Advertisement

International Urology and Nephrology

, Volume 45, Issue 6, pp 1613–1620 | Cite as

MTHFR, MTR and MTRR polymorphisms and risk of chronic kidney disease in Japanese: cross-sectional data from the J-MICC Study

  • Asahi HishidaEmail author
  • Rieko Okada
  • Yin Guang
  • Mariko Naito
  • Kenji Wakai
  • Satoyo Hosono
  • Kazuyo Nakamura
  • Tanvir Chowdhury Turin
  • Sadao Suzuki
  • Hideshi Niimura
  • Haruo Mikami
  • Jun Otonari
  • Nagato Kuriyama
  • Sakurako Katsuura
  • Michiaki Kubo
  • Hideo Tanaka
  • Nobuyuki Hamajima
Nephrology - Original Paper

Abstract

Purpose

Chronic kidney disease (CKD) is well known as a strong risk factor for both of end-stage renal disease and cardiovascular disease. To clarify the associations of MTHFR, MTR, and MTRR polymorphisms with the risk of CKD in Japanese, we examined this association among Japanese subjects using cross-sectional data.

Methods

The subjects for this analysis were 3,318 participants consecutively selected from the Japan Multi-institutional Collaborative Cohort (J-MICC) Study. The polymorphisms were genotyped by a multiplex polymerase chain reaction-based Invader assay. Age- and sex-adjusted odds ratio (aOR) of CKD with stage 3–5 was calculated for each genotype.

Results

When those with MTHFR C677T C/C were defined as references, those with MTHFR C677T C/T and T/T demonstrated the aORs for CKD of 1.14 (95 % CI 0.93–1.40) and 1.39 (1.06–1.82), respectively. Marginally significantly decreased risk of CKD with increasing number of MTR A2756G G allele (p = 0.058) was observed. Stratified analyses by plasma folate low (<7.4 ng/ml) or high (≥7.4 ng/ml) suggested significantly higher OR of CKD for those with MTHFR C677T T/T and low serum folate with the aOR of 2.07 (95 % CI 1.30–3.31) compared with that for those with MTHFR C677T T/T and high serum folate.

Conclusions

The present study found a significant association between the subjects with the T/T genotype of MTHFR C677T polymorphism and the elevated risk of CKD, which may suggest the possibility of the risk evaluation and prevention of this potentially life-threatening disease based on genetic traits in the near future.

Keywords

Chronic kidney disease Folate metabolism MTHFR Polymorphism Renal insufficiency 

Notes

Acknowledgments

The authors wish to thank Mr. Kyota Ashikawa and Ms. Tomomi Aoi at the Laboratory of Genotyping Development, Center for Genomic Medicine, RIKEN, for genotyping. The authors also thank Ms. Yoko Mitsuda and Ms. Keiko Shibata at Daiko Medical Center, Nagoya University, for their technical assistance. This study was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas of Cancer (No. 17015018) and Scientific Support Programs for Cancer Research, and Grant-in-Aid for Scientific Research on Innovative Areas (No. 221S0001) from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

Conflict of interest

None.

