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

J.E. Huffman; E. Albrecht; A. Teumer; M. Mangino; K. Kapur; T. Johnson; Z. Kutalik; N. Pirastu; G. Pistis; L.M. Lopez; T. Haller; P. Salo; A. Goel; M. Li; T. Tanaka; A. Dehghan; D. Ruggiero; G. Malerba; A.V. Smith; I.M. Nolte; L. Portas; A. Phipps-Green; L. Boteva; P. Navarro; A. Johansson; A.A. Hicks; O. Polasek; T. Esko; J.F. Peden; S. E. Harris; F. Murgia; S.H. Wild; A. Tenesa; A. Tin; E. Mihailov; A. Grotevendt; G.K. Gislason; J. Coresh; P. d'Adamo; S. Ulivi; P. Vollenweider; G. Waeber; S. Campbell; I. Kolcic; K. Fisher; M. Viigimaa; J.E. Metter; C. Masciullo; E. Trabetti; C. Bombieri; R. Sorice; A. Doring; E. Reischl; K. Strauch; A. Hofman; A. G. Uitterlinden; M. Waldenberger; H. E. Wichmann; G. Davies; A. J. Gow; N. Dalbeth; L. Stamp; J.H. Smit; M. Kirin; R. Nagaraja; M. Nauck; C. Schurmann; K. Budde; S.M. 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; P.B. Munroe; N. Hastie; H. Campbell; I. Rudan; C. Cabrera; C. Haley; O.H. Franco; T.R. Merriman; V. Gudnason; M. Pirastu; B.W. Penninx; H. Snieder; A. Metspalu; M. Ciullo; P.P. Pramstaller; A. Kottgen; V. Vitart

doi:https://doi.org/10.1371/journal.pone.0119752

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

J.E. Huffman, E. Albrecht, A. Teumer, M. Mangino, K. Kapur, T. Johnson, Z. Kutalik, N. Pirastu, G. Pistis, L.M. Lopez, T. Haller, P. Salo, A. Goel, M. Li, T. Tanaka, A. Dehghan, D. Ruggiero, G. Malerba, A.V. Smith, I.M. NolteL. Portas, A. Phipps-Green, L. Boteva, P. Navarro, A. Johansson, A.A. Hicks, O. Polasek, T. Esko, J.F. Peden, S. E. Harris, F. Murgia, S.H. Wild, A. Tenesa, A. Tin, E. Mihailov, A. Grotevendt, G.K. Gislason, J. Coresh, P. d'Adamo, S. Ulivi, P. Vollenweider, G. Waeber, S. Campbell, I. Kolcic, K. Fisher, M. Viigimaa, J.E. Metter, C. Masciullo, E. Trabetti, C. Bombieri, R. Sorice, A. Doring, E. Reischl, K. Strauch, A. Hofman, A. G. Uitterlinden, M. Waldenberger, H. E. Wichmann, G. Davies, A. J. Gow, N. Dalbeth, L. Stamp, J.H. Smit, M. Kirin, R. Nagaraja, M. Nauck, C. Schurmann, K. Budde, S.M. 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, P.B. Munroe, N. Hastie, H. Campbell, I. Rudan, C. Cabrera, C. Haley, O.H. Franco, T.R. Merriman, V. Gudnason, M. Pirastu, B.W. Penninx, H. Snieder, A. Metspalu, M. Ciullo, P.P. Pramstaller, A. Kottgen, V. Vitart

Psychiatry (VUmc)

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

34 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, P<inf>inter</inf>= 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, P<inf>difflean-overweight</inf>= 4.7 × 10^-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, P<inf>difflean-overweight</inf> = 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 <inf>difflean-obese</inf>= 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 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 - 2015

Access to Document

https://doi.org/10.1371/journal.pone.0119752

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{bd16e72dea61408097e9479e64d35dfa,

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 × 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.",

author = "J.E. 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 L.M. Lopez and T. Haller and P. Salo and A. Goel and M. Li and T. Tanaka and A. Dehghan and D. Ruggiero and G. Malerba and A.V. Smith and I.M. Nolte and L. Portas and A. Phipps-Green and L. Boteva and P. Navarro and A. Johansson and A.A. Hicks and O. Polasek and T. Esko and J.F. Peden and Harris, {S. E.} and F. Murgia and S.H. Wild and A. Tenesa and A. Tin and E. Mihailov and A. Grotevendt and G.K. 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 J.E. Metter and C. Masciullo and E. Trabetti and C. Bombieri and R. Sorice and A. Doring and E. Reischl and K. Strauch and A. Hofman and Uitterlinden, {A. G.} and M. Waldenberger and Wichmann, {H. E.} and G. Davies and Gow, {A. J.} and N. Dalbeth and L. Stamp and J.H. Smit and M. Kirin and R. Nagaraja and M. Nauck and C. Schurmann and K. Budde and S.M. 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 P.B. Munroe and N. Hastie and H. Campbell and I. Rudan and C. Cabrera and C. Haley and O.H. Franco and T.R. Merriman and V. Gudnason and M. Pirastu and B.W. Penninx and H. Snieder and A. Metspalu and M. Ciullo and P.P. Pramstaller and A. Kottgen and V. Vitart",

year = "2015",

doi = "https://doi.org/10.1371/journal.pone.0119752",

language = "English",

volume = "10",

journal = "PLOS ONE",

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, 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, 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, OH, Merriman, TR, Gudnason, V, Pirastu, M, Penninx, BW, Snieder, H, Metspalu, A, Ciullo, M, Pramstaller, PP, Kottgen, 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, J.E.

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, L.M.

AU - Haller, T.

AU - Salo, P.

AU - Goel, A.

AU - Li, M.

AU - Tanaka, T.

AU - Dehghan, A.

AU - Ruggiero, D.

AU - Malerba, G.

AU - Smith, A.V.

AU - Nolte, I.M.

AU - Portas, L.

AU - Phipps-Green, A.

AU - Boteva, L.

AU - Navarro, P.

AU - Johansson, A.

AU - Hicks, A.A.

AU - Polasek, O.

AU - Esko, T.

AU - Peden, J.F.

AU - Harris, S. E.

AU - Murgia, F.

AU - Wild, S.H.

AU - Tenesa, A.

AU - Tin, A.

AU - Mihailov, E.

AU - Grotevendt, A.

AU - Gislason, G.K.

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, J.E.

AU - Masciullo, C.

AU - Trabetti, E.

AU - Bombieri, C.

AU - Sorice, R.

AU - Doring, A.

AU - Reischl, E.

AU - Strauch, K.

AU - Hofman, A.

AU - Uitterlinden, A. G.

AU - Waldenberger, M.

AU - Wichmann, H. E.

AU - Davies, G.

AU - Gow, A. J.

AU - Dalbeth, N.

AU - Stamp, L.

AU - Smit, J.H.

AU - Kirin, M.

AU - Nagaraja, R.

AU - Nauck, M.

AU - Schurmann, C.

AU - Budde, K.

AU - Farrington, S.M.

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, P.B.

AU - Hastie, N.

AU - Campbell, H.

AU - Rudan, I.

AU - Cabrera, C.

AU - Haley, C.

AU - Franco, O.H.

AU - Merriman, T.R.

AU - Gudnason, V.

AU - Pirastu, M.

AU - Penninx, B.W.

AU - Snieder, H.

AU - Metspalu, A.

AU - Ciullo, M.

AU - Pramstaller, P.P.

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, 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.

U2 - https://doi.org/10.1371/journal.pone.0119752

DO - https://doi.org/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 -