Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients
Year: 2020
Type: review
Study design: Observational Study
Abstract: Objectives Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000–3000 years. Methods Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. Results In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10–8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients’ gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. Conclusions Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.
Source: Annals of the Rheumatic Diseases
Authors: Akiyoshi Nakayama, Masahiro Nakatochi, Yusuke Kawamura, Ken Yamamoto, Hirofumi Nakaoka, Seiko Shimizu, Toshihide Higashino, Teruhide Koyama, Asahi Hishida, Kiyonori Kuriki, Miki Watanabe, Toru Shimizu, Keiko Ooyama, Hiroshi Ooyama, Mitsuo Nagase, Yuji Hidaka, Daisuke Matsui, Takashi Tamura, Takeshi Nishiyama, Chisato Shimanoe, Sakurako Katsuura-Kamano, Naoyuki Takashima, Yuya Shirai, Makoto Kawaguchi, Mikiya Takao, Ryo Sugiyama, Yuzo Takada, Takahiro Nakamura, Hiroshi Nakashima, Masashi Tsunoda, Inaho Danjoh, Atsushi Hozawa, Kazuyoshi Hosomichi, Yu Toyoda, Yu Kubota, Tappei Takada, Hiroshi Suzuki, Blanka Stiburkova, Tanya J. Major, Tony R. Merriman, Nagato Kuriyama, Haruo Mikami, Toshiro Takezaki, Keitaro Matsuo, Sadao Suzuki, Tatsuo Hosoya, Yoichiro Kamatani, Michiaki Kubo, Kimiyoshi Ichida, Kenji Wakai, Ituro Inoue, Yukinori Okada, Nariyoshi Shinomiya, Hirotaka Matsuo
Institutions: Japan Air Self-Defense Force, National Defense Medical College, Nagoya University, National Defense Medical College Hospital, Kurume University, Kurume University Medical Center, National Institute of Genetics, Hokkaido University, Kyoto Prefectural University of Medicine, Shizuoka University, University of Shizuoka, Nagoya City University, Midorigaoka Hospital, Kyoto Industrial Health Association, Nagase (Japan), Saga University, Tokushima University, Shiga University of Medical Science, Kindai University, The University of Osaka, Teikyo University of Science, Tohoku Medical Megabank Organization, Tohoku University, Kanazawa University, University of Tokyo Hospital, Charles University, Institute of Rheumatology, General University Hospital in Prague, University of Otago, Chiba Cancer Center Research Institute, Kagoshima University, Aichi Cancer Center, Aichi Cancer Center Research Institute, Jikei University School of Medicine, Kyoto University, RIKEN Center for Integrative Medical Sciences, Center for Genomic Medicine, Graduate School of Medicine, Kyoto University, Tokyo University of Pharmacy and Life Sciences, Immunology Frontier Research Center, The University of Osaka
Language: English
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,870
Awards: G1358082575, Identification of genetic susceptibility to urate-related diseases which is characteristic to Japanese and exploration of its preventive method through molecular genetic-epidemiological analyses, Advantage of cohort study with integrated HLA information for personalized medicine, G232248983, G258026860, G2628512519, Studies searching for functional food components to control novel SUA regulators, G3179304541, Platform for Advanced Genome Science, Study on supports for molecular cohort studies, Practical application to preventive medicine by molecular epidemiological analyses on gout using international consortium framework from Japan, Comprehensive research of life style and genetic and epigenetic impact on type 2 diabetes mellitus, G4512404885, International collaboration on the research of novel urate transporters by leveraging genetic differences between the Japanese and the Czech, Elucidation of the whole picture of JR blood type by molecular genetic epidemiological analysis and its application for personalized prevention of gout, G5328517287, Molecular and epidemiological research on gout and hyperuricemia from Japan: heading toward novel genome-personalized prevention and medicine, Development of new small molecules for Met stimulator and building up foundations of medical application, G6430561316, G6488519364, Investigation of pathophysiology of gout by molecular genetic epidemiological analysis and application to genome-tailored medicine, G724245799, Platform of Supporting Cohort Study and Biospecimen Analysis, Association between lifestyle and disease risk: Mendelian randomization studies in a genome cohort
OpenAlex ID: W3014147239