Effect of Genetic Alterations in Key Genes in the Kynurenine Pathway on Suicidal Behavior (SuiKYN)

A Study on Genetic Alterations (Polymorphism) in Key Genes in the Kynurenine Pathway on Suicidal Behavior

Current research has shown that an imbalance in the Kinurenine pathway plays a role in the physiopathology of neurogenerative and mental disorders (with a decrease in neuroprotective metabolites and an increase in neurotoxic products). So far the research has concentrated on the enzymes IDO, KAT, KMO, 3HAO and QPRT which are the key players in this pathway. Several polymorphisms affecting these enzymes have been associated with certain disorders characterized by a deregulation of the inflammation and immune response (McCauley et al 2009,Tardito et al 2013, Lee et al 2014), but no studies have ever tried to find a link between these enzymes and suicidal behavior. The investigators hypothesize that people who have attempted to commit suicide will have pro-inflammatory genetic variations affecting the kynurenine pathway.

Study Overview

• Status: Recruiting
• Conditions: Suicidal Behavior; Polymorphism; Kynureninase
• Intervention / Treatment: Genetic: Analysis of Single nucleotide polymorphisms in each group.

• Study Type: Observational
• Enrollment (Anticipated): 525

Contacts and Locations

• Study Contact: Name: Jorge Lopez-Castroman, Professor; Phone Number: +33466683897; Email: Jorge.lopezcastroman@chu-nimes.fr

Study Locations

• France
  • Gard
    • Nîmes, Gard, France, 30029
      • Recruiting
      • Centre Hospitalier Universitaire de Nîmes
      • Contact: Jorge Lopez-Castroman, Professor; Phone Number: +33466683897; Email: Jorge.lopezcastroman@chu-nimes.fr
• Spain
  • Madrid, Spain, 28049
    • Recruiting
    • José-Fernandez-Piqueras

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

All patients for whom biological samples have been collected and registered in the hospital's databank for the purpose of previously registered studies : SPAD (RCB no. 2016-A01375-46), SMART-CRISIS (RCB no.: 2017-A02634-49) and SUI-PREDICT (RCB no.: 2016-A00845-46) and several studies conducted at the university hospitals of Puerta de Hierro, Ramon y Cajal et Fundacion Jiminez Diaz in Madrid, Spain, since 2004.

Description

Inclusion Criteria:

• For the "Suicide" group: Any patient aged 18 or over who has made at least one suicide attempt.
• For the control group: Any patient aged 18 or over, suffering from depression but has never attempted to commit suicide and any healthy patient who has never had any mental disorders.

Exclusion Criteria:

