Modulation of genetic associations with serum urate levels by body-mass-index in humans

Jennifer E Huffman; Eva Albrecht; Alexander Teumer; Massimo Mangino; Karen Kapur; Toby Johnson; Zoltán Kutalik; Nicola Pirastu; Giorgio Pistis; Lorna M Lopez; Toomas Haller; Perttu Salo; Anuj Goel; Man Li; Toshiko Tanaka; Abbas Dehghan; Daniela Ruggiero; Giovanni Malerba; Albert V Smith; Ilja M Nolte; Laura Portas; Amanda Phipps-Green; Lora Boteva; Pau Navarro; Asa Johansson; Andrew A Hicks; Ozren Polasek; Tõnu Esko; John F Peden; Sarah E Harris; Federico Murgia; Sarah H Wild; Albert Tenesa; Adrienne Tin; Evelin Mihailov; Anne Grotevendt; Gauti K Gislason; Josef Coresh; Pio D'Adamo; Sheila Ulivi; Peter Vollenweider; Gerard Waeber; Susan Campbell; Ivana Kolcic; Krista Fisher; Margus Viigimaa; Jeffrey E Metter; Corrado Masciullo; Elisabetta Trabetti; Cristina Bombieri; Rossella Sorice; Angela Döring; Eva Reischl; Konstantin Strauch; Albert Hofman; Andre G Uitterlinden; Melanie Waldenberger; H-Erich Wichmann; Gail Davies; Alan J Gow; Nicola Dalbeth; Lisa Stamp; Johannes H Smit; Mirna Kirin; Ramaiah Nagaraja; Matthias Nauck; Claudia Schurmann; Kathrin Budde; Susan M Farrington; Evropi Theodoratou; Antti Jula; Veikko Salomaa; Cinzia Sala; Christian Hengstenberg; Michel Burnier; Reedik Mägi; Norman Klopp; Stefan Kloiber; Sabine Schipf; Samuli Ripatti; Stefano Cabras; Nicole Soranzo; Georg Homuth; Teresa Nutile; Patricia B Munroe; Nicholas Hastie; Harry Campbell; Igor Rudan; Claudia Cabrera; Chris Haley; Oscar H Franco; Tony R Merriman; Vilmundur Gudnason; Mario Pirastu; Brenda W Penninx; Harold Snieder; Andres Metspalu; Marina Ciullo; Peter P Pramstaller; Cornelia M van Duijn; Luigi Ferrucci; Giovanni Gambaro; Ian J Deary; Malcolm G Dunlop; James F Wilson; Paolo Gasparini; Ulf Gyllensten; Tim D Spector; Alan F Wright; Caroline Hayward; Hugh Watkins; Markus Perola; Murielle Bochud; W H Linda Kao; Mark Caulfield; Daniela Toniolo; Henry Völzke; Christian Gieger; Anna Köttgen; Veronique Vitart

doi:10.1371/journal.pone.0119752

Modulation of genetic associations with serum urate levels by body-mass-index in humans

Jennifer E Huffman, Eva Albrecht, Alexander Teumer, Massimo Mangino, Karen Kapur, Toby Johnson, Zoltán Kutalik, Nicola Pirastu, Giorgio Pistis, Lorna M Lopez, Toomas Haller, Perttu Salo, Anuj Goel, Man Li, Toshiko Tanaka, Abbas Dehghan, Daniela Ruggiero, Giovanni Malerba, Albert V Smith, Ilja M NolteLaura Portas, Amanda Phipps-Green, Lora Boteva, Pau Navarro, Asa Johansson, Andrew A Hicks, Ozren Polasek, Tõnu Esko, John F Peden, Sarah E Harris, Federico Murgia, Sarah H Wild, Albert Tenesa, Adrienne Tin, Evelin Mihailov, Anne Grotevendt, Gauti K Gislason, Josef Coresh, Pio D'Adamo, Sheila Ulivi, Peter Vollenweider, Gerard Waeber, Susan Campbell, Ivana Kolcic, Krista Fisher, Margus Viigimaa, Jeffrey E Metter, Corrado Masciullo, Elisabetta Trabetti, Cristina Bombieri, Rossella Sorice, Angela Döring, Eva Reischl, Konstantin Strauch, Albert Hofman, Andre G Uitterlinden, Melanie Waldenberger, H-Erich Wichmann, Gail Davies, Alan J Gow, Nicola Dalbeth, Lisa Stamp, Johannes H Smit, Mirna Kirin, Ramaiah Nagaraja, Matthias Nauck, Claudia Schurmann, Kathrin Budde, Susan M Farrington, Evropi Theodoratou, Antti Jula, Veikko Salomaa, Cinzia Sala, Christian Hengstenberg, Michel Burnier, Reedik Mägi, Norman Klopp, Stefan Kloiber, Sabine Schipf, Samuli Ripatti, Stefano Cabras, Nicole Soranzo, Georg Homuth, Teresa Nutile, Patricia B Munroe, Nicholas Hastie, Harry Campbell, Igor Rudan, Claudia Cabrera, Chris Haley, Oscar H Franco, Tony R Merriman, Vilmundur Gudnason, Mario Pirastu, Brenda W Penninx, Harold Snieder, Andres Metspalu, Marina Ciullo, Peter P Pramstaller, Cornelia M van Duijn, Luigi Ferrucci, Giovanni Gambaro, Ian J Deary, Malcolm G Dunlop, James F Wilson, Paolo Gasparini, Ulf Gyllensten, Tim D Spector, Alan F Wright, Caroline Hayward, Hugh Watkins, Markus Perola, Murielle Bochud, W H Linda Kao, Mark Caulfield, Daniela Toniolo, Henry Völzke, Christian Gieger, Anna Köttgen, Veronique Vitart

