A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes

Ivonne Sluijs; Michael V. Holmes; Yvonne T. van der Schouw; Joline W J Beulens; Folkert W. Asselbergs; José María Huerta; Tom M. Palmer; Larraitz Arriola; Beverley Balkau; Aurelio Barricarte; Heiner Boeing; Françoise Clavel-Chapelon; Guy Fagherazzi; Paul W. Franks; Diana Gavrila; Rudolf Kaaks; Kay T ee Khaw; Tilman Kühn; Esther Molina-Montes; Lotte M axild Mortensen; Peter M. Nilsson; Kim Overvad; Domenico Palli; Salvatore Panico; J. Ramón Quirós; Olov Rolandsson; Carlotta Sacerdote; Núria Sala; Julie A. Schmidt; Robert A. Scott; Sabina Sieri; Nadia Slimani; Annemieke M W Spijkerman; Anne Tjonneland; Ruth C. Travis; Rosario Tumino; Daphne L. van der A; Stephen J. Sharp; Nita G. Forouhi; Claudia Langenberg; Elio Riboli; Nicholas J. Wareham

doi:10.2337/db14-0742

A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes

Ivonne Sluijs, Michael V. Holmes, Yvonne T. van der Schouw, Joline W J Beulens, Folkert W. Asselbergs, José María Huerta, Tom M. Palmer, Larraitz Arriola, Beverley Balkau, Aurelio Barricarte, Heiner Boeing, Françoise Clavel-Chapelon, Guy Fagherazzi, Paul W. Franks, Diana Gavrila, Rudolf Kaaks, Kay T ee Khaw, Tilman Kühn, Esther Molina-Montes, Lotte M axild MortensenPeter M. Nilsson, Kim Overvad, Domenico Palli, Salvatore Panico, J. Ramón Quirós, Olov Rolandsson, Carlotta Sacerdote, Núria Sala, Julie A. Schmidt, Robert A. Scott, Sabina Sieri, Nadia Slimani, Annemieke M W Spijkerman, Anne Tjonneland, Ruth C. Travis, Rosario Tumino, Daphne L. van der A, Stephen J. Sharp, Nita G. Forouhi, Claudia Langenberg, Elio Riboli, Nicholas J. Wareham

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

We aimed to investigate the causal effect of circulating uric acid concentrations on type 2 diabetes risk. A Mendelian randomization study was performed using a genetic score with 24 uric acid-associated loci. We used data of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, comprising 24,265 individuals of European ancestry from eight European countries. During a mean (SD) follow-up of 10 (4) years, 10,576 verified incident case subjects with type 2 diabetes were ascertained. Higher uric acid was associated with a higher diabetes risk after adjustment for confounders, with a hazard ratio (HR) of 1.20 (95% CI 1.11, 1.30) per 59.48 µmol/L (1 mg/dL) uric acid. The genetic score raised uric acid by 17 µmol/L (95% CI 15, 18) per SD increase and explained 4% of uric acid variation. By using the genetic score to estimate the unconfounded effect, we found that a 59.48 µmol/L higher uric acid concentration did not have a causal effect on diabetes (HR 1.01 [95% CI 0.87, 1.16]). Including data from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, increasing our dataset to 41,508 case subjects with diabetes, the summary odds ratio estimate was 0.99 (95% CI 0.92, 1.06). In conclusion, our study does not support a causal effect of circulating uric acid on diabetes risk. Uric acid-lowering therapies may therefore not be beneficial in reducing diabetes risk.

Original language	English
Pages (from-to)	3028-3036
Number of pages	9
Journal	Diabetes
Volume	64
Issue number	8
DOIs	https://doi.org/10.2337/db14-0742
Publication status	Published - 1 Aug 2015

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10.2337/db14-0742

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Sluijs, I., Holmes, M. V., van der Schouw, Y. T., Beulens, J. W. J., Asselbergs, F. W., Huerta, J. M., Palmer, T. M., Arriola, L., Balkau, B., Barricarte, A., Boeing, H., Clavel-Chapelon, F., Fagherazzi, G., Franks, P. W., Gavrila, D., Kaaks, R., Khaw, K. T. E., Kühn, T., Molina-Montes, E., ... Wareham, N. J. (2015). A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes. Diabetes, 64(8), 3028-3036. https://doi.org/10.2337/db14-0742