• Any patient who has expressed opposition to the use of his/her data.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Suicidal patients; Patients who have made at least one attempt to commit suicide.	Genetic: Analysis of Single nucleotide polymorphisms in each group.; The 6 single nucleotide polymorphisms (SNPs) determined will then be genotyped according to the Thermofisher Taqman technique ona 480 LightCycler (Roche Applied Science). 10% of the genotypes will be confirmed via Sanger sequencing on a 3500xl Thermofisher sequencer according to the manufacturer's recommendations.; Other Names: Determination of frequency of IDO1 rs 9657182, IDO1 rs35059413, IDO2 rs2929115, IDO2 rs2929116, KMO rs1053230, KMO rs2275163 for each group of patients.
Control group; This group will consist of two types of people: 75 healthy subjects (i.e. those who have no mental disorders and have never attempted to commit suicide) and; 150 patients suffering from depression but have never attempted to commit suicide.	Genetic: Analysis of Single nucleotide polymorphisms in each group.; The 6 single nucleotide polymorphisms (SNPs) determined will then be genotyped according to the Thermofisher Taqman technique ona 480 LightCycler (Roche Applied Science). 10% of the genotypes will be confirmed via Sanger sequencing on a 3500xl Thermofisher sequencer according to the manufacturer's recommendations.; Other Names: Determination of frequency of IDO1 rs 9657182, IDO1 rs35059413, IDO2 rs2929115, IDO2 rs2929116, KMO rs1053230, KMO rs2275163 for each group of patients.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of single nucleotide polymorphism rs9657182 of Enzyme IDO1 in the Suicide group	The presence of this genetic variation will be measured as a percentage	24 months
Presence of single nucleotide polymorphism rs9657182 of Enzyme IDO1 in the Emotion Control group	The presence of this genetic variation will be measured as a percentage	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
A. Frequency of single nucleotide polymorphism rs35059413 of Enzyme IDO1 in the Suicide group	The frequency of this genetic variation will be measured as a percentage	24 months
A. Frequency of single nucleotide polymorphism rs35059413 of Enzyme IDO1 in the Emotion Control group	The frequency of this genetic variation will be measured as a percentage	24 months
A. Frequency of single nucleotide polymorphism rs2929115 of Enzyme IDO2 in the Suicide group	The frequency of this genetic variation will be measured as a percentage	24 months
A. Frequency of single nucleotide polymorphism rs2929115 of Enzyme IDO2 in the Emotion Control group	The frequency of this genetic variation will be measured as a percentage	24 months
A. Frequency of single nucleotide polymorphism rs2929116 of Enzyme IDO2 in the Suicide group	The frequency of this genetic variation will be measured as a percentage	24 months
A. Frequency of single nucleotide polymorphism rs2929116 of Enzyme IDO2 in the Emotion Control group	The frequency of this genetic variation will be measured as a percentage	24 months
A. Frequency of single nucleotide polymorphism rs1053230 of KMO in the Suicide group	The frequency of this genetic variation will be measured as a percentage	24 months
A. Frequency of single nucleotide polymorphism rs1053230 of KMO in the Emotion Control group	The frequency of this genetic variation will be measured as a percentage	24 months
A. Frequency of single nucleotide polymorphism rs2275163 of KMO in the Suicide group	The frequency of this genetic variation will be measured as a percentage	24 months
A. Frequency of single nucleotide polymorphism rs2275163 of KMO in the Emotion Control group	The frequency of this genetic variation will be measured as a percentage	24 months
B. Simultaneous influence of the various single nucleotide polymorphisms on the functioning of the kynurenine pathway and suicidal behavior.	The numerical value of the polygenic risk score will be used to measure this criterion.	24 months
C. Percentage frequency of single nucleotide polymorphisms among patients in the Suicide group.	The frequency of single nucleotide polymorphisms, measured as a percentage, will be compared with the number of suicide attempts, the lethality, the method used and the intensity of suicidal ideation in the Suicide group. The polygenic risk score is calculated as a weighted sum of the risk alleles resulting from the study using GWAS (genome-wide association study) summary statistics data. This score is not calculated on a scale but as a relative risk compared to the unaffected population.	24 months
D. Correlation between negative life events triggering suicide attempts and the level of inflammation in the Suicide group.	Inflammation will be measured according to the level of the main pro-inflammatory cytokines in the various samples : TGF-beta. The rate of anti-inflammatory cytokines IL-2 and IL-4 will also be measured in pg/ml and mg/ml	24 months
