title: Association between 9p21 genetic variants and mortality risk in a prospective cohort of patients with type 2 diabetes (ZODIAC-15).
abstract: The genomic region at 9p21 chromosome near the CDKN2A/CDKN2B genes is associated with type 2 diabetes(T2D) and cardiovascular disease(CVD). The effect of the 9p21 locus on long-term mortality in patients with T2D has yet to be determined.We examined three single nucleotide polymorphisms (SNPs) on 9p21, consistently and independently associated with T2D (rs10811661) or CVD (rs10757278, rs2383206), in relation to the risk of total and cardiovascular mortality in diabetic patients. We also aimed to replicate the previously observed interaction between rs2383206 and glycemic control on mortality.Genotypes for three SNPs were determined in 914 individuals from a prospective cohort of T2D patients of Dutch origin. Associations with mortality were assessed using Cox proportional hazard analyses.After a median follow-up of 9.5 years, 358 out of 914 patients had died. The hazard ratio (HR) for total mortality among individuals homozygous for the T2D-risk allele of rs10811661 compared to non-homozygous individuals was 0.74(95%CI 0.59-0.93). For the carriers of both CVD-risk alleles of rs10757278, the HR for total mortality was 1.31(95%CI 1.01-1.70). We found a significant interaction between rs2383206 and HbA1c on mortality, which was higher among patients with two CVD-risk alleles in the two lowest HbA1c tertiles (HR 1.68(95%CI 1.08-2.63); HR 1.48(95%CI 1.01-2.18).In conclusion, common variants on 9p21 were associated with mortality in patients with T2D in a Dutch population. The T2D SNP was inversely associated with mortality, while the CVD SNP increased the risk for mortality. We confirmed a possible, although different, synergistic relationship between HbA1c and rs2383206 on total mortality.
authors.affiliation: Diabetes Center, Isala Clinics, PO Box 10400, 8000 GK, Zwolle, The Netherlands. g.w.d.landman@isala.nl
authors.forename: Gijs W D
authors.initials: GW
authors.lastname: Landman
authors.forename: Jana V
authors.initials: JV
authors.lastname: van Vliet-Ostaptchouk
authors.forename: Nanne
authors.initials: N
authors.lastname: Kleefstra
authors.forename: Kornelis J J
authors.initials: KJ
authors.lastname: van Hateren
authors.forename: Iefke
authors.initials: I
authors.lastname: Drion
authors.forename: Klaas H
authors.initials: KH
authors.lastname: Groenier
authors.forename: Rijk O B
authors.initials: RO
authors.lastname: Gans
authors.forename: Harold
authors.initials: H
authors.lastname: Snieder
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.forename: Henk J G
authors.initials: HJ
authors.lastname: Bilo
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000235:genetics / Q000401:mortality; D002423:Cause of Death; D002899:Chromosomes, Human, Pair 9; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000401:mortality*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006442:Glycated Hemoglobin / Q000032:analysis; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009426:Netherlands / Q000453:epidemiology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D015415:Biomarkers; D006442:Glycated Hemoglobin; C517652:hemoglobin A1c protein, human