Human Cell

, Volume 26, Issue 4, pp 133–136 | Cite as

A common missense variant of monocarboxylate transporter 9 (MCT9/SLC16A9) gene is associated with renal overload gout, but not with all gout susceptibility

  • Akiyoshi Nakayama
  • Hirotaka MatsuoEmail author
  • Takuya Shimizu
  • Hiraku Ogata
  • Yuzo Takada
  • Hiroshi Nakashima
  • Takahiro Nakamura
  • Seiko Shimizu
  • Toshinori Chiba
  • Masayuki Sakiyama
  • Chisaki Ushiyama
  • Tappei Takada
  • Katsuhisa Inoue
  • Sayo Kawai
  • Asahi Hishida
  • Kenji Wakai
  • Nobuyuki Hamajima
  • Kimiyoshi Ichida
  • Yutaka Sakurai
  • Yukio Kato
  • Toru Shimizu
  • Nariyoshi Shinomiya
Open Access
Rapid Communication


Gout is a common disease caused by hyperuricemia, which shows elevated serum uric acid (SUA) levels. From a viewpoint of urate handling in humans, gout patients can be divided into those with renal overload (ROL) gout with intestinal urate underexcretion, and those with renal underexcretion (RUE) gout. Recent genome-wide association studies (GWAS) revealed an association between SUA and a variant in human monocarboxylate transporter 9 (MCT9/SLC16A9) gene. Although the function of MCT9 remains unclear, urate is mostly excreted via intestine and kidney where MCT9 expression is observed. In this study, we investigated the relationship between a variant of MCT9 and gout in 545 patients and 1,115 healthy volunteers. A missense variant of MCT9 (K258T), rs2242206, significantly increased the risk of ROL gout (p = 0.012), with odds ratio (OR) of 1.28, although it revealed no significant association with all gout cases (p = 0.10), non-ROL gout cases (p = 0.83), and RUE gout cases (p = 0.34). In any case groups and the control group, minor allele frequencies of rs2242206 were >0.40. Therefore, rs2242206 is a common missense variant and is revealed to have an association with ROL gout, indicating that rs2242206 relates to decreased intestinal urate excretion rather than decreased renal urate excretion. Our study provides clues to better understand the pathophysiology of gout as well as the physiological roles of MCT9.


Gouty arthritis Single nucleotide polymorphism (SNP) Gut urate excretion Carnitine Solute carrier (SLC) family transporter 


Gout, known for its painful arthritis, is a common disease and a consequence of hyperuricemia [1], which shows elevated serum uric acid (SUA) levels. Generally, patients can be divided into those with renal overload (ROL) gout and those with renal underexcretion (RUE) gout [2], according to their pathophysiological mechanisms of urate handling. A recent meta-analysis of genome-wide association studies (GWAS) [3] and its replication study [4] revealed that human monocarboxylate transporter 9 (MCT9/SLC16A9) has a relationship with SUA variation. Although the function of MCT9 is not known, it is a member of the solute-carrier (SLC) transporter that is expressed in several urate-excreting organs, including intestine and kidney. In this study, we investigated the effects of an MCT9 variant on the susceptibility to gout in patients and healthy volunteers.

Materials and methods

Patients and clinical parameters for urate handling

All procedures were carried out in accordance with the standards of the institutional ethical committees involved in this project and the Declaration of Helsinki, and with written informed consent of each study participant. We collected information on 545 male gout cases from outpatients of gout clinics in Midorigaoka Hospital (Osaka, Japan). All of them were clinically diagnosed with primary gout according to criteria established by the American College of Rheumatology [5]. As a control group, information on 1,115 male individuals with normal SUA (≤7.0 mg/dl) and with no history of gout was collected from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study [6]. Mean age with standard deviation (SD) of case and control groups was 54.2 ± 13.4 and 52.6 ± 8.3 years, respectively, and mean body mass index (BMI) was 24.8 ± 3.6 and 23.2 ± 2.8 kg/m2, respectively. Gout patients with high (>25 mg/h/1.73 m2) urinary urate excretion (UUE) [2, 7, 8, 9] were defined as having ROL gout; those with low (≤25 mg/h/1.73 m2) UUE were described as having non-ROL gout. Cases represented as RUE gout were characterized by low (<5.5 %) fractional excretion of uric acid (FEUA) [2, 10] on the basis of the normal FEUA range (5.5–11.1 %) [11], as previously described. Among all 545 gout cases, urate handling data, such as UUE and FEUA, were available in 463 cases, and the numbers of ROL gout, non-ROL gout, and RUE gout were 257, 206, and 273 patients, respectively.

