A Mendelian randomization study of circulating uric acid and type 2 diabetes

Ivonne Sluijs; Michael V Holmes; Yvonne T van der Schouw; Joline Wj 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 Tee Khaw; Tilman Kühn; Esther Molina-Montes; Lotte Maxild 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 Mw Spijkerman; Anne Tjonneland; Ruth C Travis Dphil; Rosario Tumino; Daphne L van der A; Stephen J Sharp; Nita G Forouhi; Claudia Langenberg; Elio Riboli; Nicholas J Wareham; InterAct consortium

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 Wj 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 Tee Khaw, Tilman Kühn, Esther Molina-Montes, Lotte Maxild 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 Mw Spijkerman, Anne Tjonneland, Ruth C Travis Dphil, Rosario Tumino, Daphne L van der A, Stephen J Sharp, Nita G Forouhi, Claudia Langenberg, Elio Riboli, Nicholas J Wareham, InterAct consortium

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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 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 type 2 diabetes cases were ascertained. Higher uric acid associated with higher diabetes risk following adjustment for confounders, with a 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. Using the genetic score to estimate the unconfounded effect 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 DIAGRAM consortium, increasing our dataset to 41,508 diabetes cases, the summary OR 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
Journal	Diabetes
Volume	64
Issue number	8
Pages (from-to)	3028-3036
Number of pages	9
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db14-0742
Publication status	Published - 2015

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Sluijs, I., Holmes, M. V., van der Schouw, Y. T., Beulens, J. W., 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., Kühn, T., Molina-Montes, E., ... InterAct consortium (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{4d83d6869acf4345b7b26e4324b9b1c9,

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 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 type 2 diabetes cases were ascertained. Higher uric acid associated with higher diabetes risk following adjustment for confounders, with a 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. Using the genetic score to estimate the unconfounded effect 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 DIAGRAM consortium, increasing our dataset to 41,508 diabetes cases, the summary OR 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 Wj} 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 Tee} and Tilman K{\"u}hn and Esther Molina-Montes and Mortensen, {Lotte Maxild} 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 Mw} and Anne Tjonneland and {Travis Dphil}, {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} and {InterAct consortium}",

note = "{\textcopyright} 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.",

year = "2015",

doi = "10.2337/db14-0742",

language = "English",

volume = "64",

pages = "3028--3036",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "8",

}

Sluijs, I, Holmes, MV, van der Schouw, YT, Beulens, JW, 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, KT, Kühn, T, Molina-Montes, E, Mortensen, LM, 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, AM, Tjonneland, A, Travis Dphil, RC, Tumino, R, van der A, DL, Sharp, SJ, Forouhi, NG, Langenberg, C, Riboli, E, Wareham, NJ & InterAct consortium 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 Wj

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 Tee

AU - Kühn, Tilman

AU - Molina-Montes, Esther

AU - Mortensen, Lotte Maxild

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 Mw

AU - Tjonneland, Anne

AU - Travis Dphil, 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

AU - InterAct consortium

PY - 2015

Y1 - 2015

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 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 type 2 diabetes cases were ascertained. Higher uric acid associated with higher diabetes risk following adjustment for confounders, with a 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. Using the genetic score to estimate the unconfounded effect 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 DIAGRAM consortium, increasing our dataset to 41,508 diabetes cases, the summary OR 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 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 type 2 diabetes cases were ascertained. Higher uric acid associated with higher diabetes risk following adjustment for confounders, with a 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. Using the genetic score to estimate the unconfounded effect 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 DIAGRAM consortium, increasing our dataset to 41,508 diabetes cases, the summary OR 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.

U2 - 10.2337/db14-0742

DO - 10.2337/db14-0742

M3 - Journal article

C2 - 25918230

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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