Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans

JE Huffman; E Albrecht; A Teumer; M Mangino; K Kapur; T Johnson; Z Kutalik; N Pirastu; G Pistis; LM Lopez; T Haller; P Salo; A Goel; M Li; T Tanaka; Abbas Dehghan; D Ruggiero; G Malerba; AV Smith; IM (Ilja) Nolte; L Portas; A Phipps-Green; L Boteva; P Navarro; A Johansson; AA Hicks; O Polasek; T Esko; JF Peden; SE Harris; F Murgia; SH Wild; A Tenesa; A Tin; E Mihailov; A Grotevendt; GK Gislason; J Coresh; P d'Adamo; S Ulivi; P Vollenweider; G Waeber; S Campbell; I Kolcic; K Fisher; M Viigimaa; JE Metter; C Masciullo; E Trabetti; C Bombieri; R Sorice; A Doring; E Reischl; K Strauch; Bert Hofman; André Uitterlinden; M Waldenberger; HE Wichmann; G Davies; AJ Gow; N Dalbeth; L Stamp; JH Smit; M Kirin; R Nagaraja; M Nauck; C Schurmann; K Budde; SM Farrington; E Theodoratou; A Jula; V Salomaa; C Sala; C Hengstenberg; M Burnier; R Magi; N Klopp; S Kloiber; S Schipf; S Ripatti; S Cabras; N Soranzo; G Homuth; T Nutile; PB Munroe; N Hastie; H Campbell; I Rudan; C Cabrera; C Haley; OH Franco Duran; TR Merriman; V Gudnason; M Pirastu; BW Penninx; H Snieder; A Metspalu; M Ciullo; PP Pramstaller; Cornelia Duijn; L Ferrucci; G Gambaro; IJ Deary; MG Dunlop; JF Wilson; P Gasparini; U Gyllensten; TD Spector; AF Wright; C Hayward; H Watkins; M Perola; M Bochud; WHL Kao; M Caulfield; D Toniolo; H Volzke; C Gieger; A Kottgen; V Vitart

doi:10.1371/journal.pone.0119752

Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans

JE Huffman, E Albrecht, A Teumer, M Mangino, K Kapur, T Johnson, Z Kutalik, N Pirastu, G Pistis, LM Lopez, T Haller, P Salo, A Goel, M Li, T Tanaka, Abbas Dehghan, D Ruggiero, G Malerba, AV Smith, IM (Ilja) NolteL Portas, A Phipps-Green, L Boteva, P Navarro, A Johansson, AA Hicks, O Polasek, T Esko, JF Peden, SE Harris, F Murgia, SH Wild, A Tenesa, A Tin, E Mihailov, A Grotevendt, GK Gislason, J Coresh, P d'Adamo, S Ulivi, P Vollenweider, G Waeber, S Campbell, I Kolcic, K Fisher, M Viigimaa, JE Metter, C Masciullo, E Trabetti, C Bombieri, R Sorice, A Doring, E Reischl, K Strauch, Bert Hofman, André Uitterlinden, M Waldenberger, HE Wichmann, G Davies, AJ Gow, N Dalbeth, L Stamp, JH Smit, M Kirin, R Nagaraja, M Nauck, C Schurmann, K Budde, SM Farrington, E Theodoratou, A Jula, V Salomaa, C Sala, C Hengstenberg, M Burnier, R Magi, N Klopp, S Kloiber, S Schipf, S Ripatti, S Cabras, N Soranzo, G Homuth, T Nutile, PB Munroe, N Hastie, H Campbell, I Rudan, C Cabrera, C Haley, OH Franco Duran, TR Merriman, V Gudnason, M Pirastu, BW Penninx, H Snieder, A Metspalu, M Ciullo, PP Pramstaller, Cornelia Duijn, L Ferrucci, G Gambaro, IJ Deary, MG Dunlop, JF Wilson, P Gasparini, U Gyllensten, TD Spector, AF Wright, C Hayward, H Watkins, M Perola, M Bochud, WHL Kao, M Caulfield, D Toniolo, H Volzke, C Gieger, A Kottgen, V Vitart

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

38 Citations (Scopus)

10 Downloads (Pure)

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, P-inter= 2.6 x 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 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	Undefined/Unknown
Journal	PLoS One (print)
Volume	10
Issue number	3
DOIs	https://doi.org/10.1371/journal.pone.0119752
Publication status	Published - 2015

Research programs

EMC MM-01-39-09-A
EMC NIHES-01-64-01

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1371/journal.pone.0119752

85.pdfFinal published version, 504 KB

http://hdl.handle.net/1765/78922

Cite this

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., ... Vitart, V. (2015). Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans. PLoS One (print), 10(3). https://doi.org/10.1371/journal.pone.0119752

