1. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes
- Author
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Nakayama, A., Nakaoka, H., Yamamoto, K., Sakiyama, M., Shaukat, A., Toyoda, Y., Okada, Y., Kamatani, Y., Nakamura, T., Takada, T., Inoue, K., Yasujima, T., Yuasa, H., Shirahama, Y., Nakashima, H., Shimizu, S., Higashino, T., Kawamura, Y., Ogata, H., Kawaguchi, M., Ohkawa, Y., Danjoh, I., Tokumasu, A., Ooyama, K., Ito, T., Kondo, T., Wakai, K., Stiburkova, B., Pavelka, K., Stamp, L.K., Dalbeth, N., Sakurai, Y., Suzuki, H, Hosoyamada, M., Fujimori, S., Yokoo, T., Hosoya, T., Inoue, I., Takahashi, A., Kubo, M., Ooyama, H., Shimizu, T., Ichida, K., Shinomiya, N., Merriman, T.R., Matsuo, H., Andres, M, Joosten, L.A., Janssen, M.C.H., Jansen, T.L., Liote, F., Radstake, T.R., Riches, P.L., So, A., and Tauches, A.K.
- Subjects
0301 basic medicine ,Male ,Native Hawaiian or Other Pacific Islander ,Gout ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Organic Anion Transporters ,Genome-wide association study ,Cell Cycle Proteins ,Urate transport ,Histones ,chemistry.chemical_compound ,0302 clinical medicine ,Japan ,Immunology and Allergy ,Medicine ,Cation Transport Proteins ,Genetics ,biology ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Middle Aged ,DNA-Binding Proteins ,SLC22A12 ,Sodium-Phosphate Cotransporter Proteins, Type I ,musculoskeletal diseases ,Adult ,congenital, hereditary, and neonatal diseases and abnormalities ,Genotype ,Organic Cation Transport Proteins ,Immunology ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,White People ,03 medical and health sciences ,Rheumatology ,Asian People ,Gene Polymorphism ,Humans ,Genetic Predisposition to Disease ,Aged ,030203 arthritis & rheumatology ,business.industry ,Arthritis ,Case-control study ,nutritional and metabolic diseases ,Proteins ,Clinical and Epidemiological Research ,medicine.disease ,030104 developmental biology ,chemistry ,Genetic Loci ,Case-Control Studies ,biology.protein ,Uric acid ,Gene polymorphism ,business ,Genome-Wide Association Study - Abstract
ObjectiveA genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific.MethodsPutative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study.ResultsIn addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (pā8): urate transporter genes (SLC22A12andSLC17A1) andHIST1H2BF-HIST1H4Efor all gout cases, andNIPAL1andFAM35Afor the renal underexcretion gout subtype. WhileNIPAL1encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, andFAM35Awas associated with gout in all cases. A meta-analysis of the three populations revealedFAM35Ato be associated with gout at a genome-wide level of significance (pmeta=3.58×10ā8).ConclusionsOur findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.
- Published
- 2016