Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: A meta-analysis

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Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes : A meta-analysis. / Lotta, Luca A.; Sharp, Stephen J.; Burgess, Stephen; Perry, John R B; Stewart, Isobel D.; Willems, Sara M.; Luan, Jian'an; Ardanaz, Eva; Arriola, Larraitz; Balkau, Beverley; Boeing, Heiner; Deloukas, Panos; Forouhi, Nita G.; Franks, Paul W.; Grioni, Sara; Kaaks, Rudolf; Key, Timothy J.; Navarro, Carmen; Nilsson, Peter M.; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, Jose Ramón; Riboli, Elio; Rolandsson, Olov; Sacerdote, Carlotta; Salamanca-Fernandez, Elena; Slimani, Nadia; Spijkerman, Annemieke M W; Tjonneland, Anne; Tumino, Rosario; Van Der A, Daphne L.; Van Der Schouw, Yvonne T.; McCarthy, Mark I.; Barroso, Inês; O'Rahilly, Stephen; Savage, David B.; Sattar, Naveed; Langenberg, Claudia; Scott, Robert A.; Wareham, Nicholas J.

In: JAMA: The Journal of the American Medical Association, Vol. 316, No. 13, 04.10.2016, p. 1383-1391.

Research output: Contribution to journalArticle

Harvard

Lotta, LA, Sharp, SJ, Burgess, S, Perry, JRB, Stewart, ID, Willems, SM, Luan, J, Ardanaz, E, Arriola, L, Balkau, B, Boeing, H, Deloukas, P, Forouhi, NG, Franks, PW, Grioni, S, Kaaks, R, Key, TJ, Navarro, C, Nilsson, PM, Overvad, K, Palli, D, Panico, S, Quirós, JR, Riboli, E, Rolandsson, O, Sacerdote, C, Salamanca-Fernandez, E, Slimani, N, Spijkerman, AMW, Tjonneland, A, Tumino, R, Van Der A, DL, Van Der Schouw, YT, McCarthy, MI, Barroso, I, O'Rahilly, S, Savage, DB, Sattar, N, Langenberg, C, Scott, RA & Wareham, NJ 2016, 'Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: A meta-analysis', JAMA: The Journal of the American Medical Association, vol. 316, no. 13, pp. 1383-1391. https://doi.org/10.1001/jama.2016.14568

APA

Lotta, L. A., Sharp, S. J., Burgess, S., Perry, J. R. B., Stewart, I. D., Willems, S. M., Luan, J., Ardanaz, E., Arriola, L., Balkau, B., Boeing, H., Deloukas, P., Forouhi, N. G., Franks, P. W., Grioni, S., Kaaks, R., Key, T. J., Navarro, C., Nilsson, P. M., ... Wareham, N. J. (2016). Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: A meta-analysis. JAMA: The Journal of the American Medical Association, 316(13), 1383-1391. https://doi.org/10.1001/jama.2016.14568

CBE

Lotta LA, Sharp SJ, Burgess S, Perry JRB, Stewart ID, Willems SM, Luan J, Ardanaz E, Arriola L, Balkau B, Boeing H, Deloukas P, Forouhi NG, Franks PW, Grioni S, Kaaks R, Key TJ, Navarro C, Nilsson PM, Overvad K, Palli D, Panico S, Quirós JR, Riboli E, Rolandsson O, Sacerdote C, Salamanca-Fernandez E, Slimani N, Spijkerman AMW, Tjonneland A, Tumino R, Van Der A DL, Van Der Schouw YT, McCarthy MI, Barroso I, O'Rahilly S, Savage DB, Sattar N, Langenberg C, Scott RA, Wareham NJ. 2016. Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: A meta-analysis. JAMA: The Journal of the American Medical Association. 316(13):1383-1391. https://doi.org/10.1001/jama.2016.14568

MLA

Vancouver

Author

Lotta, Luca A. ; Sharp, Stephen J. ; Burgess, Stephen ; Perry, John R B ; Stewart, Isobel D. ; Willems, Sara M. ; Luan, Jian'an ; Ardanaz, Eva ; Arriola, Larraitz ; Balkau, Beverley ; Boeing, Heiner ; Deloukas, Panos ; Forouhi, Nita G. ; Franks, Paul W. ; Grioni, Sara ; Kaaks, Rudolf ; Key, Timothy J. ; Navarro, Carmen ; Nilsson, Peter M. ; Overvad, Kim ; Palli, Domenico ; Panico, Salvatore ; Quirós, Jose Ramón ; Riboli, Elio ; Rolandsson, Olov ; Sacerdote, Carlotta ; Salamanca-Fernandez, Elena ; Slimani, Nadia ; Spijkerman, Annemieke M W ; Tjonneland, Anne ; Tumino, Rosario ; Van Der A, Daphne L. ; Van Der Schouw, Yvonne T. ; McCarthy, Mark I. ; Barroso, Inês ; O'Rahilly, Stephen ; Savage, David B. ; Sattar, Naveed ; Langenberg, Claudia ; Scott, Robert A. ; Wareham, Nicholas J. / Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes : A meta-analysis. In: JAMA: The Journal of the American Medical Association. 2016 ; Vol. 316, No. 13. pp. 1383-1391.

