Obesity risk – GNB3 C825T

There are lots of different genetic variants that add a little bit to your risk of being overweight. These genetic variants, of course, combine with environmental factors such as food choices, sleep, and toxin exposure.

This article looks into a well-studied variant that can increase the risk of obesity, hypertension, and cardiovascular events and focuses on some applicable lifehacks that can help reduce those risks.

Is obesity a genetic problem?

GNB3 gene codes for a protein that transfers a signal from the cell’s surface into the cell, thus causing a response. Therefore, a genetic variant in this gene that alters its function can cause a variety of responses within different cells.

One relatively well-studied GNB3 variant, rs5443 or C825T, confers a 2x to 3x risk of obesity.[ref]

This one genetic change is found in varying percentages in different population groups. While the minor allele is T for most populations, it is the most common allele for those of African descent. For example, about 10% of Caucasians carry two copies of the variant (T/T), while Africans have approximately 80% of most population groups carrying the variant allele.

Before we get into the weight-related aspect of this SNP, let’s look at a couple of other things linked to it.

• A 2014 study looked at the 10-year event-free survival rate for a group of over 4000 Caucasian subjects. The study found that males with the T/T genotype had a higher risk (2.6x) of a hard coronary event (non-fatal heart attack).[ref]
• Many studies link this variant to a higher risk of hypertension[ref]
• A 2014 study of professional basketball players looked at peak oxygen consumption, anaerobic test parameters, and knee isokinetic muscle strength. The study found that the T/T genotype lowered the capacity for athletic performance.[ref]
• A 2012 Polish study found that the rs5443 T variants have associations with higher systolic and diastolic blood pressure and response to a dobutamine stress echocardiography.[ref]
• A Japanese study found that the T/T genotype had lower fasting blood glucose and a reduced risk of diabetes. The study went on to look at the association between salt consumption, the rs5443 variants, and the risk of diabetes. It found that the reduced risk of diabetes for the C/T and T/T genotypes was only for those in the lower salt category (less than 12.4 g/ day). The study’s introduction discussed the idea that the activation of the sodium-proton exchanger by GNB3s involves issues arising from these variants.[ref] The study brings up a good point that other studies may not be taking salt consumption into account, which could be a part of regional/ ethnic differences in study results.  
• A 2014 study looked at the effectiveness of isosorbide dinitrate and hydralazine (a medicine approved by the FDA only for African Americans with congestive heart failure) regarding the 825T allele. The T/T genotype was associated with a greater therapeutic effect.[ref] (Note that the T allele is most common in Africans with some groups having up to 80% T/T)
• A 2007 study of migraine and cluster headache patients found that T/T carriers were almost three times more likely to respond to triptans. This migraine medication is a serotonin receptor agonist.
• No association was found between this variant and THS or thyroid function.[ref]

Weight-related studies:

• A 2009 study looked at weight loss using sibutramine treatment in relation to the rs5443 variant. The study found that compared to placebo, those with rs5443 T/T and TC lost weight using sibutramine (7.4kgs vs. 3.4 kg) while those with the wildtype, C/C, had no significant weight loss.[ref] (Sibutramine is a serotonin-norepinephrine reuptake inhibitor known as Meridia in the US. It was withdrawn from the market in 2010 due to increased strokes and heart attacks.)
• A 2005 study looked at weight gain with clozapine (an antidepressant). The study found “Patients with the T/T type experienced significantly more weight gain (16.2±2.5%) compared to those with C/T (9.3±1.2%) or C/C types (5.5±2.4%) after long-term clozapine treatment (P=0.003).”[ref]
• A 2009 Korean study on blood pressure found that those with rs5443 T/T had significantly higher body weight than C/T and C/C individuals.[ref]
• A 2014 study also found higher serum lipids and visceral fat for the T allele.[ref]
• Not all studies have found a link between obesity and rs5443 SNP. A study in a Taiwanese population did not find an association.[ref]
• There seems to be an environmental link to obesity with this SNP. A study of young people from Zimbabwe found a link between the T allele and obesity, but only for those living in the capital city. People from rural Zimbabwe didn’t have the same link to obesity. The discussion part of the study brings up the following point: “It is tempting to speculate that the 825T allele might be neutral as long as lifestyle resembles that of our hunter-gatherer ancestors but may become detrimental upon Westernization. Thus, the presence of the 825T allele can only increase the risk for obesity in concert with certain behavioral or environmental factors, but clearly does not cause obesity by its sole presence.”[ref]
• Women carrying the T/T alleles gained more weight in pregnancy than those with C/C or C/T.[ref][ref]

How does this GNB3 polymorphism work?

Apparently, this variant isn’t actually what causes the changes in the signaling activity, but it is associated with a deletion further along. “This polymorphism does not affect the amino acid sequence. However, the T allele is in almost complete linkage disequilibrium with a series of other polymorphisms within the GNB3 gene, the so-called ‘T-haplotype’, which is associated with deletion of nucleotides 498–620 of exon 9, due to alternative splicing. It has been shown that this splice variant is functional and is postulated to be associated with enhanced signaling activity.”[ref]

The consensus seems to be that this variant induces a “splice variant,” which is a structural change in the beta subunit. The change in the beta subunit appears to help the GDP exit and increase the activity of the G protein. The link to higher blood pressure comes from an increased sensitivity to vasoactive pressor hormones.[ref]

Re-cap and tie it together:

The T allele leads to enhanced signaling for a G Protein beta, which causes the alpha subunit to be more active. It leads to overall more sensitivity to certain hormones.

Serotonin, dopamine, and norepinephrine are involved.

Sodium plays a role. Na+ / H+ exchanger activity is involved, as is an influence of high salt (>12.4 g/ day) diet.

“GNB3 plays a role in alpha2-adrenergic signaling”[ref] and “Human fat cells express both lipolytic β- and antilipolytic α₂-adrenergic receptors (α₂-ARs).”[ref]

Lipolysis breaks down fat cells, so an antilipolytic effect would keep the fat stored in the fat cells.

Estrogen upregulates the number of antilipolytic α₂-adrenergic receptors, specifically in subcutaneous fat.[ref]

In a study on the effect of the C825T variant on lipolysis: “Fat cells of T/T carriers showed a significant 10-fold decrease in the half-maximum effective concentration of agonists selective for lipolytic beta(1)- and beta(2)-adrenoceptors as well as for the antilipolytic alpha(2)A-adrenoceptor. In T/T carriers, maximum beta-adrenoceptor agonist-stimulated lipolysis was decreased, but the maximum antilipolytic effect of alpha(2)-adrenoceptors was less marked. Norepinephrine-induced adipocyte lipolysis and circulating fasting levels of free fatty acids and glycerol were reduced by half in T/T carriers.”[ref] This study also found, “Our lipolysis data, therefore, suggest that the T-to-C substitution alters the Gβ₃ protein in a way that decreases signaling of β₁–_, β₂-, and α₂-adrenoceptors for adipocyte lipolysis at some earlier steps above protein kinase A. The polymorphism may have a more marked effect on Gα_s– than Gα_i-coupling, as responsiveness for norepinephrine was decreased in adipocytes of T/T carriers. Norepinephrine’s effects on lipolysis reflect the net sum of β- and α₂– adrenoceptor signaling.”[ref]

Lifehacks:

Possible weight loss strategies for GNB3 variants:

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