I’m geeking out this week and diving deep into the genetics of weight and obesity.
One fairly well-studied variant, rs5443, confers a 2x to 3x risk of obesity and is found in the GNB3 gene.
So what is the GNB3 gene? The G protein β-polypeptide 3 gene (GNB3) is involved in translating signals from the cell surface into a cellular response. A Nobel Prize was awarded in 1994 for the discovery of G-proteins and their role in signaling. So if your last biology class was prior to 1994, here is a video explaining G proteins: https://www.youtube.com/watch?v=wC2_7Ror3qY The Wikipedia article on G proteins is also good to read.
rs5443 – minor allele is T, also known as GNB3 C825T (v.4 and v.5)
While the minor allele is T for most populations, it is actually the most common allele for those of African descent. For example, Caucasians have approximately 10% with TT while Africans have approximately 80%.
In a nutshell, this variant has been linked to cardiovascular events, hypertension, and obesity.
Before we get into the weight-related aspect of this SNP, let’s look at a couple of other things that are 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 TT genotype had a higher risk (2.6x) of a hard coronary event (non-fatal heart attack). [ref]
- Many studies link this snp 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 TT genotype lowered the capacity for athletic performance. [ref]
- A 2012 Polish study found that the rs5443 T variants were associated with higher systolic and diastolic blood pressure as well as response to a dobutamine stress echocardiography. [ref]
- A Japanese study found that the TT genotype was associated with 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 CT and TT genotypes was only for those in the lower salt category (less than 12.4 g/ day). In the introduction to the study, it discussed the idea that the activation of the sodium-proton exchanger by GNB3s is involved in the issues arising from this 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) in regards to the 825T allele. The TT genotype was associated with greater therapeutic effect. [ref] (Note that the T allele is most common in Africans with some groups having up to 80% TT)
- A 2007 study of migraine and cluster headache patients found that TT carriers were almost three times more likely to respond to triptans, a migraine medication which is a serotonin receptor agonists.
- No association was found between this variant and THS or thyroid function. [ref]
- 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 TT and TC lost weight using sibutramine (7.4kgs vs 3.4 kg) while those with the wildtype, CC, had no significant weight loss. [ref] (Sibutramine is a serotonin-norepinephrine reuptake inhibitor that was 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 TT type experienced significantly more weight gain (16.2±2.5%) compared to those with CT (9.3±1.2%) or CC types (5.5±2.4%) after long-term clozapine treatment (P=0.003).” [ref]
- A 2009 Korean study on blood pressure also found that those with rs5443 TT had significantly higher body weight than CT and CC 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 the rs5443 SNP. A study in a Taiwanese population did not find an association. [ref]
- There definitely 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 TT alleles gained more weight in pregnancy than those with CC or CT. [ref] and [ref]
How does this GNB3 polymorphism work?
First off, apparently this variant isn’t exactly what actually causes the changes in the signaling activity, but it is linked to 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]
If you watched the video (above) on the G proteins, it explains how the alpha subunit is turned on and off, releasing GDP in the cell. 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 is theorized 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 the vasoactive pressor hormones. [ref]
A 1999 study, Worldwide Ethnic Distribution of the G Protein B3 Subunit 825T Allaele and Its Association with Obesity in Caucasian, Chinese and Black African Individuals, is worth reading for the background on how the variant may affect both BMI and blood pressure. It looks at it from the “thrifty” gene hypothesis.
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. This 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 from high salt (>12.4 g/ day) diet.
Lipolysis is the breaking down of 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 TT 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 TT 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 TT 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 Gαs– than Gαi-coupling, as responsiveness for norepinephrine was decreased in adipocytes of TT carriers. Norepinephrine’s effects on lipolysis reflect the net sum of β- and α2– adrenoceptor signaling” [ref]
Possible weight loss strategies for GNB3 variants:
Norepinephrine levels could be boosted using foods with tyrosine and phenylalanine such as bananas, chicken, cheese, chocolate. Be Brain Fit has a good article outlining balancing norepinephrine naturally. Edited to add: Maca, a Peruvian medicinal plant, was shown to raise both dopamine and norepinephrine in a 2014 study involving mice. [ref] Also, anyone with COMT variants may want to be careful with anything that changes dopamine and norepinephrine levels.
Fasting may not be the way to go. A 2009 study looked at the effects of an 8-day modified medical fast (<350 kcal/day) stratified by GNB3 C825T polymorphism type. It found “Whereas weight loss was not dependent on genotype, both mood and hunger were significantly associated with genotype, with homozygous CC genotype carriers having best mood (p = 0.004) and least hunger (p = 0.036) during fasting compared to TT genotype carriers.” … “Pronounced mental discomfort during fasting in 825T allele carriers might partly explain their increased risk for obesity. The strong association between the subjective response to fasting with GNB3 genotypes indicates a role of the gene in the behavioral regulation of food intake, which should be further considered in nutritional intervention studies.” [ref]
Yohimbine is an alpha2 adrenoceptor antagonist. It makes sense to me that it might work for weight loss in those who have GNB3 825T. (Note that I could be completely wrong on this.)
- A small study looked at the effects of noradrenaline on vasoconstriction in skin based on GNB3 825T variant status and found that T allele carriers had a significantly enhanced response compared to those with CC. Pretreatment with yohimbine caused T allele carriers to have the same response as those with CC. [ref]
- Yohimbine increased plasma nonesterified fatty acids and noradrenaline without a significant increase in insulin. [ref] It has been used, especially in the bodybuilding community, for weight loss for many years.
- Examine.com is an excellent reference for finding out more about supplements. Check out the Yohimbine page there. The research there talks about yohimbine being metabolized through CYP2D6 with poor metabolizers having increased side effects such as anxiety. Be sure to check out your CYP2D6 results on my free detox report using your 23andMe data.
- Note that there are some that report pretty serious side effects from Yohimbine for some people! Please do your research before starting any supplement.
A Japanese herbal weight loss supplement, bofutsushosan, has been studied in relation to this variant. The study did find that those with the TT and CT alleles lost a little more body fat with this supplement compared to CC. But when you look at the numbers, overall the study subjects lost no more with the supplement than the placebo (average weight loss of around 2 lbs over 8 weeks). The discussion at the end of the study brings up the fact that the ephedra in the supplement was thought to be what worked best for those with the 825 T alleles. Ephedrine stimulates norepinephrine. [ref] Supversity has an article on bofutsushosan if you are interested in learning more. I believe that supplements with ephedra are banned in the US.
While sibutramine was shown to work better for those with the T allele in some studies, a study combining sibutramine with orlistat found that the “GNB3 825T allele was associated with blunted fat mass reduction in obese females.” [ref] Note that sibutramine is no longer on the market due to increased cardiovascular events (i.e. heart attacks!). Orlistat is sold as Alli in the US.