Genetic and statistical analyses

Genomic DNA was extracted from whole peripheral blood cells [12]. Genotyping of rs2242206, a common missense variant of MCT9/SLC16A9, gene was performed by TaqMan Assay-By-Design method (Applied Biosystems) with a LightCycler 480 (Roche Diagnostics) [13, 14]. To confirm genotypes, direct sequencing was performed with the following primers: forward, 5′-AGTGTCTGAGCTGCAAATTC-3′ and reverse 5′-CAAAAGAAATCTGCATGGAAC-3′. DNA sequencing analysis was performed with a 3130×l Genetic Analyzer (Applied Biosystems) [15]. For all calculations in the statistical analysis, SPSS v.17.0J (IBM Japan Inc., Tokyo, Japan) was used; χ 2 test was used for association analysis.


Table 1 shows result of genotyping for rs2242206 in 545 gout patients and 1,115 healthy controls. The call rate for rs2242206 was 99.9 %. Its p value for Hardy–Weinberg equilibrium was 0.79, which suggested mistyping was not obtained. As shown in Table 1, all minor allele frequencies (MAFs) of rs2242206 were >0.40 for all gout cases, ROL cases, non-ROL cases, and the control group, indicating this single nucleotide polymorphism (SNP) was very common in both case and control groups. Rs2242206 significantly increased the susceptibility to ROL gout cases (p = 0.012), with the odds ratio (OR) of 1.28, although it revealed no significant association with all gout cases (p = 0.10), non-ROL gout cases (p = 0.83), and RUE gout cases (p = 0.34).
Table 1

Association analysis of rs2242206, a common missense variant of MCT9 gene, for gout patients



Allele frequency mode





p value


95 % CI

Case groups

 All gout








 ROL gout








 Non-ROL gout








Control group





CI confidence interval, MAF minor allele frequency, OR odds ratio, ROL renal overload


This study shows that rs2242206, a common missense variant in MCT9 gene, is associated with ROL gout but not with overall gout susceptibility. As rs2242206 (in exon 5 of MCT9) is close to rs12356193 (in intron 5), rs2242206 is sometimes used as a substitute for rs12356193, in which a genome-wide association with SUA was demonstrated [16, 17]. In addition, minor alleles of rs12356193 was not detected for Japanese individuals in HapMap data, and rs2242206 is a missense variant of MCT9 (K258T), which is a possible dysfunctional mutation. We therefore investigated the relationship between MCT9 and Japanese gout cases using rs2242206.

A previous study of a small sample (92 participants) by Polašek et al. [16] revealed no relationship between MCT9 rs2242206 and SUA. Although our results show that rs2242206 has no association with overall gout susceptibility, rs2242206 significantly increased the risk of ROL gout. In humans, one third of urate is excreted from the intestine and most of the rest via the kidney. We previously reported that ROL is caused by decreased intestinal urate excretion due to urate transporter ABCG2 dysfunction [2]. As our study presented here shows that rs2242206 increases the risk of ROL gout but not of RUE gout, the minor allele of rs2242206 should decrease intestinal urate excretion. Our study therefore suggests that MCT9 might have a role in intestinal urate excretion: it is possible that it transports urate, but there is no report that MCT9 is a urate transporter in humans as far as we know. On the other hand, Kolz et al. [3] reported a strong triangular association among rs12356193 in MCT9, SUA levels, and metabolites (DL-carnitine and propionyl-l-carnitine), implying that MCT9 indirectly affects extra-renal urate excretion, for instance, by transporting carnitine-related compounds. Whereas further genetic and functional study of human MCT9 is necessary, our study suggests that it has a possible physiological role in urate excretion from human intestinal epithelial cells.