D. Correlation between negative life events triggering suicide attempts and the level of inflammation in the Affective Controls group.	Inflammation will be measured according to the level of the main pro-inflammatory cytokines in the various samples : TGF-beta. The rate of anti-inflammatory cytokines IL-2 and IL-4 will also be measured in pg/ml and mg/ml	24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of rs35059413 of IDO1 involved in the kynurenine pathway in the Suicide group	The frequency of rs35059413 of IDO1 involved in the kynurenine pathway in the suicide group will be measured as a percentage.	24 months
Frequency of rs35059413 of IDO1 involved in the kynurenine pathway in the Healthy Control group	The frequency of rs35059413 of IDO1 involved in the kynurenine pathway in the healthy controls group will be measured as a percentage.	24 months
Frequency of rs2929115 of IDO2 involved in the kynurenine pathway in the Suicide group	The frequency of rs2929115 of IDO2 involved in the kynurenine pathway in the suicide group will be measured as a percentage	24 months
Frequency of rs2929115 of IDO2 involved in the kynurenine pathway in the Healthy Controls group	The frequency of rs2929115 of IDO2 involved in the kynurenine pathway in the healthy controls group will be measured as a percentage	24 months
Frequency of rs2929116 of IDO2 involved in the kynurenine pathway in the Suicide group	The frequency of rs2929116 of IDO2 involved in the kynurenine pathway in the suicide group will be measured as a percentage	24 months
Frequency of rs2929116 of IDO2 involved in the kynurenine pathway in the Healthy Controls group	The frequency of rs2929116 of IDO2 involved in the kynurenine pathway in the Affective Control group will be measured as a percentage	24 months
Frequency of rs1053230 of KMO involved in the kynurenine pathway in the Suicide group	The frequency of rs1053230 of KMO involved in the kynurenine pathway in the suicide group will be measured as a percentage	24 months
Frequency of rs1053230 of KMO involved in the kynurenine pathway in the Healthy Controls group	The frequency of rs1053230 of KMO involved in the kynurenine pathway in the healthy controls group will be measured as a percentage	24 months
Frequency of rs2275163 of KMO involved in the kynurenine pathway in the Suicide group	The frequency of rs2275163 of KMO involved in the kynurenine pathway in the suicide group will be measured as a percentage	24 months
Frequency of rs2275163 of KMO involved in the kynurenine pathway in the Healthy Controls group	The frequency of rs2275163 of KMO involved in the kynurenine pathway in the healthy controls group will be measured as a percentage	24 months
Age of patients in the Suicide group	The age of patients in the suicide group will be recorded for statistical purposes	24 months
Age of patients in the Healthy Controls group	The age of patients in the healthy controls group will be recorded for statistical purposes	24 months
Weight of patients in the Suicide group	The weight of patients in the suicide group will be recorded in kg for statistical purposes	24 months
Weight of patients in the Healthy Controls group	The weight of patients in the healthy controls group will be recorded in kg for statistical purposes	24 months
Height of patients in the Suicide group	The height of patients in the suicide group will be recorded in centimeters for statistical purposes	24 months
Height of patients in the Healthy Controls group	The height of patients in the healthy controls group will be recorded in centimeters for statistical purposes	24 months
Gender of patients in the Suicide group	The gender of patients in the suicide group will be recorded for statistical purposes	24 months
Gender of patients in the Healthy Controls group	The gender of patients in the healthy controls group will be recorded for statistical purposes	24 months
Gene frequency of patients in the Suicide group	The gene frequency of patients in the suicide group will be recorded as a percentage for statistical purposes	24 months
Gene frequency of patients in the Healthy Controls group	The gene frequency of patients in the healthy controls group will be recorded as a percentage for statistical purposes	24 months
Cytokine concentration: patients in the Suicide group	The cytokine concentration of patients in the suicide group will be recorded in pg/l	24 months
Cytokine concentration: patients in the Healthy Controls group	The cytokine concentration of patients in the healthy controls group will be recorded in pg/l	24 months

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Nīmes
• Collaborators: Universidad Autonoma de Madrid

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 1, 2019
• Primary Completion (ANTICIPATED): June 1, 2022
• Study Completion (ANTICIPATED): September 1, 2022

Study Registration Dates

• First Submitted: September 14, 2020
• First Submitted That Met QC Criteria: September 24, 2020
• First Posted (ACTUAL): September 25, 2020

Study Record Updates

• Last Update Posted (ACTUAL): April 20, 2022
• Last Update Submitted That Met QC Criteria: April 19, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Inflammation; Suicide; Kynurenine
• Other Study ID Numbers: NIMAO/2019-2/JLC-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No