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 & 100 others 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, 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 journalArticle

16 Citations (Scopus)

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 × 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDAR-ADD, 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 × 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight = 9.1 × 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 (P difflean-obese= 2 × 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 obsogenic environment.

Original languageEnglish (US)
Article numbere0119752
JournalPloS one
Volume10
Issue number3
DOIs
StatePublished - Mar 26 2015

Fingerprint

Uric Acid
body mass index
Body Mass Index
Modulation
loci
Serum
Genes
Genome
genome
Gout
Genome-Wide Association Study
Biosynthesis
Adipocytes
gout
Single Nucleotide Polymorphism
Polysaccharides
Estradiol
Obesity
Regression Analysis
Association reactions

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Huffman, J. E., Albrecht, E., Teumer, A., Mangino, M., Kapur, K., Johnson, T., ... Vitart, V. (2015). Modulation of genetic associations with serum urate levels by body-mass-index in humans. PloS one, 10(3), [e0119752]. https://doi.org/10.1371/journal.pone.0119752

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

In: PloS one, Vol. 10, No. 3, e0119752, 26.03.2015.

Research output: Contribution to journalArticle

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, E, Masciullo, C, Trabetti, E, Bombieri, C, Sorice, R, Döring, A, Reischl, E, Strauch, K, Hofman, A, Uitterlinden, AG, Waldenberger, M, Wichmann, HE, 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, Linda Kao, WH, 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
Huffman JE, Albrecht E, Teumer A, Mangino M, Kapur K, Johnson T et al. Modulation of genetic associations with serum urate levels by body-mass-index in humans. PloS one. 2015 Mar 26;10(3). e0119752. https://doi.org/10.1371/journal.pone.0119752
Huffman, Jennifer E. ; Albrecht, Eva ; Teumer, Alexander ; Mangino, Massimo ; Kapur, Karen ; Johnson, Toby ; Kutalik, Zoltán ; Pirastu, Nicola ; Pistis, Giorgio ; Lopez, Lorna M. ; Haller, Toomas ; Salo, Perttu ; Goel, Anuj ; Li, Man ; Tanaka, Toshiko ; Dehghan, Abbas ; Ruggiero, Daniela ; Malerba, Giovanni ; Smith, Albert V. ; Nolte, Ilja M. ; Portas, Laura ; Phipps-Green, Amanda ; Boteva, Lora ; Navarro, Pau ; Johansson, Asa ; Hicks, Andrew A. ; Polasek, Ozren ; Esko, Tõnu ; Peden, John F. ; Harris, Sarah E. ; Murgia, Federico ; Wild, Sarah H. ; Tenesa, Albert ; Tin, Adrienne ; Mihailov, Evelin ; Grotevendt, Anne ; Gislason, Gauti K. ; Coresh, Josef ; D'Adamo, Pio ; Ulivi, Sheila ; Vollenweider, Peter ; Waeber, Gerard ; Campbell, Susan ; Kolcic, Ivana ; Fisher, Krista ; Viigimaa, Margus ; Metter, E. ; Masciullo, Corrado ; Trabetti, Elisabetta ; Bombieri, Cristina ; Sorice, Rossella ; Döring, Angela ; Reischl, Eva ; Strauch, Konstantin ; Hofman, Albert ; Uitterlinden, Andre G. ; Waldenberger, Melanie ; Wichmann, H. Erich ; Davies, Gail ; Gow, Alan J. ; Dalbeth, Nicola ; Stamp, Lisa ; Smit, Johannes H. ; Kirin, Mirna ; Nagaraja, Ramaiah ; Nauck, Matthias ; Schurmann, Claudia ; Budde, Kathrin ; Farrington, Susan M. ; Theodoratou, Evropi ; Jula, Antti ; Salomaa, Veikko ; Sala, Cinzia ; Hengstenberg, Christian ; Burnier, Michel ; Mägi, Reedik ; Klopp, Norman ; Kloiber, Stefan ; Schipf, Sabine ; Ripatti, Samuli ; Cabras, Stefano ; Soranzo, Nicole ; Homuth, Georg ; Nutile, Teresa ; Munroe, Patricia B. ; Hastie, Nicholas ; Campbell, Harry ; Rudan, Igor ; Cabrera, Claudia ; Haley, Chris ; Franco, Oscar H. ; Merriman, Tony R. ; Gudnason, Vilmundur ; Pirastu, Mario ; Penninx, Brenda W. ; Snieder, Harold ; Metspalu, Andres ; Ciullo, Marina ; Pramstaller, Peter P. ; Van Duijn, Cornelia M. ; Ferrucci, Luigi ; Gambaro, Giovanni ; Deary, Ian J. ; Dunlop, Malcolm G. ; Wilson, James F. ; Gasparini, Paolo ; Gyllensten, Ulf ; Spector, Tim D. ; Wright, Alan F. ; Hayward, Caroline ; Watkins, Hugh ; Perola, Markus ; Bochud, Murielle ; Linda Kao, W. H. ; Caulfield, Mark ; Toniolo, Daniela ; Völzke, Henry ; Gieger, Christian ; Köttgen, Anna ; Vitart, Veronique. / Modulation of genetic associations with serum urate levels by body-mass-index in humans. In: PloS one. 2015 ; Vol. 10, No. 3.
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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 × 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDAR-ADD, 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 × 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight = 9.1 × 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 (P difflean-obese= 2 × 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 obsogenic environment.",
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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, 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 - Linda Kao, W. H.

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 × 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDAR-ADD, 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 × 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight = 9.1 × 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 (P difflean-obese= 2 × 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 obsogenic 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 × 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDAR-ADD, 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 × 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight = 9.1 × 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 (P difflean-obese= 2 × 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 obsogenic environment.

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