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

Abstract / Description of output

We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

Original language	English
Article number	e0119752
Journal	PLoS ONE
Volume	10
Issue number	3
DOIs	https://doi.org/10.1371/journal.pone.0119752
Publication status	Published - 26 Mar 2015

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10.1371/journal.pone.0119752

journal.pone.0119752Final published version, 504 KB

RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.
Deary, I., Gale, C., Holmes, M., Logie, P., Maclullich, A., Porteous, D., Seckl, J., Starr, J., Wardlaw, J. & Okely, J.
1/09/13 → 31/08/19
Project: Research
Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.
Maclullich, A.
1/09/13 → 31/08/19
Project: Research
Disconnected Mind [Phase 2]
Wardlaw, J.
UK-based charities
1/01/11 → 31/03/16
Project: Research

Cite this

Huffman, J. E., Albrecht, E., Teumer, A., Mangino, M., Kapur, K., Johnson, T., Kutalik, Z., Pirastu, N., Pistis, G., Lopez, L. M., Haller, T., Salo, P., Goel, A., Li, M., Tanaka, T., Dehghan, A., Ruggiero, D., Malerba, G., Smith, A. V., ... Vitart, V. (2015). Modulation of genetic associations with serum urate levels by body-mass-index in humans. PLoS ONE, 10(3), Article e0119752. https://doi.org/10.1371/journal.pone.0119752

@article{3477e61ab5bc44fa9b849f2dea8ccd7b,

title = "Modulation of genetic associations with serum urate levels by body-mass-index in humans",