@article{844f3ecdcb1f41fa952d6bc0052a70f5,

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, P-inter= 2.6 x 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 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 = "JE Huffman and E Albrecht and A Teumer and M Mangino and K Kapur and T Johnson and Z Kutalik and N Pirastu and G Pistis and LM Lopez and T Haller and P Salo and A Goel and M Li and T Tanaka and Abbas Dehghan and D Ruggiero and G Malerba and AV Smith and Nolte, {IM (Ilja)} and L Portas and A Phipps-Green and L Boteva and P Navarro and A Johansson and AA Hicks and O Polasek and T Esko and JF Peden and SE Harris and F Murgia and SH Wild and A Tenesa and A Tin and E Mihailov and A Grotevendt and GK Gislason and J Coresh and P d'Adamo and S Ulivi and P Vollenweider and G Waeber and S Campbell and I Kolcic and K Fisher and M Viigimaa and JE Metter and C Masciullo and E Trabetti and C Bombieri and R Sorice and A Doring and E Reischl and K Strauch and Bert Hofman and Andr{\'e} Uitterlinden and M Waldenberger and HE Wichmann and G Davies and AJ Gow and N Dalbeth and L Stamp and JH Smit and M Kirin and R Nagaraja and M Nauck and C Schurmann and K Budde and SM Farrington and E Theodoratou and A Jula and V Salomaa and C Sala and C Hengstenberg and M Burnier and R Magi and N Klopp and S Kloiber and S Schipf and S Ripatti and S Cabras and N Soranzo and G Homuth and T Nutile and PB Munroe and N Hastie and H Campbell and I Rudan and C Cabrera and C Haley and {Franco Duran}, OH and TR Merriman and V Gudnason and M Pirastu and BW Penninx and H Snieder and A Metspalu and M Ciullo and PP Pramstaller and Cornelia Duijn and L Ferrucci and G Gambaro and IJ Deary and MG Dunlop and JF Wilson and P Gasparini and U Gyllensten and TD Spector and AF Wright and C Hayward and H Watkins and M Perola and M Bochud and WHL Kao and M Caulfield and D Toniolo and H Volzke and C Gieger and A Kottgen and V Vitart",

year = "2015",

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

language = "Undefined/Unknown",

volume = "10",

journal = "PLoS One (print)",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "3",

}

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, Doring, A, Reischl, E, Strauch, K, Hofman, B , Uitterlinden, A, 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, Magi, 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 Duran, OH, Merriman, TR, Gudnason, V, Pirastu, M, Penninx, BW, Snieder, H, Metspalu, A, Ciullo, M, Pramstaller, PP, Duijn, C, 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, Volzke, H, Gieger, C, Kottgen, A & Vitart, V 2015, 'Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans', PLoS One (print), vol. 10, no. 3. 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, JE

AU - Albrecht, E

AU - Teumer, A

AU - Mangino, M

AU - Kapur, K

AU - Johnson, T

AU - Kutalik, Z

AU - Pirastu, N

AU - Pistis, G

AU - Lopez, LM

AU - Haller, T

AU - Salo, P

AU - Goel, A

AU - Li, M

AU - Tanaka, T

AU - Dehghan, Abbas

AU - Ruggiero, D

AU - Malerba, G

AU - Smith, AV

AU - Nolte, IM (Ilja)

AU - Portas, L

AU - Phipps-Green, A

AU - Boteva, L

AU - Navarro, P

AU - Johansson, A

AU - Hicks, AA

AU - Polasek, O

AU - Esko, T

AU - Peden, JF

AU - Harris, SE

AU - Murgia, F

AU - Wild, SH

AU - Tenesa, A

AU - Tin, A

AU - Mihailov, E

AU - Grotevendt, A

AU - Gislason, GK

AU - Coresh, J

AU - d'Adamo, P

AU - Ulivi, S

AU - Vollenweider, P

AU - Waeber, G

AU - Campbell, S

AU - Kolcic, I

AU - Fisher, K

AU - Viigimaa, M

AU - Metter, JE

AU - Masciullo, C

AU - Trabetti, E

AU - Bombieri, C

AU - Sorice, R

AU - Doring, A

AU - Reischl, E

AU - Strauch, K

AU - Hofman, Bert

AU - Uitterlinden, André

AU - Waldenberger, M

AU - Wichmann, HE

AU - Davies, G

AU - Gow, AJ

AU - Dalbeth, N

AU - Stamp, L

AU - Smit, JH

AU - Kirin, M

AU - Nagaraja, R

AU - Nauck, M

AU - Schurmann, C

AU - Budde, K

AU - Farrington, SM

AU - Theodoratou, E

AU - Jula, A

AU - Salomaa, V

AU - Sala, C

AU - Hengstenberg, C

AU - Burnier, M

AU - Magi, R

AU - Klopp, N

AU - Kloiber, S

AU - Schipf, S

AU - Ripatti, S

AU - Cabras, S

AU - Soranzo, N

AU - Homuth, G

AU - Nutile, T

AU - Munroe, PB

AU - Hastie, N

AU - Campbell, H

AU - Rudan, I

AU - Cabrera, C

AU - Haley, C

AU - Franco Duran, OH

AU - Merriman, TR

AU - Gudnason, V

AU - Pirastu, M

AU - Penninx, BW

AU - Snieder, H

AU - Metspalu, A

AU - Ciullo, M

AU - Pramstaller, PP

AU - Duijn, Cornelia

AU - Ferrucci, L

AU - Gambaro, G

AU - Deary, IJ

AU - Dunlop, MG

AU - Wilson, JF

AU - Gasparini, P

AU - Gyllensten, U

AU - Spector, TD

AU - Wright, AF

AU - Hayward, C

AU - Watkins, H

AU - Perola, M

AU - Bochud, M

AU - Kao, WHL

AU - Caulfield, M

AU - Toniolo, D

AU - Volzke, H

AU - Gieger, C

AU - Kottgen, A

AU - Vitart, V

PY - 2015

Y1 - 2015

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, P-inter= 2.6 x 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 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, P-inter= 2.6 x 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 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 (print)

JF - PLoS One (print)

IS - 3

ER -