variant possess lower receptor density due to enhanced down-regulation of the β-2 ARs and thus they experience reduced receptor efficiency. Daghestani et al. (2012) proposes that in addition to the diminished number of β-2 ARs, a catecholamine-resistance of the β-2 AR may exist when the mutation leads to altered receptor binding, and thus a blunted effect, of catecholamines. Both suggested mechanisms are said to eventually lead to reduced lipolysis and potentially more fat mass accumulation over time.
An observational study from Daghestani et al. (2012) found the Arg16Gly polymorphism to be associated with overweight and obesity in Saudi individuals whilst Mattevi et al. (2014) also found the polymorphism in association with higher body mass index (BMI) and waist circumference in Brazilian men.
A meta-analysis from Zhang et al. (2014) investigating the evidence for ADBR2 and obesity susceptibility, has however found no association between the Arg16Gly polymorphism and obesity in the studied populations. This reiterates previous findings in which the SNP was not a significant contributing factor to obesity in Korean subjects nor in Japanese men.
There are some conflicting reports regarding which allele, Arg16 or Gly16, is mainly associated with overweight, obesity and other health implications. Several studies have found that Arg16 is associated with a higher BMI, while others reported a protective effect from this allele. The study from Daghestani et al. (2012) reported that Saudi participants homozygous for the Gly16 allele had a significantly greater BMI, waist and hip circumference as well as cholesterol, triglycerides, HOMA-IR and plasma leptin than those carrying an Arg16 allele. In a Taiwanese population, homozygosity for Arg16 (GG) was labelled as an independent risk factor for developing T2DM whereas in Japanese participants, Gly16 homozygotes possessed significantly higher levels of fasting insulin.
An older study from Ellsworth et al. (2002) did however find an age-dependent association in male subjects, where the relationship between the Arg16Gly polymorphism and obesity risk became stronger with age. In this study, longitudinal data was collected by performing cross-sectional screenings in 1151 African-American and Caucasian males and females over a 24-year period as part of the Bogalusa Heart Study. Males who were homozygous for the Gly16 variant (Gly/Gly) eventually reached an 8% higher BMI and 50% higher subscapular skinfold measurement at 32 years of age as compared to the males with Arg/Arg genotypes. This data suggested that the β-2 AR may modulate the tendency for weight gain from childhood to young adulthood in males.
Regarding respiratory diseases, being homozygous for Arg16 is said to significantly influence the development of chronic obstructive pulmonary disease (COPD).
ABBR2 Gln27Glu C>G
The β-ARs are widely distributed transmembrane receptors, belonging to the G protein-coupled receptor superfamily and their signalling pathway is stimulated by endogenous catecholamines, epinephrine and norepinephrine. Other than lipolysis in adipose and muscle tissue, these receptors are reported to regulate thermogenesis, resting metabolic rate and energy balance; these roles implying its ability to potentially control body weight over time. Insulin is a noteworthy inhibitor of catecholamine-stimulated lipolysis as it reduces the β-2 AR effects of epinephrine. The distribution and affinity of ARs on human adipocytes are speculated to influence the differences in lipid metabolism and fat distribution between men and women. It is also mentioned that the β-2 ARs may play a role in modifying glucose metabolism.
The ADRB2 gene, located on chromosome 5q31-q32 and encoding for the β-2 AR with 413 amino acids, has more than 80 SNPs identified within its coding region. The glutamine (Gln) to glutamic acid (Glu) amino acid change at codon 27, within the N-terminus of the β-2 AR, is said to alter the receptor structure and function.
Research studies seem to report contradicting findings with some showing no significant difference between obesity-related traits in Glu27-carriers and non-carriers whilst others report no association with obesity altogether. Some studies found significant associations with obesity risk in Glu27-carriers, such as in Swedish women as well as in Asians, Pacific Islanders and American Indians, but not in Europeans according to a meta-analysis considering 17 studies. In a study of Oceanic populations (Tonga and Solomon Islands), the association with obesity risk was no longer considered significant after adjustment for another SNP (rs34623097) since these were found to be in linkage equilibrium with each other.