RIS

TY - JOUR

T1 - Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes

T2 - A meta-analysis

AU - Lotta, Luca A.

AU - Sharp, Stephen J.

AU - Burgess, Stephen

AU - Perry, John R B

AU - Stewart, Isobel D.

AU - Willems, Sara M.

AU - Luan, Jian'an

AU - Ardanaz, Eva

AU - Arriola, Larraitz

AU - Balkau, Beverley

AU - Boeing, Heiner

AU - Deloukas, Panos

AU - Forouhi, Nita G.

AU - Franks, Paul W.

AU - Grioni, Sara

AU - Kaaks, Rudolf

AU - Key, Timothy J.

AU - Navarro, Carmen

AU - Nilsson, Peter M.

AU - Overvad, Kim

AU - Palli, Domenico

AU - Panico, Salvatore

AU - Quirós, Jose Ramón

AU - Riboli, Elio

AU - Rolandsson, Olov

AU - Sacerdote, Carlotta

AU - Salamanca-Fernandez, Elena

AU - Slimani, Nadia

AU - Spijkerman, Annemieke M W

AU - Tjonneland, Anne

AU - Tumino, Rosario

AU - Van Der A, Daphne L.

AU - Van Der Schouw, Yvonne T.

AU - McCarthy, Mark I.

AU - Barroso, Inês

AU - O'Rahilly, Stephen

AU - Savage, David B.

AU - Sattar, Naveed

AU - Langenberg, Claudia

AU - Scott, Robert A.

AU - Wareham, Nicholas J.

PY - 2016/10/4

Y1 - 2016/10/4

N2 - IMPORTANCE Low-density lipoprotein cholesterol (LDL-C)-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes. OBJECTIVE To investigate whether LDL-C-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (ie, HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS The associations with type 2 diabetes and coronary artery disease of LDL-C-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50 775 individuals with type 2 diabetes and 270 269 controls and 60 801 individuals with coronary artery disease and 123 504 controls. Data collection took place in Europe and the United States between 1991 and 2016. EXPOSURES Low-density lipoprotein cholesterol-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) for type 2 diabetes and coronary artery disease. RESULTS Low-density lipoprotein cholesterol-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L [38.7-mg/dL] reduction in LDL-C of 0.61 [95%CI, 0.42-0.88]; P = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 [95%CI, 1.70-3.43]; P .001). For PCSK9 genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95%CI, 1.02-1.38; P = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk (I2 = 0%for heterogeneity in genetic associations; P = .93). However, associations with type 2 diabetes were heterogeneous (I2 = 77.2%; P = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles. CONCLUSIONS AND RELEVANCE In thismeta-analysis, exposure to LDL-C-lowering genetic variants in or near NPC1L1 and other geneswas associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.

AB - IMPORTANCE Low-density lipoprotein cholesterol (LDL-C)-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, similar to the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are associated with the risk of type 2 diabetes. OBJECTIVE To investigate whether LDL-C-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (ie, HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS The associations with type 2 diabetes and coronary artery disease of LDL-C-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50 775 individuals with type 2 diabetes and 270 269 controls and 60 801 individuals with coronary artery disease and 123 504 controls. Data collection took place in Europe and the United States between 1991 and 2016. EXPOSURES Low-density lipoprotein cholesterol-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, and LDLR. MAIN OUTCOMES AND MEASURES Odds ratios (ORs) for type 2 diabetes and coronary artery disease. RESULTS Low-density lipoprotein cholesterol-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (OR for a genetically predicted 1-mmol/L [38.7-mg/dL] reduction in LDL-C of 0.61 [95%CI, 0.42-0.88]; P = .008) and directly associated with type 2 diabetes (OR for a genetically predicted 1-mmol/L reduction in LDL-C of 2.42 [95%CI, 1.70-3.43]; P .001). For PCSK9 genetic variants, the OR for type 2 diabetes per 1-mmol/L genetically predicted reduction in LDL-C was 1.19 (95%CI, 1.02-1.38; P = .03). For a given reduction in LDL-C, genetic variants were associated with a similar reduction in coronary artery disease risk (I2 = 0%for heterogeneity in genetic associations; P = .93). However, associations with type 2 diabetes were heterogeneous (I2 = 77.2%; P = .002), indicating gene-specific associations with metabolic risk of LDL-C-lowering alleles. CONCLUSIONS AND RELEVANCE In thismeta-analysis, exposure to LDL-C-lowering genetic variants in or near NPC1L1 and other geneswas associated with a higher risk of type 2 diabetes. These data provide insights into potential adverse effects of LDL-C-lowering therapy.

UR - http://www.scopus.com/inward/record.url?scp=84995776151&partnerID=8YFLogxK

U2 - 10.1001/jama.2016.14568

DO - 10.1001/jama.2016.14568

M3 - Article

C2 - 27701660

AN - SCOPUS:84995776151

VL - 316

SP - 1383

EP - 1391

JO - JAMA: The Journal of the American Medical Association

JF - JAMA: The Journal of the American Medical Association

SN - 0098-7484

IS - 13

ER -