@article{b84c24d887784004a5592c3b293d4085,

title = "A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes",

abstract = "We aimed to investigate the causal effect of circulating uric acid concentrations on type 2 diabetes risk. A Mendelian randomization study was performed using a genetic score with 24 uric acid-associated loci. We used data of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, comprising 24,265 individuals of European ancestry from eight European countries. During a mean (SD) follow-up of 10 (4) years, 10,576 verified incident case subjects with type 2 diabetes were ascertained. Higher uric acid was associated with a higher diabetes risk after adjustment for confounders, with a hazard ratio (HR) of 1.20 (95% CI 1.11, 1.30) per 59.48 µmol/L (1 mg/dL) uric acid. The genetic score raised uric acid by 17 µmol/L (95% CI 15, 18) per SD increase and explained 4% of uric acid variation. By using the genetic score to estimate the unconfounded effect, we found that a 59.48 µmol/L higher uric acid concentration did not have a causal effect on diabetes (HR 1.01 [95% CI 0.87, 1.16]). Including data from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, increasing our dataset to 41,508 case subjects with diabetes, the summary odds ratio estimate was 0.99 (95% CI 0.92, 1.06). In conclusion, our study does not support a causal effect of circulating uric acid on diabetes risk. Uric acid-lowering therapies may therefore not be beneficial in reducing diabetes risk. ",

author = "Ivonne Sluijs and Holmes, {Michael V.} and {van der Schouw}, {Yvonne T.} and Beulens, {Joline W J} and Asselbergs, {Folkert W.} and Huerta, {Jos{\'e} Mar{\'i}a} and Palmer, {Tom M.} and Larraitz Arriola and Beverley Balkau and Aurelio Barricarte and Heiner Boeing and Fran{\c c}oise Clavel-Chapelon and Guy Fagherazzi and Franks, {Paul W.} and Diana Gavrila and Rudolf Kaaks and Khaw, {Kay T ee} and Tilman K{\"u}hn and Esther Molina-Montes and Mortensen, {Lotte M axild} and Nilsson, {Peter M.} and Kim Overvad and Domenico Palli and Salvatore Panico and Quir{\'o}s, {J. Ram{\'o}n} and Olov Rolandsson and Carlotta Sacerdote and N{\'u}ria Sala and Schmidt, {Julie A.} and Scott, {Robert A.} and Sabina Sieri and Nadia Slimani and Spijkerman, {Annemieke M W} and Anne Tjonneland and Travis, {Ruth C.} and Rosario Tumino and {van der A}, {Daphne L.} and Sharp, {Stephen J.} and Forouhi, {Nita G.} and Claudia Langenberg and Elio Riboli and Wareham, {Nicholas J.}",

year = "2015",

month = aug,

day = "1",

doi = "10.2337/db14-0742",

language = "English",

volume = "64",

pages = "3028--3036",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "8",

}

Sluijs, I, Holmes, MV, van der Schouw, YT, Beulens, JWJ, Asselbergs, FW, Huerta, JM, Palmer, TM, Arriola, L, Balkau, B, Barricarte, A, Boeing, H, Clavel-Chapelon, F, Fagherazzi, G, Franks, PW, Gavrila, D, Kaaks, R, Khaw, KTE, Kühn, T, Molina-Montes, E, Mortensen, LMA, Nilsson, PM, Overvad, K, Palli, D, Panico, S, Quirós, JR, Rolandsson, O, Sacerdote, C, Sala, N, Schmidt, JA, Scott, RA, Sieri, S, Slimani, N, Spijkerman, AMW, Tjonneland, A, Travis, RC, Tumino, R, van der A, DL, Sharp, SJ, Forouhi, NG, Langenberg, C, Riboli, E & Wareham, NJ 2015, 'A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes', Diabetes, vol. 64, no. 8, pp. 3028-3036. https://doi.org/10.2337/db14-0742

TY - JOUR

T1 - A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes

AU - Sluijs, Ivonne

AU - Holmes, Michael V.

AU - van der Schouw, Yvonne T.

AU - Beulens, Joline W J

AU - Asselbergs, Folkert W.

AU - Huerta, José María

AU - Palmer, Tom M.

