Genetic Variant SCL2A2 Is Associated with Risk of Cardiovascular Disease – Assessing the Individual and Cumulative Effect of 46 Type 2 Diabetes Related Genetic Variants

PLOS ONE, Dec 2019

Aim 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.

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Genetic Variant SCL2A2 Is Associated with Risk of Cardiovascular Disease – Assessing the Individual and Cumulative Effect of 46 Type 2 Diabetes Related Genetic Variants

et al. (2012) Genetic Variant SCL2A2 Is Associated with Risk of Cardiovascular Disease - Assessing the Individual and Cumulative Effect of 46 Type 2 Diabetes Related Genetic Variants. PLoS ONE 7(11): e50418. doi:10.1371/journal.pone.0050418 Genetic Variant SCL2A2 Is Associated with Risk of Cardiovascular Disease - Assessing the Individual and Cumulative Effect of 46 Type 2 Diabetes Related Genetic Variants Anders Borglykke 0 Niels Grarup 0 Thomas Spars 0 Allan Linneberg 0 Mogens Fenger 0 Jrgen Jeppesen 0 Torben Hansen 0 Oluf Pedersen 0 Torben Jrgensen 0 Florian Kronenberg, Innsbruck Medical University, Austria 0 1 Research Centre for Prevention and Health, Glostrup University Hospital , Glostrup , Denmark , 2 The Novo Nordisk Foundation Centre for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen , Copenhagen , Denmark , 3 University Hospital of Copenhagen , Hvidovre , Denmark , 4 Faculty of Health Sciences, University of Copenhagen , Copenhagen , Denmark , 5 Department of Medicine, Glostrup University Hospital , Glostrup , Denmark , 6 Faculty of Health Sciences, University of Southern Denmark , Odense, Denmark , 7 Hagedorn Research Institute, Gentofte, Denmark, 8 Faculty of Health Sciences, University of Aarhus , Aarhus , Denmark , 9 Medical Faculty, University of Aalborg , Aalborg , Denmark Aim: 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, 1.0071.188 , 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. - Funding: The study was funded by Lundbeck Foundation and produced by The Lundbeck Foundation Centre of Applied Medical Genomics for Personalized Disease Prediction, Prevention, and Care (www.LuCAMP.org). Further funding was received from The Health Insurance Foundation (grant number 2010 B 131). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Although the western world have experienced a substantial decrease in the mortality of cardiovascular disease (CVD) during the last three or four decades [1] CVD is still a leading cause of morbidity and premature mortality worldwide. The decrease in mortality can be attributed to decrease in case-fatality through improved treatment but the major contribution is due to a decrease in incidence. The latter is largely the result of many years of preventive efforts targeted the classical risk factors for CVD such as smoking, elevated serum cholesterol and hypertension. Even though the classical risk factors explain most of the risk associated with CVD there is still a part of the aetiology that lacks explanation. This is seen in cardiovascular risk prediction where established scoring schemes such as the European SCORE or the American Framingham model uses conventional risk factors to predict future risk of CVD, but still a substantial number of events occur in the proportion of the population that is not in high risk as assessed throu (...truncated)


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Anders Borglykke, Niels Grarup, Thomas Sparsø, Allan Linneberg, Mogens Fenger, Jørgen Jeppesen, Torben Hansen, Oluf Pedersen, Torben Jørgensen. Genetic Variant SCL2A2 Is Associated with Risk of Cardiovascular Disease – Assessing the Individual and Cumulative Effect of 46 Type 2 Diabetes Related Genetic Variants, PLOS ONE, 2012, Volume 7, Issue 11, DOI: 10.1371/journal.pone.0050418