abstract = "We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.",

author = "Huffman, {Jennifer E} and Eva Albrecht and Alexander Teumer and Massimo Mangino and Karen Kapur and Toby Johnson and Zolt{\'a}n Kutalik and Nicola Pirastu and Giorgio Pistis and Lopez, {Lorna M} and Toomas Haller and Perttu Salo and Anuj Goel and Man Li and Toshiko Tanaka and Abbas Dehghan and Daniela Ruggiero and Giovanni Malerba and Smith, {Albert V} and Nolte, {Ilja M} and Laura Portas and Amanda Phipps-Green and Lora Boteva and Pau Navarro and Asa Johansson and Hicks, {Andrew A} and Ozren Polasek and T{\~o}nu Esko and Peden, {John F} and Harris, {Sarah E} and Federico Murgia and Wild, {Sarah H} and Albert Tenesa and Adrienne Tin and Evelin Mihailov and Anne Grotevendt and Gislason, {Gauti K} and Josef Coresh and Pio D'Adamo and Sheila Ulivi and Peter Vollenweider and Gerard Waeber and Susan Campbell and Ivana Kolcic and Krista Fisher and Margus Viigimaa and Metter, {Jeffrey E} and Corrado Masciullo and Elisabetta Trabetti and Cristina Bombieri and Rossella Sorice and Angela D{\"o}ring and Eva Reischl and Konstantin Strauch and Albert Hofman and Uitterlinden, {Andre G} and Melanie Waldenberger and H-Erich Wichmann and Gail Davies and Gow, {Alan J} and Nicola Dalbeth and Lisa Stamp and Smit, {Johannes H} and Mirna Kirin and Ramaiah Nagaraja and Matthias Nauck and Claudia Schurmann and Kathrin Budde and Farrington, {Susan M} and Evropi Theodoratou and Antti Jula and Veikko Salomaa and Cinzia Sala and Christian Hengstenberg and Michel Burnier and Reedik M{\"a}gi and Norman Klopp and Stefan Kloiber and Sabine Schipf and Samuli Ripatti and Stefano Cabras and Nicole Soranzo and Georg Homuth and Teresa Nutile and Munroe, {Patricia B} and Nicholas Hastie and Harry Campbell and Igor Rudan and Claudia Cabrera and Chris Haley and Franco, {Oscar H} and Merriman, {Tony R} and Vilmundur Gudnason and Mario Pirastu and Penninx, {Brenda W} and Harold Snieder and Andres Metspalu and Marina Ciullo and Pramstaller, {Peter P} and {van Duijn}, {Cornelia M} and Luigi Ferrucci and Giovanni Gambaro and Deary, {Ian J} and Dunlop, {Malcolm G} and Wilson, {James F} and Paolo Gasparini and Ulf Gyllensten and Spector, {Tim D} and Wright, {Alan F} and Caroline Hayward and Hugh Watkins and Markus Perola and Murielle Bochud and Kao, {W H Linda} and Mark Caulfield and Daniela Toniolo and Henry V{\"o}lzke and Christian Gieger and Anna K{\"o}ttgen and Veronique Vitart",

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doi = "10.1371/journal.pone.0119752",

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Huffman, JE, Albrecht, E, Teumer, A, Mangino, M, Kapur, K, Johnson, T, Kutalik, Z, Pirastu, N, Pistis, G, Lopez, LM, Haller, T, Salo, P, Goel, A, Li, M, Tanaka, T, Dehghan, A, Ruggiero, D, Malerba, G, Smith, AV, Nolte, IM, Portas, L, Phipps-Green, A, Boteva, L, Navarro, P, Johansson, A, Hicks, AA, Polasek, O, Esko, T, Peden, JF, Harris, SE, Murgia, F, Wild, SH , Tenesa, A, Tin, A, Mihailov, E, Grotevendt, A, Gislason, GK, Coresh, J, D'Adamo, P, Ulivi, S, Vollenweider, P, Waeber, G, Campbell, S, Kolcic, I, Fisher, K, Viigimaa, M, Metter, JE, Masciullo, C, Trabetti, E, Bombieri, C, Sorice, R, Döring, A, Reischl, E, Strauch, K, Hofman, A, Uitterlinden, AG, Waldenberger, M, Wichmann, H-E, Davies, G, Gow, AJ, Dalbeth, N, Stamp, L, Smit, JH, Kirin, M, Nagaraja, R, Nauck, M, Schurmann, C, Budde, K, Farrington, SM , Theodoratou, E, Jula, A, Salomaa, V, Sala, C, Hengstenberg, C, Burnier, M, Mägi, R, Klopp, N, Kloiber, S, Schipf, S, Ripatti, S, Cabras, S, Soranzo, N, Homuth, G, Nutile, T, Munroe, PB, Hastie, N, Campbell, H , Rudan, I, Cabrera, C, Haley, C, Franco, OH, Merriman, TR, Gudnason, V, Pirastu, M, Penninx, BW, Snieder, H, Metspalu, A, Ciullo, M, Pramstaller, PP, van Duijn, CM, Ferrucci, L, Gambaro, G, Deary, IJ , Dunlop, MG , Wilson, JF, Gasparini, P, Gyllensten, U, Spector, TD, Wright, AF, Hayward, C, Watkins, H, Perola, M, Bochud, M, Kao, WHL, Caulfield, M, Toniolo, D, Völzke, H, Gieger, C, Köttgen, A & Vitart, V 2015, 'Modulation of genetic associations with serum urate levels by body-mass-index in humans', PLoS ONE, vol. 10, no. 3, e0119752. https://doi.org/10.1371/journal.pone.0119752

TY - JOUR

T1 - Modulation of genetic associations with serum urate levels by body-mass-index in humans

