CRTC2 polymorphism as a risk factor for the incidence of metabolic syndrome in patients with solid organ transplantation

• Published in: The pharmacogenomics journal Vol. 17; no. 1; pp. 69 - 75
• Main Authors: Quteineh, L, Bochud, P-Y, Golshayan, D, Crettol, S, Venetz, J-P, Manuel, O, Kutalik, Z, Treyer, A, Lehmann, R, Mueller, N J, Binet, I, van Delden, C, Steiger, J, Mohacsi, P, Dufour, J-f, Soccal, P M, Pascual, M, Eap, C B
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2017; Nature Publishing Group
• Subjects: 45; 45/77; 631/208/2489; 692/53/2423; Biomedical and Life Sciences; Biomedicine; Body mass index; Body weight; Cholesterol; Cyclic AMP response element-binding protein; Diabetes mellitus; Diabetes Mellitus - epidemiology; Diabetes Mellitus - genetics; Dyslipidemias - epidemiology; Dyslipidemias - genetics; Gene Expression; Gene Frequency; Gene polymorphism; Genetic Predisposition to Disease; Genotype & phenotype; Glucose metabolism; Heterozygote; High density lipoprotein; Homozygote; Human Genetics; Humans; Hyperlipidemia; Incidence; Kidney transplantation; Linear Models; Logistic Models; Metabolic syndrome; Metabolic Syndrome - diagnosis; Metabolic Syndrome - epidemiology; Metabolic Syndrome - genetics; Multivariate Analysis; Obesity; Obesity - epidemiology; Obesity - genetics; Odds Ratio; Oncology; Organ Transplantation - adverse effects; original-article; Overweight; Pharmacotherapy; Phenotype; Polymorphism, Single Nucleotide; Prevalence; Psychopharmacology; Replication; Risk Assessment; Risk Factors; Switzerland - epidemiology; Tacrolimus; Time Factors; Transcription; Transcription Factors - genetics; Transplants & implants; Treatment Outcome
• ISSN: 1470-269X; 1473-1150
• DOI: 10.1038/tpj.2015.82

Metabolic syndrome after transplantation is a major concern following solid organ transplantation (SOT). The CREB-regulated transcription co-activator 2 (CRTC2) regulates glucose metabolism. The effect of
CRTC2
polymorphisms on new-onset diabetes after transplantation (NODAT) was investigated in a discovery sample of SOT recipients (
n
1
=197). Positive results were tested for replication in two samples from the Swiss Transplant Cohort Study (STCS,
n
2
=1294 and
n
3
=759). Obesity and other metabolic traits were also tested. Associations with metabolic traits in population-based samples (
n
4
=46’186,
n
5
=123’865,
n
6
>100,000) were finally analyzed. In the discovery sample,
CRTC2 rs8450
-
AA
genotype was associated with NODAT, fasting blood glucose and body mass index (
P
corrected
<0.05).
CRTC2 rs8450
-
AA
genotype was associated with NODAT in the second STCS replication sample (odd ratio (OR)=2.01,
P
=0.04). In the combined STCS replication samples, the effect of
rs8450
-
AA
genotype on NODAT was observed in patients having received SOT from a deceased donor and treated with tacrolimus (
n
=395, OR=2.08,
P
=0.02) and in non-kidney transplant recipients (OR=2.09,
P
=0.02). Moreover,
rs8450
-
AA
genotype was associated with overweight or obesity (
n
=1215, OR=1.56,
P
=0.02), new-onset hyperlipidemia (
n
=1007, OR=1.76,
P
=0.007), and lower high-density lipoprotein-cholesterol (
n
=1214, β=-0.08,
P
=0.001). In the population-based samples, a proxy of
rs8450G>A
was significantly associated with several metabolic abnormalities.
CRTC2 rs8450G>A
appears to have an important role in the high prevalence of metabolic traits observed in patients with SOT. A weak association with metabolic traits was also observed in the population-based samples.