The authors thank all patients and volunteers involved in this study. We also thank J. Abe, K. Gotanda, Y. Morimoto, N. Katsuta, Y. Utsumi, S. Terashige and H. Inoue, National Defense Medical College, Tokorozawa, Japan, and T. Sugiura, Kanazawa University, Kanazawa, Japan for genetic analysis and helpful discussion. This study was supported by grants from the Ministry of Education, Science, and Culture of Japan, the Ministry of Health, Labor and Welfare of Japan, the Ministry of Defense of Japan, the Japan Society for the Promotion of Science, the Kawano Masanori Memorial Foundation for Promotion of Pediatrics, the AstraZeneca VRI Research Grant, the Takeda Science Foundation, and the Gout Research Foundation of Japan.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359(17):1811–21.PubMedCrossRefGoogle Scholar
  2. 2.
    Ichida K, Matsuo H, Takada T, Nakayama A, Murakami K, Shimizu T, et al. Decreased extra-renal urate excretion is a common cause of hyperuricemia. Nat Commun. 2012;3:764.PubMedCrossRefGoogle Scholar
  3. 3.
    Kolz M, Johnson T, Sanna S, Teumer A, Vitart V, Perola M, et al. Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genet. 2009;5(6):e1000504.PubMedCrossRefGoogle Scholar
  4. 4.
    van der Harst P, Bakker SJ, de Boer RA, Wolffenbuttel BH, Johnson T, Caulfield MJ, et al. Replication of the five novel loci for uric acid concentrations and potential mediating mechanisms. Hum Mol Genet. 2010;19(2):387–95.PubMedCrossRefGoogle Scholar
  5. 5.
    Wallace SL, Robinson H, Masi AT, Decker JL, McCarty DJ, Yu TF. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum. 1977;20(3):895–900.PubMedCrossRefGoogle Scholar
  6. 6.
    Hamajima N, J-MICC Study Group. The Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study) to detect gene-environment interactions for cancer. Asian Pac J Cancer Prev. 2007;8(2):317–23.PubMedGoogle Scholar
  7. 7.
    Becker MA. Hyperuricemia and gout. In: Scriver CR, Childs B, Kinzler KW, Vogelstein B, editors. The metabolic & molecular bases of inherited disease. 8th ed. New York: McGraw-Hill; 2001. p. 2513–35.Google Scholar
  8. 8.
    Wortmann RL. Gout and hyperuricemia. Curr Opin Rheumatol. 2002;14(3):281–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Wortmann RL. Disorders of purine and pyrimidine metabolism. In: Fauci AS, Braunwald E, Kasper D, Hauser SL, Long DL, Jameson JL, et al, editors. Harrison’s Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. p. 2444–9.Google Scholar
  10. 10.
    Urano W, Taniguchi A, Anzai N, Inoue E, Kanai Y, Yamanaka M, et al. Sodium-dependent phosphate cotransporter type 1 sequence polymorphisms in male patients with gout. Ann Rheum Dis. 2010;69(6):1232–4.PubMedCrossRefGoogle Scholar
  11. 11.
    The guideline revising committee of Japanese Society of Gout and Nucleic Acid Metabolism. Diagnosis of hyperuricemia and gout. In: The guideline revising committee of Japanese Society of Gout and Nucleic Acid Metabolism, editor. Guideline for the management of hyperuricemia and gout. 2nd ed. Osaka: Medical Review; 2010. p. 60–72.Google Scholar
  12. 12.
    Matsuo H, Chiba T, Nagamori S, Nakayama A, Domoto H, Phetdee K, et al. Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. Am J Hum Genet. 2008;83(6):744–51.PubMedCrossRefGoogle Scholar
  13. 13.
    Margraf RL, Mao R, Wittwer CT. Rapid diagnosis of MEN2B using unlabeled probe melting analysis and the LightCycler 480 instrument. J Mol Diagn. 2008;10(2):123–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Matsuo H, Takada T, Ichida K, Nakamura T, Nakayama A, Ikebuchi Y, et al. Common defects of ABCG2, a high-capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population. Sci Transl Med. 2009;1(5):5ra11.PubMedCrossRefGoogle Scholar
  15. 15.
    Matsuo H, Ichida K, Takada T, Nakayama A, Nakashima H, Nakamura T, et al. Common dysfunctional variants in ABCG2 are a major cause of early-onset gout. Sci Rep. 2013;3:2014.PubMedCrossRefGoogle Scholar
  16. 16.
    Polašek O, Jerončić I, Mulić R, Klišmanić Z, Pehlić M, Zemunik T, et al. Common variants in SLC17A3 gene affect intra-personal variation in serum uric acid levels in longitudinal time series. Croat Med J. 2010;51(1):32–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Gunjača G, Boban M, Pehlić M, Zemunik T, Budimir D, Kolčić I, et al. Predictive value of 8 genetic loci for serum uric acid concentration. Croat Med J. 2010;51(1):23–31.PubMedCrossRefGoogle Scholar