AU - Arriola, Larraitz

AU - Balkau, Beverley

AU - Barricarte, Aurelio

AU - Boeing, Heiner

AU - Clavel-Chapelon, Françoise

AU - Fagherazzi, Guy

AU - Franks, Paul W.

AU - Gavrila, Diana

AU - Kaaks, Rudolf

AU - Khaw, Kay T ee

AU - Kühn, Tilman

AU - Molina-Montes, Esther

AU - Mortensen, Lotte M axild

AU - Nilsson, Peter M.

AU - Overvad, Kim

AU - Palli, Domenico

AU - Panico, Salvatore

AU - Quirós, J. Ramón

AU - Rolandsson, Olov

AU - Sacerdote, Carlotta

AU - Sala, Núria

AU - Schmidt, Julie A.

AU - Scott, Robert A.

AU - Sieri, Sabina

AU - Slimani, Nadia

AU - Spijkerman, Annemieke M W

AU - Tjonneland, Anne

AU - Travis, Ruth C.

AU - Tumino, Rosario

AU - van der A, Daphne L.

AU - Sharp, Stephen J.

AU - Forouhi, Nita G.

AU - Langenberg, Claudia

AU - Riboli, Elio

AU - Wareham, Nicholas J.

PY - 2015/8/1

Y1 - 2015/8/1

N2 - We aimed to investigate the causal effect of circulating uric acid concentrations on type 2 diabetes risk. A Mendelian randomization study was performed using a genetic score with 24 uric acid-associated loci. We used data of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, comprising 24,265 individuals of European ancestry from eight European countries. During a mean (SD) follow-up of 10 (4) years, 10,576 verified incident case subjects with type 2 diabetes were ascertained. Higher uric acid was associated with a higher diabetes risk after adjustment for confounders, with a hazard ratio (HR) of 1.20 (95% CI 1.11, 1.30) per 59.48 µmol/L (1 mg/dL) uric acid. The genetic score raised uric acid by 17 µmol/L (95% CI 15, 18) per SD increase and explained 4% of uric acid variation. By using the genetic score to estimate the unconfounded effect, we found that a 59.48 µmol/L higher uric acid concentration did not have a causal effect on diabetes (HR 1.01 [95% CI 0.87, 1.16]). Including data from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, increasing our dataset to 41,508 case subjects with diabetes, the summary odds ratio estimate was 0.99 (95% CI 0.92, 1.06). In conclusion, our study does not support a causal effect of circulating uric acid on diabetes risk. Uric acid-lowering therapies may therefore not be beneficial in reducing diabetes risk.

AB - We aimed to investigate the causal effect of circulating uric acid concentrations on type 2 diabetes risk. A Mendelian randomization study was performed using a genetic score with 24 uric acid-associated loci. We used data of the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study, comprising 24,265 individuals of European ancestry from eight European countries. During a mean (SD) follow-up of 10 (4) years, 10,576 verified incident case subjects with type 2 diabetes were ascertained. Higher uric acid was associated with a higher diabetes risk after adjustment for confounders, with a hazard ratio (HR) of 1.20 (95% CI 1.11, 1.30) per 59.48 µmol/L (1 mg/dL) uric acid. The genetic score raised uric acid by 17 µmol/L (95% CI 15, 18) per SD increase and explained 4% of uric acid variation. By using the genetic score to estimate the unconfounded effect, we found that a 59.48 µmol/L higher uric acid concentration did not have a causal effect on diabetes (HR 1.01 [95% CI 0.87, 1.16]). Including data from the Diabetes Genetics Replication And Meta-analysis (DIAGRAM) consortium, increasing our dataset to 41,508 case subjects with diabetes, the summary odds ratio estimate was 0.99 (95% CI 0.92, 1.06). In conclusion, our study does not support a causal effect of circulating uric acid on diabetes risk. Uric acid-lowering therapies may therefore not be beneficial in reducing diabetes risk.

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U2 - 10.2337/db14-0742

DO - 10.2337/db14-0742

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AN - SCOPUS:84943357645

SN - 0012-1797

VL - 64

SP - 3028

EP - 3036

JO - Diabetes

JF - Diabetes

IS - 8

ER -

A Mendelian Randomization Study of Circulating Uric Acid and Type 2 Diabetes

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