While the association between the Gln27Glu polymorphism and obesity remains unclear, research is also contradictory on which allele (Gln or Glu) is considered the risk and favourable allele. Although the studies mentioned above find the Glu27-allele associated with obesity risk, some intervention studies tend to agree, however, that the Glu27-allele seems protective to weight balance. In Saliba et al. (2014) the Gln27Glu polymorphism did not seem to moderate weight loss in obese Brazilian women, but it was reported that carriers of the Glu27-allele had a statistically significant lower mean BMI (pre- and post-intervention) compared to non-carriers, suggesting the protective effect of this polymorphism
Dietary management is considered essential for G-allele carriers (Arg16), thus the employment if energy restriction.
An intervention study investigating the body weight and body composition changes in response to a 12-week energy-restricted diet in 78 obese Spanish women found no association between the Arg16Gly polymorphism and body anthropometric outcomes. This corresponds to findings of a 7-week dietary intervention amongst 109 obese Brazilian women. Following modest energy restriction, study participants showed no significant difference in weight loss between carriers and non-carriers of the Arg16Gly polymorphism.
Lagou et al. (2011) reported a significant interaction between the Arg16Gly polymorphism and vigorous physical activity on visceral adipose tissue and waist circumference whereby Gly16 homozygotes benefited less from increased physical activity to reduce their weight. It is recommended that, due to a blunted response to catecholamine-induced lipolysis, Gly16 homozygotes should focus on managing dietary intake to reduce body weight. Arg16 allele carriers (GG and AG) may benefit more from increasing physical activity to mobilise fat stores and lose weight.
A quasi-experimental study from Saliba et al. (2014) found no moderating effect of the Gln27Glu polymorphism on weight loss in adult obese Brazilian women following a 7-week dietary intervention. Szendrei et al. (2016) also reported no influence of the Gln27Glu polymorphism ion body composition changes following a 22-week hypocaloric diet and exercise-based intervention in a Spanish population.
Ruiz et al. (2011) reported, in contrast, an interaction between the Gln27Glu polymorphism and diet on body weight in Spanish obese women. Women carrying the Glu27-allele had a larger reduction in body weight and lean mass than non-Glu carriers following a 12-week energy-restricted diet (mixed macronutrients with a 600-kcal energy deficit based on each participant’s resting metabolic rate). A previous study also observed that overfeeding induced more weight gain and increased fat mass in the Gln/Gln genotype as compared with Glu-allele carriers.
This agrees with other research findings, suggesting that homozygotes for the Gln-allele (CC) may experience more weight loss resistance and a more significant reduction in resting metabolic rate following diet therapy.
Maintaining a carbohydrate intake of <49% of total energy is suggested for optimal weight management.
A case-control study including 313 obese and normal weight Spanish men and women found that carbohydrate intake above 49% of total energy intake may be associated with higher obesity risk and higher insulin levels in women carrying the Glu27-allele.
The above mentioned study revealed that the effect of the Gln27Glu polymorphism on obesity risk was altered by the macronutrient composition of the diet, when adjusted for age and physical activity. Martinez et al. (2003) proposed that a higher carbohydrate intake may increase the obesity risk in women carrying the Glu27-allele by its association not only with a hyperinsulinemic response in these subjects but also with changes in the carbohydrate/fat proportions oxidized because of an impaired β-2 AR function. The author states that previous studies demonstrating a decline in fat oxidation as well as hyperinsulinemia when polymorphisms adversely affect β-AR function, may explain why carriers of the Glu27-allele may show an impaired response to high carbohydrate intake.
The interaction between adrenergic genes and physical activity has been suggested by previous authors. An earlier report has suggested that physical activity may counteract the effect of the Gln27Glu polymorphism in weight control. Similarly, different effects of the Glu27-allele have been found in sedentary and active people with differences in fat oxidation reported between Gln27 and Glu27-allele carriers in two studies. It has been proposed that Gln/Gln genotypic individuals may benefit from physical activity to reduce body weight.
A 6-month diet and exercise-based intervention study from Szendrei et al. (2016) found that Spanish men carrying the Glu27-allele had greater weight reductions than non-carriers only when supervised with exercise.
Contrary to the above mentioned reports, no significant interaction was found between the Gln27Glu polymorphism and weight loss or body composition changes after a program based on resistance training in women was completed. Also, an older study showed that individuals with the Gln27Glu polymorphism (Glu27-carriers) was somewhat weight loss resistant in response to physical activity, possibly because they are less able to use adipose stores as a source of fuel after exercise.
Beta 1, Beta 2 and Beta 3 Adrenergic Receptor Gene Polymorphisms in a Southeastern European Population
Katsarou et al, 2018.