Common dysfunctional variants of ABCG2 have stronger impact on hyperuricemia progression than typical environmental risk factors

doi:10.1038/srep05227

. 2014 Jun 9:4:5227.

doi: 10.1038/srep05227.

Common dysfunctional variants of ABCG2 have stronger impact on hyperuricemia progression than typical environmental risk factors

Akiyoshi Nakayama¹, Hirotaka Matsuo², Hirofumi Nakaoka³, Takahiro Nakamura⁴, Hiroshi Nakashima⁵, Yuzo Takada⁶, Yuji Oikawa⁷, Tappei Takada⁸, Masayuki Sakiyama⁹, Seiko Shimizu⁹, Yusuke Kawamura⁹, Toshinori Chiba⁹, Junko Abe⁹, Kenji Wakai¹⁰, Sayo Kawai¹⁰, Rieko Okada¹⁰, Takashi Tamura¹⁰, Yuka Shichijo⁹, Airi Akashi⁹, Hiroshi Suzuki⁸, Tatsuo Hosoya¹¹, Yutaka Sakurai⁵, Kimiyoshi Ichida¹², Nariyoshi Shinomiya⁹

Affiliations

¹ 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].
² 1] Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan [2].
³ Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-0801, Japan.
⁴ 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.
⁵ Department of Preventive Medicine and Public Health, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
⁶ The Central Research Institute, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
⁷ Department of Laboratory Medicine, Toho University Ohashi Medical Center, 2-17-6 Ohashi, Meguro-ku, Tokyo 153-8515, Japan.
⁸ 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.
⁹ Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
¹⁰ Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
¹¹ 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.
¹² 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.

PMID: 24909660
PMCID: PMC5381477
DOI: 10.1038/srep05227

Common dysfunctional variants of ABCG2 have stronger impact on hyperuricemia progression than typical environmental risk factors

Akiyoshi Nakayama et al. Sci Rep. 2014.

. 2014 Jun 9:4:5227.

doi: 10.1038/srep05227.

Authors

Affiliations

¹ 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].
² 1] Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan [2].
³ Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka 411-0801, Japan.
⁴ 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.
⁵ Department of Preventive Medicine and Public Health, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
⁶ The Central Research Institute, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
⁷ Department of Laboratory Medicine, Toho University Ohashi Medical Center, 2-17-6 Ohashi, Meguro-ku, Tokyo 153-8515, Japan.
⁸ 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.
⁹ Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
¹⁰ Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
¹¹ 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.
¹² 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.

PMID: 24909660
PMCID: PMC5381477
DOI: 10.1038/srep05227

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.

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Conflict of interest statement

There is potential competing interest: H.M., T.N., T. Takada, K.I. and N.S. have a patent pending based on the work reported in this paper. The other authors declare that they have no conflict of interest.

Figures

**Figure 1. Population-attributable risk percent (PAR%) of ABCG2 dysfunction for hyperuricemia in 5,005 participants.**
For the boxes, the red shaded area means PAR% of ABCG2 dysfunction; the width represents the frequency of ABCG2 dysfunction in the population, and the height shows the risk ratio.

**Figure 2. Serum uric acid (SUA) levels according to each ABCG2 function.**
All bars show mean ± s.e.m.

See this image and copyright information in PMC

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References

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1. Choi H. K., Atkinson K., Karlson E. W., Willett W. & Curhan G. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 363, 1277–1281 (2004). - PubMed

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[1] Rott K. T. & Agudelo C. A. Gout. JAMA 289, 2857–2860 (2003). - PubMed

[2] Rott K. T. & Agudelo C. A. Gout. JAMA 289, 2857–2860 (2003). - PubMed

[3] Wortmann R. L. in Harrison's Principles of Internal Medicine (eds Anthony, S. et al.) 2444–2449 (McGraw-Hill, 2008).

[4] Wortmann R. L. in Harrison's Principles of Internal Medicine (eds Anthony, S. et al.) 2444–2449 (McGraw-Hill, 2008).

[5] Adams F. & Society S. The Genuine Works of Hippocrates. (Sydenham Society, 1849).

[6] Adams F. & Society S. The Genuine Works of Hippocrates. (Sydenham Society, 1849).

[7] Williams P. T. Effects of diet, physical activity and performance, and body weight on incident gout in ostensibly healthy, vigorously active men. Am. J. Clin. Nutr. 87, 1480–1487 (2008). - PMC - PubMed

[8] Williams P. T. Effects of diet, physical activity and performance, and body weight on incident gout in ostensibly healthy, vigorously active men. Am. J. Clin. Nutr. 87, 1480–1487 (2008). - PMC - PubMed

[9] Choi H. K., Atkinson K., Karlson E. W., Willett W. & Curhan G. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 363, 1277–1281 (2004). - PubMed

[10] Choi H. K., Atkinson K., Karlson E. W., Willett W. & Curhan G. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 363, 1277–1281 (2004). - PubMed

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Common dysfunctional variants of ABCG2 have stronger impact on hyperuricemia progression than typical environmental risk factors

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Common dysfunctional variants of ABCG2 have stronger impact on hyperuricemia progression than typical environmental risk factors

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