title: CRTC2 polymorphism as a risk factor for the incidence of metabolic syndrome in patients with solid organ transplantation.
abstract: 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 (n1=197). Positive results were tested for replication in two samples from the Swiss Transplant Cohort Study (STCS, n2=1294 and n3=759). Obesity and other metabolic traits were also tested. Associations with metabolic traits in population-based samples (n4=46'186, n5=123'865, n6>100,000) were finally analyzed. In the discovery sample, CRTC2 rs8450-AA genotype was associated with NODAT, fasting blood glucose and body mass index (Pcorrected<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.
authors.affiliation: Department of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Lausanne University Hospital, Prilly, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Quteineh
authors.affiliation: Service of Infectious Diseases, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: P-Y
authors.initials: PY
authors.lastname: Bochud
authors.affiliation: Transplant Center, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Golshayan
authors.affiliation: Department of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Lausanne University Hospital, Prilly, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Crettol
authors.affiliation: Transplant Center, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: J-P
authors.initials: JP
authors.lastname: Venetz
authors.affiliation: Service of Infectious Diseases, Lausanne University Hospital, Lausanne, Switzerland.|Transplant Center, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: O
authors.initials: O
authors.lastname: Manuel
authors.affiliation: Institute of Social and Preventive Medicine, Lausanne University Hospital, Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Z
authors.identifier: 0000-0001-8285-7523
authors.initials: Z
authors.lastname: Kutalik
authors.affiliation: Department of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Lausanne University Hospital, Prilly, Switzerland.
authors.forename: A
authors.identifier: 0000-0002-4533-7761
authors.initials: A
authors.lastname: Treyer
authors.affiliation: Service of Endocrinology and Diabetes, University Hospital, Zurich, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Lehmann
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital, Zurich, Switzerland.
authors.forename: N J
authors.initials: NJ
authors.lastname: Mueller
authors.affiliation: Service of Nephrology and Transplantation Medicine, Kantonsspital, St Gallen, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Binet
authors.affiliation: Service of Infectious Diseases, University Hospital, Geneva, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: van Delden
authors.affiliation: Service of Nephrology, University Hospital, Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Steiger
authors.affiliation: Departments of Cardiology Swiss Cardiovascular Centre, University Hospital, Bern, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Mohacsi
authors.affiliation: Department of Clinical Pharmacology, University Hospital, Bern, Switzerland.
authors.forename: J-F
authors.initials: JF
authors.lastname: Dufour
authors.affiliation: Service of Pulmonary Medicine, University Hospital, Geneva, Switzerland.
authors.forename: P M
authors.initials: PM
authors.lastname: Soccal
authors.affiliation: Transplant Center, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Pascual
authors.affiliation: Department of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Lausanne University Hospital, Prilly, Switzerland.|School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland.
authors.forename: C B
authors.initials: CB
authors.lastname: Eap
mesh_terms: D003920:Diabetes Mellitus / Q000453:epidemiology / Q000235:genetics; D050171:Dyslipidemias / Q000453:epidemiology / Q000235:genetics; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D015994:Incidence; D016014:Linear Models; D016015:Logistic Models; D024821:Metabolic Syndrome / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D015999:Multivariate Analysis; D009765:Obesity / Q000453:epidemiology / Q000235:genetics; D016017:Odds Ratio; D016377:Organ Transplantation / Q000009:adverse effects*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D018570:Risk Assessment; D012307:Risk Factors; D013557:Switzerland / Q000453:epidemiology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: C493245:CRTC2 protein, human; D014157:Transcription Factors