SLC6A4

Meta-analysis Confirm SLC6A4 variants (5-HTTLPR) are associated with SSRI response and adverse effects.

http://www.ncbi.nlm.nih.gov/pubmed/18982004 [198]

http://www.ncbi.nlm.nih.gov/pubmed/17146470 [199]

http://www.ncbi.nlm.nih.gov/pubmed/22137564 [200]

“…we systematically reviewed literature, selecting 33 studies for an exploratory analysis without any a priori hypothesis. Then we analyzed separately 19 studies performed on Caucasians and 11 on Asians.

We tested two phenotypes–remission and response rates–and three genotype comparisons–ll versus ls/ss, ss versus ll/ls and ll versus ss – using the Cochrane review manager. Evaluations were performed

separately for SSRIs and mixed/other drugs. Possible clinical modulators were investigated. In the exploratory analysis, we found an association between l allele and l/l genotype and remission. When the

analysis was split for ethnic group, in Caucasians we found an association between l allele and both response (OR = 1.58, C.I. 1.16-2.16, p = 0.004), and remission (OR = 1.53, C.I. 1.14-2.04, p = 0.004) in

the SSRI group. Only a marginal association between l allele and remission (OR = 1.41, C.I. 1.02-1.95, p = 0.04) survived pooling together mixed antidepressant treatments. In Asians, a small effect of 5-

HTTLPR on remission for mixed antidepressants was detected (OR = 2.10, C.I. 1.15-3.84, p = 0.02).” [200]

Variants of SLC6A4 Influence the Outcome of Antidepressant Therapy in Psychiatric Inpatients.

http://www.ncbi.nlm.nih.gov/pubmed/17617292 [201]

http://www.ncbi.nlm.nih.gov/pubmed/25980509 [202]

http://www.ncbi.nlm.nih.gov/pubmed/23973251 [203]

http://www.ncbi.nlm.nih.gov/pubmed/24192302 [163] http://www.ncbi.nlm.nih.gov/pubmed/24558768 [204]

“This paper gives an overview of 35 studies investigating the efficacy of SSRI antidepressants in dependence of 5-HTTLPR polymorphism… Briefly, the great majority of studies conducted have shown

that L-allele carriers have a faster and better response to SSRI antidepressants, if they are Caucasians…Pharmacogenetic analysis of 5-HTTLPR polymorphism has proven to be economically

cost-effective considering the recurrent course of the disease. It would appear that the response to SSRI antidepressants and the development of adverse reactions are associated with 5-HTTLPR

polymorphism in Caucasians and this pharmacogenetic analysis could be one of the first in future clinical practice.” [204]

Serotonin transporter 5-HTTLPR genotype moderates the effects of childhood adversity on posttraumatic stress disorder risk: a replication study.

http://www.ncbi.nlm.nih.gov/pubmed/22693124 [205]

“We reported that the 5-HTTLPR polymorphism in the promoter region of the serotonin transporter gene (SLC6A4) moderates the effect of childhood adversity on posttraumatic stress disorder (PTSD) risk. In

the present study, we considered 5,178 subjects (a group with generally high substance dependence comorbidity, as for our previous study) using similar methodology to replicate our previous results. We

found that, as reported in our previous study, in individuals with childhood adversity, the presence of one or two copies of the S allele of 5-HTTLPR increased the risk to develop PTSD. This gene environment interaction effect was present in European Americans (EAs), but not in African Americans (AAs; EAs, OR = 1.49, 95% CI = 1.07-2.08, P = 0.019; AAs, OR = 0.90, 95% CI = 0.60-1.35, P = 0.62).”

[205]

An examination of the association between 5-HTTLPR, combat exposure, and PTSD diagnosis among U.S. veterans.

http://www.ncbi.nlm.nih.gov/pubmed/25793742 [206]

Objective was to, “…examine the association between the 5-HTTLPR polymorphism of the serotonin transporter (SLC6A4) gene, combat exposure, and posttraumatic stress disorder (PTSD) diagnosis and

among two samples of combat-exposed veterans…The first sample included 550 non-Hispanic Black (NHB) combat-exposed veterans. The second sample included 555 non-Hispanic White (NHW) combat exposed veterans…Within the NHB sample, a significant additive effect was observed for 5-HTTLPR (OR = 1.502, p = .0025), such that the odds of having a current diagnosis of PTSD increased by 1.502

for each additional S' allele. No evidence for an association between 5-HTTLPR and PTSD was observed in the NHW sample…The present study suggests that there may be an association between