References

  1. 1.
    Taal MW (2012) Chronic kidney disease 10 years on: what have we learned? Curr Opin Nephrol Hypertens 21:607–611PubMedCrossRefGoogle Scholar
  2. 2.
    Nagata M, Ninomiya T, Doi Y, Yonemoto K, Kubo M, Hata J, Tsuruya K, Kiyohara Y (2010) Trends in the prevalence of chronic kidney disease and its risk factors in a general Japanese population: the Hisayama Study. Nephrol Dial Transplant 25:2557–2564PubMedCrossRefGoogle Scholar
  3. 3.
    Matsuo S, Yasuda Y, Imai E, Horio M (2010) Current status of estimated glomerular filtration rate (eGFR) equations for Asians and an approach to create a common eGFR equation. Nephrology (Carlton) 15(Suppl 2):45–48CrossRefGoogle Scholar
  4. 4.
    Wattanakit K, Folsom AR, Selvin E, Coresh J, Hirsch AT, Weatherley BD (2007) Kidney function and risk of peripheral arterial disease: results from the Atherosclerosis Risk in Communities (ARIC) Study. J Am Soc Nephrol 18:629–636PubMedCrossRefGoogle Scholar
  5. 5.
    Swaminathan S, Shah SV (2011) Novel inflammatory mechanisms of accelerated atherosclerosis in kidney disease. Kidney Int 80:453–463PubMedCrossRefGoogle Scholar
  6. 6.
    Chade AR, Lerman A, Lerman LO (2005) Kidney in early atherosclerosis. Hypertension 45:1042–1049PubMedCrossRefGoogle Scholar
  7. 7.
    Tanaka T, Scheet P, Giusti B, Bandinelli S, Piras MG, Usala G, Lai S, Mulas A, Corsi AM, Vestrini A, Sofi F, Gori AM, Abbate R, Guralnik J, Singleton A, Abecasis GR, Schlessinger D, Uda M, Ferrucci L (2009) Genome-wide association study of vitamin B6, vitamin B12, folate, and homocysteine blood concentrations. Am J Hum Genet 84:477–482PubMedCrossRefGoogle Scholar
  8. 8.
    Montjean D, Benkhalifa M, Dessolle L, Cohen-Bacrie P, Belloc S, Siffroi JP, Ravel C, Bashamboo A, McElreavey K (2011) Polymorphisms in MTHFR and MTRR genes associated with blood plasma homocysteine concentration and sperm counts. Fertil Steril 95:635–640PubMedCrossRefGoogle Scholar
  9. 9.
    Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G (1999) Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA 96:12810–12815PubMedCrossRefGoogle Scholar
  10. 10.
    Dong Q, Tang G, He M, Cai Y, Cai Y, Xing H, Sun L, Li J, Zhang Y, Fan F, Wang B, Sun N, Liu L, Xu X, Hou F, Shen H, Xu X, Huo Y (2012) Methylenetetrahydrofolate reductase C677T polymorphism is associated with estimated glomerular filtration rate in hypertensive Chinese males. BMC Med Genet 13:74PubMedCrossRefGoogle Scholar
  11. 11.
    Hamajima N, J-MICC Study Group (2007) The Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study) to detect gene–environment interactions for cancer. Asian Pac J Cancer Prev 8:317–323PubMedGoogle Scholar
  12. 12.
    Wakai K, Hamajima N, Okada R, Naito M, Morita E, Hishida A, J-MICC Study Group et al (2010) Profile of participants and genotype distributions of 108 polymorphisms in a cross-sectional study to elucidate associations between genotypes and lifestyle and clinical factors: a project in the Japan Multi-institutional Collaborative Cohort (J-MICC) Study. J Epidemiol 21:223–235CrossRefGoogle Scholar
  13. 13.
    Tokudome Y, Goto C, Imaeda N, Hasegawa T, Kato R, Hirose K, Tajima K, Tokudome S (2005) Relative validity of a short food frequency questionnaire for assessing nutrient intake versus three-day weighed diet records in middle-aged Japanese. J Epidemiol 15:135–145PubMedCrossRefGoogle Scholar
  14. 14.
    Ohnishi Y, Tanaka T, Ozaki K, Yamada R, Suzuki H, Nakamura Y (2001) A high-throughput SNP typing system for genome-wide association studies. J Hum Genet 46:471–477PubMedCrossRefGoogle Scholar
  15. 15.
    Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A, Collaborators developing the Japanese equation for estimated GFR (2009) Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53:982–992PubMedCrossRefGoogle Scholar
  16. 16.
    Budtz-Jørgensen E, Keiding N, Grandjean P, Weihe P (2007) Confounder selection in environmental epidemiology: assessment of health effects of prenatal mercury exposure. Ann Epidemiol 17:27–35PubMedCrossRefGoogle Scholar
  17. 17.
