title: Genetic variant SLC2A2 [corrected] Is associated with risk of cardiovascular disease – assessing the individual and cumulative effect of 46 type 2 diabetes related genetic variants.
abstract: OBJECTIVE
  To assess the individual and combined effect of 46 type 2 diabetes related risk alleles on incidence of a composite CVD endpoint.
  
  
  METHODS
  Data from the first Danish MONICA study (N = 3523) and the Inter99 study (N = 6049) was used. Using Cox proportional hazard regression the individual effect of each risk allele on incident CVD was analyzed. Risk was presented as hazard ratios (HR) per risk allele.
  
  
  RESULTS
  During 80,859 person years 1441 incident cases of CVD (fatal and non-fatal) occurred in the MONICA study. In Inter99 942 incident cases were observed during 61,239 person years. In the Danish MONICA study four gene variants were significantly associated with incident CVD independently of known diabetes status at baseline; SLC2A2 rs11920090 (HR 1.147, 95% CI 1.027-1.283 , P = 0.0154), C2CD4A rs7172432 (1.112, 1.027-1.205 , P = 0.0089), GCKR rs780094 (1.094, 1.007-1.188 , P = 0.0335) and C2CD4B rs11071657 (1.092, 1.007-1.183 , P = 0.0323). The genetic score was significantly associated with increased risk of CVD (1.025, 1.010-1.041, P = 0.0016). In Inter99 two gene variants were associated with risk of CVD independently of diabetes; SLC2A2 (HR 1.180, 95% CI 1.038-1.341 P = 0.0116) and FTO (0.909, 0.827-0.998, P = 0.0463). Analysing the two populations together we found SLC2A2 rs11920090 (HR 1.164, 95% CI 1.070-1.267, P = 0.0004) meeting the Bonferroni corrected threshold for significance. GCKR rs780094 (1.076, 1.010-1.146, P = 0.0229), C2CD4B rs11071657 (1.067, 1.003-1.135, P = 0.0385) and NOTCH2 rs10923931 (1.104 (1.001 ; 1.217 , P = 0.0481) were found associated with CVD without meeting the corrected threshold. The genetic score was significantly associated with increased risk of CVD (1.018, 1.006-1.031, P = 0.0043).
  
  
  CONCLUSIONS
  This study showed that out of the 46 genetic variants examined only the minor risk allele of SLC2A2 rs11920090 was significantly (P = 0.0005) associated with a composite endpoint of incident CVD below the threshold for statistical significance corrected for multiple testing. This potential pathway needs further exploration.
authors.affiliation: Research Centre for Prevention and Health, Glostrup University Hospital, Glostrup, Denmark. anders.borglykke@regionh.dk
authors.forename: Anders
authors.initials: A
authors.lastname: Borglykke
authors.forename: Niels
authors.initials: N
authors.lastname: Grarup
authors.forename: Thomas
authors.initials: T
authors.lastname: Sparsø
authors.forename: Allan
authors.initials: A
authors.lastname: Linneberg
authors.forename: Mogens
authors.initials: M
authors.lastname: Fenger
authors.forename: Jørgen
authors.initials: J
authors.lastname: Jeppesen
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Torben
authors.initials: T
authors.lastname: Jørgensen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000483:Alleles; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D002318:Cardiovascular Diseases / Q000150:complications / Q000235:genetics* / Q000401:mortality; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics* / Q000401:mortality; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D051273:Glucose Transporter Type 2 / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics; D051883:Receptor, Notch2 / Q000235:genetics; D012306:Risk; D017422:Sequence Analysis, DNA
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C485100:GCKR protein, human; D051273:Glucose Transporter Type 2; D008565:Membrane Proteins; C497764:NOTCH2 protein, human; D011506:Proteins; D051883:Receptor, Notch2; C495680:SLC2A2 protein, human; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human