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© The Author(s) 2013

Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

Authors and Affiliations

  • Akiyoshi Nakayama
    • 1
    • 2
  • Hirotaka Matsuo
    • 1
    Email author
  • Takuya Shimizu
    • 3
  • Hiraku Ogata
    • 1
  • Yuzo Takada
    • 4
  • Hiroshi Nakashima
    • 5
  • Takahiro Nakamura
    • 6
  • Seiko Shimizu
    • 1
  • Toshinori Chiba
    • 1
  • Masayuki Sakiyama
    • 1
  • Chisaki Ushiyama
    • 7
  • Tappei Takada
    • 8
  • Katsuhisa Inoue
    • 9
  • Sayo Kawai
    • 10
  • Asahi Hishida
    • 11
  • Kenji Wakai
    • 10
  • Nobuyuki Hamajima
    • 11
  • Kimiyoshi Ichida
    • 12
  • Yutaka Sakurai
    • 5
  • Yukio Kato
    • 3
  • Toru Shimizu
    • 13
  • Nariyoshi Shinomiya
    • 1
  1. 1.Department of Integrative Physiology and Bio-Nano MedicineNational Defense Medical CollegeTokorozawaJapan
  2. 2.Medical Group, Headquarters, Iwo-to Air Base GroupJapan Air Self-Defense ForceOgasawaraJapan
  3. 3.Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan
  4. 4.Laboratory for BiofunctionsThe Central Research Institute, National Defense Medical CollegeTokorozawaJapan
  5. 5.Department of Preventive Medicine and Public HealthNational Defense Medical CollegeTokorozawaJapan
  6. 6.Laboratory for MathematicsNational Defense Medical CollegeTokorozawaJapan
  7. 7.Department of Biology, Faculty of ScienceToho UniversityFunabashiJapan
  8. 8.Department of Pharmacy, Faculty of Medicine, The University of Tokyo HospitalThe University of TokyoTokyoJapan
  9. 9.Department of Biopharmaceutics, School of PharmacyTokyo University of Pharmacy and Life SciencesTokyoJapan
  10. 10.Department of Preventive MedicineNagoya University Graduate School of MedicineNagoyaJapan
  11. 11.Department of Healthcare AdministrationNagoya University Graduate School of MedicineNagoyaJapan
  12. 12.Department of PathophysiologyTokyo University of Pharmacy and Life SciencesTokyoJapan
  13. 13.Midorigaoka HospitalTakatsukiJapan

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