OBJECTIVE: Uric acid is the primary end product of purine metabolism. Increased serum uric acid levels have been associated with gouty arthritis as well as with a variety of cardiovascular-related phenotypes. This study was undertaken to investigate associations between uric acid levels and single-nucleotide polymorphisms (SNPs). METHODS: A 500,000-SNP genome-wide association study of serum uric acid levels was performed in a cohort of Old Order Amish from Lancaster County, Pennsylvania. RESULTS: The scan confirmed a previously identified region on chromosome 4 to be strongly associated with uric acid levels (P = 4.2 x 10(-11) for rs10489070). Followup genotyping revealed that a nonsynonymous coding SNP (Val253Ile; rs16890979) in GLUT9 was most strongly associated with uric acid levels, with each copy of the minor allele associated with a decrease of 0.47 mg/dl in the uric acid level (95% confidence interval 0.31-0.63 [P = 1.43 x 10(-11)]). The effect of this variant tended to be stronger in women than in men (P = 0.16 for sex-genotype interaction). The genotype effect was not modified by the inclusion of several cardiovascular risk factors, suggesting that GLUT9 is directly related to uric acid homeostasis. The SNP identified in the genome-wide scan in the Amish population (rs10489070) was also significantly associated with gout in the Framingham Heart Study (P = 0.004). CONCLUSION: Our findings indicate that GLUT9, which is expressed in the kidney, may be a novel regulator of uric acid elimination and that a common nonsynonymous variant in this gene contributes to abnormalities in uric acid homeostasis and gout.
OBJECTIVE:Uric acid is the primary end product of purine metabolism. Increased serum uric acid levels have been associated with gouty arthritis as well as with a variety of cardiovascular-related phenotypes. This study was undertaken to investigate associations between uric acid levels and single-nucleotide polymorphisms (SNPs). METHODS: A 500,000-SNP genome-wide association study of serum uric acid levels was performed in a cohort of Old Order Amish from Lancaster County, Pennsylvania. RESULTS: The scan confirmed a previously identified region on chromosome 4 to be strongly associated with uric acid levels (P = 4.2 x 10(-11) for rs10489070). Followup genotyping revealed that a nonsynonymous coding SNP (Val253Ile; rs16890979) in GLUT9 was most strongly associated with uric acid levels, with each copy of the minor allele associated with a decrease of 0.47 mg/dl in the uric acid level (95% confidence interval 0.31-0.63 [P = 1.43 x 10(-11)]). The effect of this variant tended to be stronger in women than in men (P = 0.16 for sex-genotype interaction). The genotype effect was not modified by the inclusion of several cardiovascular risk factors, suggesting that GLUT9 is directly related to uric acid homeostasis. The SNP identified in the genome-wide scan in the Amish population (rs10489070) was also significantly associated with gout in the Framingham Heart Study (P = 0.004). CONCLUSION: Our findings indicate that GLUT9, which is expressed in the kidney, may be a novel regulator of uric acid elimination and that a common nonsynonymous variant in this gene contributes to abnormalities in uric acid homeostasis and gout.
Authors: Braxton D Mitchell; Patrick F McArdle; Haiqing Shen; Evadnie Rampersaud; Toni I Pollin; Lawrence F Bielak; Cashell Jaquish; Julie A Douglas; Marie-Hélène Roy-Gagnon; Paul Sack; Rosalie Naglieri; Scott Hines; Richard B Horenstein; Yen-Pei C Chang; Wendy Post; Kathleen A Ryan; Nga Hong Brereton; Ruth E Pakyz; John Sorkin; Coleen M Damcott; Jeffrey R O'Connell; Charles Mangano; Mary Corretti; Robert Vogel; William Herzog; Matthew R Weir; Patricia A Peyser; Alan R Shuldiner Journal: Am Heart J Date: 2008-03-05 Impact factor: 4.749
Authors: Ana M Valdes; Megan L Wolfe; Eamonn J O'Brien; Nigel K Spurr; Warren Gefter; Andrew Rut; Pieter H E Groot; Daniel J Rader Journal: Arterioscler Thromb Vasc Biol Date: 2002-11-01 Impact factor: 8.311
Authors: Robert Augustin; Mary O Carayannopoulos; Lia O Dowd; John E Phay; Jeffrey F Moley; Kelle H Moley Journal: J Biol Chem Date: 2004-01-22 Impact factor: 5.157
Authors: Mark Caulfield; Patricia Munroe; Janine Pembroke; Nilesh Samani; Anna Dominiczak; Morris Brown; Nigel Benjamin; John Webster; Peter Ratcliffe; Suzanne O'Shea; Jeanette Papp; Elizabeth Taylor; Richard Dobson; Joanne Knight; Stephen Newhouse; Joel Hooper; Wai Lee; Nick Brain; David Clayton; G Mark Lathrop; Martin Farrall; John Connell Journal: Lancet Date: 2003-06-21 Impact factor: 79.321
Authors: Chris Wallace; Stephen J Newhouse; Peter Braund; Feng Zhang; Martin Tobin; Mario Falchi; Kourosh Ahmadi; Richard J Dobson; Ana Carolina B Marçano; Cother Hajat; Paul Burton; Panagiotis Deloukas; Morris Brown; John M Connell; Anna Dominiczak; G Mark Lathrop; John Webster; Martin Farrall; Tim Spector; Nilesh J Samani; Mark J Caulfield; Patricia B Munroe Journal: Am J Hum Genet Date: 2008-01 Impact factor: 11.025
Authors: Andrew D Rule; Mariza de Andrade; Martha Matsumoto; Tom H Mosley; Sharon Kardia; Stephen T Turner Journal: Rheumatology (Oxford) Date: 2010-12-24 Impact factor: 7.580
Authors: Jessica Becker; Jens R Wendland; Britta Haenisch; Markus M Nöthen; Johannes Schumacher Journal: Eur J Hum Genet Date: 2011-08-17 Impact factor: 4.246
Authors: Afshin Parsa; Eric Brown; Matthew R Weir; Jeffrey C Fink; Alan R Shuldiner; Braxton D Mitchell; Patrick F McArdle Journal: Kidney Int Date: 2011-12-21 Impact factor: 10.612
Authors: Guanjie Chen; Daniel Shriner; Ayo P Doumatey; Jie Zhou; Amy R Bentley; Lin Lei; Adebowale Adeyemo; Charles N Rotimi Journal: Hum Mol Genet Date: 2020-02-01 Impact factor: 6.150