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Mechanism

  • The T allele may cause lower CB1 receptor numbers and less CB1 activation, although this has not been experimentally confirmed (R).
  • With this variation, the receptors also don't become significantly less sensitive when activated (R)
  • The T allele of this polymorphism could result in an increase in receptor protein production (via more stable mRNA) (R).

The Minor "T" allele is associated with:

  • Better response to antidepressants (T, SSRIs, Women) (R).
  • Reduced the development of stress, depression and anhedonia when exposed to stressful life events/abuse (T) (R).
  • Considerably less likely to report lifetime lack of pleasure (anhedonia) and depression in those who experienced childhood physical abuse (T) (R) (57% CC compared to 29% CT or TT) (R). 
  • Higher adiponectin (R).
  • A higher stress response, anxiety, a higher risk for depression (dependent on low BDNF) and more severe IBD (although the later onset of it) (Each T) (R).
  • 2.5X increased odds of major depression (T) (R).
  •  PTSD (T) (P = 0.011) (R).
  • Anorexia and bulimia (T) (R).
  • Later disease onset of Crohns and Colitis (T) (R).
  • Reduced risk of colitis (TT) (p = 0.01, OR 0.30) (R).
  • Being thin (T) (p = 0.0005) (R,R2).

The Major "C" allele is associated with:

  • Less pleasure in life (anhedonia) when exposed to stressful life events (C) (R).
  • Better response to antidepressants (C, male) (R).
  • 2X increased the risk for low adiponectin (C) (R).
  • Developing Crohns before 40 years of age (CC) (R).
  • Increased BMI (CC, Italian study, healthy population) (R).

Function

This polymorphism does not change the amino acid sequence of the mature protein. However, it may have functional effects (by changing mRNA stability or translation). This could affect the CB1 receptor function (thereby affecting CB1 associated behaviors) (R).

The T allele of rs1049353 may cause lower receptor numbers and less activation. With this variation, the receptors also don't become significantly less sensitive when activated (R) - i.e. you don't build up tolerance.

Another study mentions that the T allele of this polymorphism could result in an increase in receptor protein production (via more stable mRNA) (R).

The Good

The T allele of this polymorphism exerts some level of protection against stress and depression. Specifically, one report has demonstrated in two separate populations that carriers of the T allele are protected against the development of anhedonia and major depression in adulthood following early life stress or abuse (R).

In women the T allele responds better to antidepressants (SSRI's), while in males the C allele responds better to antidepressants (R).

The T allele reduced the development of depression when exposed to stressful life events, whereas those with the C allele experienced less pleasure in life (anhedonia) (R).

In CT or TT, those who experienced childhood physical abuse were considerably less likely to report lifetime lack of pleasure (anhedonia) and depression (R).

While 57% of those homozygous for the major allele reported anhedonia, only 29% of those who were carriers of the minor allele reported it (p < 0.02) (R).

Individuals who carried one or more copies of the T allele who reported being exposed to physical abuse during childhood were not at increased risk for anhedonia or for major depression (R).

Taken together, these studies would suggest that the T allele results in some level of protection against the development of depression, particularly in response to stress exposure (R).

Each T allele increases adiponectin because of reduced activation of the cannabinoid system.  Over-activation of the cannabinoid system leads to the creation of fat cells and significantly reduced adiponectin levels (R).

The C allele causes 2X increased risk for low adiponectin (R).

Adiponectin decreases obesity, fasting insulin, glucose and triglyceride levels. It increases HDL and insulin sensitivity (R).

T is protective against Crohns and Colitis.  People carrying the T allele have a later disease onset (R).

Compared to healthy controls, TT had a reduced risk to develop colitis (p = 0.01, OR 0.30). (R).

CC were more likely to develop Crohn's before 40 years of age (p = 5.9x10(-7)) than carriers of the T allele (R).

The T allele had a lower BMI than CC (p = 0.0005) (RR2).  CC has been shown to be associated with an increased BMI in an Italian study of a healthy population (R).

The Bad

One study mentions that each T causes intestinal inflammation, a higher stress response, anxiety, a higher risk for depression (dependent on low BDNF) and more severe IBD (although later onset of it) (R).

Another study mentions that there's a 2.46X increased odds of major depression for those carrying the T allele (R).

T was associated with PTSD (P = 0.011) (R).

T was more common in anorexic and bulimic patients (R).

rs1049353

Parent Gene: CNR1
Importance: 5
Minor Allele: T = 13%
Major Allele: C = 87%
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