title: Common dysfunctional variants of ABCG2 have stronger impact on hyperuricemia progression than typical environmental risk factors.
abstract: Gout/hyperuricemia is a common multifactorial disease having typical environmental risks. Recently, common dysfunctional variants of ABCG2, a urate exporter gene also known as BCRP, are revealed to be a major cause of gout/hyperuricemia. Here, we compared the influence of ABCG2 dysfunction on serum uric acid (SUA) levels with other typical risk factors in a cohort of 5,005 Japanese participants. ABCG2 dysfunction was observed in 53.3% of the population investigated, and its population-attributable risk percent (PAR%) for hyperuricemia was 29.2%, much higher than those of the other typical environmental risks, i.e. overweight/obesity (BMI ≥ 25.0; PAR% = 18.7%), heavy drinking (>196 g/week (male) or >98 g/week (female) of pure alcohol; PAR% = 15.4%), and aging (≥60 years old; PAR% = 5.74%). SUA significantly increased as the ABCG2 function decreased (P = 5.99 × 10(-19)). A regression analysis revealed that ABCG2 dysfunction had a stronger effect than other factors; a 25% decrease in ABCG2 function was equivalent to "an increase of BMI by 1.97-point" or "552.1 g/week alcohol intake as pure ethanol" in terms of ability to increase SUA. Therefore, ABCG2 dysfunction originating from common genetic variants has a much stronger impact on the progression of hyperuricemia than other familiar risks. Our study provides a better understanding of common genetic factors for common diseases.
authors.affiliation: 1] Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan [2] Medical Group, Headquarters, Iwo-to Air Base Group, Japan Air Self-Defense Force, Iwo-to, Ogasawara, Tokyo 100-2100, Japan [3].
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Nakayama
authors.affiliation: 1] Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan [2].
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Matsuo
authors.affiliation: Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-0801, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nakaoka
authors.affiliation: 1] Laboratory for Mathematics, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan [2] Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Core for Genomic Medicine, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Preventive Medicine and Public Health, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakashima
authors.affiliation: The Central Research Institute, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Takada
authors.affiliation: Department of Laboratory Medicine, Toho University Ohashi Medical Center, 2-17-6 Ohashi, Meguro-ku, Tokyo 153-8515, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Oikawa
authors.affiliation: Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Tappei
authors.initials: T
authors.lastname: Takada
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Sakiyama
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kawamura
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Chiba
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Abe
authors.affiliation: Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Wakai
authors.affiliation: Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Sayo
authors.initials: S
authors.lastname: Kawai
authors.affiliation: Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Rieko
authors.initials: R
authors.lastname: Okada
authors.affiliation: Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Shichijo
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Airi
authors.initials: A
authors.lastname: Akashi
authors.affiliation: Department of Pharmacy, The University of Tokyo Hospital, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: 1] Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, 3-19-18 Shinbashi, Minato-ku, Tokyo 105-8471, Japan [2] Department of Pathophysiology and Therapy in Chronic Kidney Disease, Jikei University School of Medicine, 3-19-18 Shinbashi, Minato-ku, Tokyo 105-8471, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Hosoya
authors.affiliation: Department of Preventive Medicine and Public Health, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sakurai
authors.affiliation: 1] Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, 3-19-18 Shinbashi, Minato-ku, Tokyo 105-8471, Japan [2] Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachiouji, Tokyo 192-0392, Japan.
authors.forename: Kimiyoshi
authors.initials: K
authors.lastname: Ichida
authors.affiliation: Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors.forename: Nariyoshi
authors.initials: N
authors.lastname: Shinomiya
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006073:Gout / Q000097:blood / Q000235:genetics; D006801:Humans; D033461:Hyperuricemia / Q000097:blood / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D012307:Risk Factors; D014527:Uric Acid / Q000097:blood
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D014527:Uric Acid