Weight Loss Genetics – Ghrelin

This is the beginning of a series of articles looking at the genetic SNPs involved in weight loss.

One of the first things to come to mind when wanting to lose weight is controlling appetite.  Everyone who has been on a diet understands the craving and desire to eat more.  So let’s take a look at what causes a person to feel ‘hungry’.

Ghrelin is a hormone that regulates energy and stimulates appetite.  It is also thought to be involved in gastrointestinal motility, insulin secretion, and gastric acid secretion. [ref]  It is secreted mainly in the lining of the stomach and then acts on the central nervous system as a signal for hunger.  There is an interesting article by Precision Nutrition on Leptin, ghrelin, and weight loss.    I highly recommend reading it for background information.

GHRL gene

GHRL is the gene that “encodes the ghrelin-obestatin preproprotein that is cleaved to yield two peptides, ghrelin and obestatin.” [ref]  There are several polymorphisms in the GHRL gene that have been studied in reference to obesity and appetite.  Some of the studies have come up with inconsistent results.  Here are a couple of the studies that do show an association with obesity:

  • rs4684677 (A allele is the minor allele for 23andMe orientation) was associated with obesity in a 2009 European study, but the conclusion drawn by the study was that it isn’t a major contributor.[ref]
  • Ghrelin is also thought to be associated with blood pressure and rs34911341 was associated with hypertension.  [ref]
  • rs35683 ( A allele) was found to be associated with BMI in several studies [ref]

A 2014 review of ghrelin studies came to the conclusion that “The effects of ghrelin gene polymorphism, is a complex area of investigation, due to ghrelin‘s interplay with a host of various factors part of an integrative network. However, taken together, results suggest that there are no or nonsignificant effects of the common genetic variants.” [ref]

CLOCK gene

A Spanish study of 1,495 overweight people looked at the CLOCK (Circadian Locomotor Output Cycles Kaput) gene in reference to obesity. The CLOCK gene regulates our circadian rhythm and is involved in metabolism.  The CLOCK 3111A/G snp is rs1801260 (G allele being the minor allele for 23andMe orientation). In the study, participants were put on a lower carb and high protein diet.  Those with rs1801260 GG and AG lost less weight compared to those with AA, particularly among older participants.  Plasma ghrelin levels were higher in those with GG and AG compared to those with AA, and again this was particularly true in older participants (over age 38).  Also, G allele carriers slept a little less on average than those with AA.  [ref]

A 2012 study also showed that rs1801260 G allele carriers had a higher resistance to weight loss, higher ghrelin levels, and ate a diet higher in saturated fat and lower in carbohydrates as compared to those with the AA allele.  It also confirmed other studies showing that those with the G allele tend to be more active in the evening than the morning. [ref]

APOA2 (Apolipoprotein A2)

Several studies have looked at the association between APOA2, BMI and saturated fat intake.

A recent study found that rs5082 (GG is risk allele for 23andMe orientation) is associated with greater weight and waist circumference for those with a saturated fatty acid intake of over 22g/day.  Ghrelin levels were also found to be higher in the GG group.  [ref]    A study from 2007 on that same polymorphism also found GG to be associated with higher BMI.  Interestingly, while those with the GG polymorphisms on average had higher fat and protein intake, their percentage of carbohydrate intake was lower.  [ref]

BChE (Butyrylcholinesterase)

An interesting study from Feb. 2015 looked at the hydrolyzation of ghrelin by butyrylcholinesterase (BChE).  The study initially was looking at mice in a cocaine study.  It stated that “we now find that circulating BChE has a large impact on aggressive behavior in mice that is attributable to its ability to inactivate ghrelin, a peptide hormone involved in hunger, feeding, and stress.” [ref]   The introduction of the study gives more background information on BChE:

Butyrylcholinesterase (BChE, EC is ubiquitous in higher vertebrates, hydrolyzing a range of substrates such as acetylcholine and cocaine. It is widely viewed as a “backup enzyme” in cholinergic neurotransmission and a general-purpose metabolizer of bioactive esters in the diet (1). BChE was isolated 80 y ago (2) but was never tied definitively to a more specific physiological role. We now propose that one of its major functions is to hydrolyze ghrelin, a unique octanoyl peptide that stimulates hunger and feeding (3). In 2004, De Vriese et al. (4) reported that purified BChE releases ghrelin’s octanoyl group in vitro, converting it into a putatively inactive “desacyl” form. The physiological relevance of that effect was, apparently, never pursued. [study in PubMed]

Another review looked at the association between BChE and obesity markers and found that “On the other hand, plasma BChE activity was significantly elevated in both type 1 and 2 diabetes, compared with the control subjects. In addition, BChE activity was positively associated with serum concentrations of cholesterol and triglycerides and with measures of overweight, obesity, and body fat distribution.”  [ref]  I’m not sure if this means that obesity causes BChE levels to rise or if higher BChE levels cause obesity.  Looking at the mouse study (above), it seems that increasing the BChE levels lead to inactivation of ghrelin.   Another 2015 study also “concluded that BChE is physiologically relevant for the hydrolysis of ghrelin.” [ref]

Going down that rabbit trail, there are several polymorphisms that significantly decrease BChE levels.  One is rs1799807 with G allele leading to decreased BChE.    For rs28933389, the A allele is associated with decreased BChE, and for rs28933390, the A allele is associated with BChE deficiency. [ref]  If you have any of those fairly rare SNPs, you should read up more on BChE deficiency.    A more common polymorphism that leads to a 30% reduction in BChE is the rs1803274 (T allele) which is referred to in studies as the K variant.  This polymorphisms also has been investigate in cocaine use in humans with the T allele being a risk factor for cocaine or crack addiction.  [ref]      A 2013 study in Brazil showed that two BChE SNPs (not included in 23andMe results) were associated with higher BMI, higher triglycerides, and lower BChE enzyme activity.  [ref]

FTO gene

The FTO gene, nicknamed the ‘fatso’ gene, has been studied extensively in association with fat mass.

A 2014 Swedish study on older adults found that for rs17817449, those carrying the G allele had higher ghrelin levels after an overnight fast. [ref]  Many other studies have linked that same allele to a risk for obesity.

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