AU - Huffman, Jennifer E

AU - Albrecht, Eva

AU - Teumer, Alexander

AU - Mangino, Massimo

AU - Kapur, Karen

AU - Johnson, Toby

AU - Kutalik, Zoltán

AU - Pirastu, Nicola

AU - Pistis, Giorgio

AU - Lopez, Lorna M

AU - Haller, Toomas

AU - Salo, Perttu

AU - Goel, Anuj

AU - Li, Man

AU - Tanaka, Toshiko

AU - Dehghan, Abbas

AU - Ruggiero, Daniela

AU - Malerba, Giovanni

AU - Smith, Albert V

AU - Nolte, Ilja M

AU - Portas, Laura

AU - Phipps-Green, Amanda

AU - Boteva, Lora

AU - Navarro, Pau

AU - Johansson, Asa

AU - Hicks, Andrew A

AU - Polasek, Ozren

AU - Esko, Tõnu

AU - Peden, John F

AU - Harris, Sarah E

AU - Murgia, Federico

AU - Wild, Sarah H

AU - Tenesa, Albert

AU - Tin, Adrienne

AU - Mihailov, Evelin

AU - Grotevendt, Anne

AU - Gislason, Gauti K

AU - Coresh, Josef

AU - D'Adamo, Pio

AU - Ulivi, Sheila

AU - Vollenweider, Peter

AU - Waeber, Gerard

AU - Campbell, Susan

AU - Kolcic, Ivana

AU - Fisher, Krista

AU - Viigimaa, Margus

AU - Metter, Jeffrey E

AU - Masciullo, Corrado

AU - Trabetti, Elisabetta

AU - Bombieri, Cristina

AU - Sorice, Rossella

AU - Döring, Angela

AU - Reischl, Eva

AU - Strauch, Konstantin

AU - Hofman, Albert

AU - Uitterlinden, Andre G

AU - Waldenberger, Melanie

AU - Wichmann, H-Erich

AU - Davies, Gail

AU - Gow, Alan J

AU - Dalbeth, Nicola

AU - Stamp, Lisa

AU - Smit, Johannes H

AU - Kirin, Mirna

AU - Nagaraja, Ramaiah

AU - Nauck, Matthias

AU - Schurmann, Claudia

AU - Budde, Kathrin

AU - Farrington, Susan M

AU - Theodoratou, Evropi

AU - Jula, Antti

AU - Salomaa, Veikko

AU - Sala, Cinzia

AU - Hengstenberg, Christian

AU - Burnier, Michel

AU - Mägi, Reedik

AU - Klopp, Norman

AU - Kloiber, Stefan

AU - Schipf, Sabine

AU - Ripatti, Samuli

AU - Cabras, Stefano

AU - Soranzo, Nicole

AU - Homuth, Georg

AU - Nutile, Teresa

AU - Munroe, Patricia B

AU - Hastie, Nicholas

AU - Campbell, Harry

AU - Rudan, Igor

AU - Cabrera, Claudia

AU - Haley, Chris

AU - Franco, Oscar H

AU - Merriman, Tony R

AU - Gudnason, Vilmundur

AU - Pirastu, Mario

AU - Penninx, Brenda W

AU - Snieder, Harold

AU - Metspalu, Andres

AU - Ciullo, Marina

AU - Pramstaller, Peter P

AU - van Duijn, Cornelia M

AU - Ferrucci, Luigi

AU - Gambaro, Giovanni

AU - Deary, Ian J

AU - Dunlop, Malcolm G

AU - Wilson, James F

AU - Gasparini, Paolo

AU - Gyllensten, Ulf

AU - Spector, Tim D

AU - Wright, Alan F

AU - Hayward, Caroline

AU - Watkins, Hugh

AU - Perola, Markus

AU - Bochud, Murielle

AU - Kao, W H Linda

AU - Caulfield, Mark

AU - Toniolo, Daniela

AU - Völzke, Henry

AU - Gieger, Christian

AU - Köttgen, Anna

AU - Vitart, Veronique

PY - 2015/3/26

Y1 - 2015/3/26

N2 - We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

AB - We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.

U2 - 10.1371/journal.pone.0119752

DO - 10.1371/journal.pone.0119752

M3 - Article

C2 - 25811787

SN - 1932-6203

VL - 10

JO - PLoS ONE

JF - PLoS ONE

IS - 3

M1 - e0119752

ER -

Modulation of genetic associations with serum urate levels by body-mass-index in humans

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RA2661 Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2. Main Budget.

Centre for Cognitive Ageing and Cognitive Epidemiology Phase 2.

Disconnected Mind [Phase 2]

Cite this