5-HTTLPR genotype and PTSD diagnosis among NHB veterans; however, no evidence for the hypothesized 5-HTTLPR x combat interaction was found.” [206]

Interaction between SLC6A4 promoter variants and childhood trauma on the age at onset of bipolar disorders.

http://www.ncbi.nlm.nih.gov/pubmed/26542422 [213]

“Age at onset (AAO) of bipolar disorders (BD) could be influenced both by a repeat length polymorphism (5HTTLPR) in the promoter region of the serotonin transporter gene (SLC6A4) and exposure to

childhood trauma. We assessed 308 euthymic patients with BD for the AAO of their first mood episode and childhood trauma. Patients were genotyped for the 5HTTLPR (long/short variant) and the rs25531.

Genotypes were classified on functional significance (LL, LS, and SS)…These results remained significant after correction using FDR. Regression models suggested an interaction between emotional

neglect and 'SS' genotype on the AAO (p = 0.009) and no further interaction with other trauma subtypes. Partial replication was obtained in the Brazilian sample, showing an interaction between

emotional abuse and 'LS' genotype on the AAO (p = 0.02). In conclusion, an effect of childhood trauma on AAO of BD was observed only in patients who carry a specific stress responsiveness-related

SLC6A4 promoter genotype.” [213]

SLC6A4 variants are associated with cortisol response to psychosocial stress.

https://www.ncbi.nlm.nih.gov/pubmed/20006325 [207]

http://www.ncbi.nlm.nih.gov/pubmed/26464328 [208]

https://www.ncbi.nlm.nih.gov/pubmed/17353910 [209]

https://www.ncbi.nlm.nih.gov/pubmed/24821403 [210]

https://www.ncbi.nlm.nih.gov/pubmed/18005940 [211] 

“Recent evidence indicates that individuals who are homozygous for the short (s) allele in the promoter region of the serotonin transporter gene have higher rates of depression and other psychiatric disorders as a function of exposure to increasing levels of stressful life events than do individuals who have one or two copies of the long (l) allele. Despite the reliability of this association, the mechanism by which this polymorphism confers risk for psychopathology in the presence of stress is not understood. This study was designed to examine the formulation that individuals who are homozygous for the s allele are characterized by a greater biological reactivity to stress than are their counterparts who have one or two copies of the l allele…Girls at high (n = 25) and low (n = 42) risk for depression by virtue of the presence or absence of a family history of this disorder were genotyped and exposed to a standardized laboratory stress task. Cortisol levels were assessed before the stressor, after the stressor, and during an extended recovery period. Girls who were homozygous for the s allele produced higher and more prolonged levels of cortisol in response to the stressor than did girls with an l allele. These findings indicate that the 5-HTTLPR polymorphism is associated with biological stress reactivity, which may increase susceptibility to depression in the face of stressful life events.” [211]

https://www.ncbi.nlm.nih.gov/pubmed/26136163 [212]

“The serotonin transporter genetic variant 5HTTLPR influences activation and feedback control of the hypothalamic-pituitary-adrenal axis, and has been shown to influence the effect of stressful life events on behavioral health…Distinct and interactive effects of 5HTTLPR long allele carriage [L] versus homozygous short allele carriage [SS]) and prior trauma exposure (low versus high) were evaluated,

after which a priori group comparisons were performed between hypothesized high resilience (L/low) and low resilience (SS/high) groups. For sNGF, L/low produced the greatest sNGF throughout stress

exposure while SS/high demonstrated the smallest; L/high and SS/low bisected these two extremes and were nearly identical to each other (i.e., SS/high < SS/low = L/high < L/low). Thus, 5HTTLPR and prior

trauma exposure demonstrated counterbalancing (additive) forces.” [212]

SLC6A4 S/S genotype is Associated with Violent Suicide in Male Citalopram Users

https://www.ncbi.nlm.nih.gov/pubmed/?term=28608626 [214]

In this study, researchers tested the hypothesis that the genetic variants associated with decreased citalopram efficiency, 5HTTLPR/rs25531… is more frequent among citalopram users committing suicide

than among the citalopram users in general. The study population comprised 349 suicide victims (184 males and 165 females). Based on the suicide method used, cases were divided into two groups;

violent (88 males and 49 females) and non-violent (96 males and 116 females). The control group (284; 159 males and 125 females) consisted of citalopram users who died of causes other than suicide.

Researchers found that male citalopram users with low functioning s/s genotype of 5HTTLPR/rs25531 were at increased risk to commit violent suicide (OR 2.50, 95%CI 1.15-5.42, p = 0.020).[214]