    Ito T, Inoue E, Kamatani N (2004) Association test algorithm between a qualitative phenotype and a haplotype or haplotype set using simultaneous estimation of haplotype frequencies, diplotype configurations and diplotype-based penetrances. Genetics 168:2339–2348PubMedCrossRefGoogle Scholar
  18. 18.
    Okada R, Wakai K, Naito M, Morita E, Kawai S, Hamajima N, Hara M, Takashima N, Suzuki S, Takezaki T, Ohnaka K, Arisawa K, Hirohata H, Matsuo K, Mikami H, Kubo M, Tanaka H, Japan Multi-Institutional Collaborative Cohort (J-MICC) Study Group (2012) Pro-/anti-inflammatory cytokine gene polymorphisms and chronic kidney disease: a cross-sectional study. BMC Nephrol 13:2PubMedCrossRefGoogle Scholar
  19. 19.
    Kawamoto R, Kohara K, Oka Y, Tomita H, Tabara Y, Miki T (2005) An association of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and ischemic stroke. J Stroke Cerebrovasc Dis 14:67–74PubMedCrossRefGoogle Scholar
  20. 20.
    Engbersen AM, Franken DG, Boers GH, Stevens EM, Trijbels FJ, Blom HJ (1995) Thermolabile 5,10-methylenetetrahydrofolate reductase as a cause of mild hyperhomocysteinemia. Am J Hum Genet 56:142–150PubMedGoogle Scholar
  21. 21.
    Foster MC, Ghuman N, Hwang SJ, Murabito JM, Fox CS (2013) Low ankle-brachial index and the development of rapid estimated GFR decline and CKD. Am J Kidney Dis 61:204–210Google Scholar
  22. 22.
    Kim OJ, Hong SP, Ahn JY, Hong SH, Hwang TS, Kim SO, Yoo W, Oh D, Kim NK (2007) Influence of combined methionine synthase (MTR 2756 A>G) and methylenetetrahydrofolate Reductase (MTHFR 677 C>T) polymorphisms to plasma homocysteine levels in Korean patients with ischemic stroke. Yonsei Med J 48:201–209PubMedCrossRefGoogle Scholar
  23. 23.
    Feix A, Frische-Polanz R, Kletzmayr J, Vychytil A, Hori WH, Sunder-Plassmann G, Fodinger M (2001) Increased prevalence of combined MTR and MTHFR genotypes among individuals with severely elevated total homocysteine plasma levels. Am J Kidney Dis 38:956–964PubMedCrossRefGoogle Scholar
  24. 24.
    Ju W, Smith S, Kretzler M (2012) Genomic biomarkers for chronic kidney disease. Transl Res 159:290–302PubMedCrossRefGoogle Scholar
  25. 25.
    Guttormsen AB, Ueland PM, Nesthus I, Nygård O, Schneede J, Vollset SE, Refsum H (1996) Determinants and vitamin responsiveness of intermediate hyperhomocysteinemia (> or = 40 μmol/l). The Hordaland Homocysteine Study. J Clin Invest 98:2174–2183PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Asahi Hishida
    • 1
    Email author
  • Rieko Okada
    • 1
  • Yin Guang
    • 1
  • Mariko Naito
    • 1
  • Kenji Wakai
    • 1
  • Satoyo Hosono
    • 2
  • Kazuyo Nakamura
    • 3
  • Tanvir Chowdhury Turin
    • 4
    • 5
  • Sadao Suzuki
    • 6
  • Hideshi Niimura
    • 7
  • Haruo Mikami
    • 8
  • Jun Otonari
    • 9
  • Nagato Kuriyama
    • 10
  • Sakurako Katsuura
    • 11
  • Michiaki Kubo
    • 12
  • Hideo Tanaka
    • 2
  • Nobuyuki Hamajima
    • 13
  1. 1.Department of Preventive MedicineNagoya University Graduate School of MedicineShowa-ku, NagoyaJapan
  2. 2.Division of Epidemiology and PreventionAichi Cancer Center Research InstituteNagoyaJapan
  3. 3.St. Mary’s College Faculty of NursingKurumeJapan
  4. 4.Department of Health ScienceShiga University of Medical ScienceOtsuJapan
  5. 5.Department of MedicineUniversity of CalgaryCalgaryCanada
  6. 6.Department of Public HealthNagoya City University Graduate School of Medical SciencesNagoyaJapan
  7. 7.Department of International Island and Community MedicineKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan
  8. 8.Division of EpidemiologyChiba Cancer Center Research InstituteChibaJapan
  9. 9.Department of Preventive MedicineKyushu University Graduate School of Medical SciencesFukuokaJapan
  10. 10.Department of Social Medicine and Cultural SciencesKyoto Prefectural University of MedicineKyotoJapan
  11. 11.Department of Preventive Medicine, Institute of Health BiosciencesThe University of Tokushima Graduate SchoolTokushimaJapan
  12. 12.Center for Genomic MedicineRIKENYokohamaJapan
  13. 13.Young Leaders’ ProgramNagoya University Graduate School of MedicineNagoyaJapan

Personalised recommendations