Skip to main content
SpringerLink
Log in

The MTHFR gene polymorphism is associated with lean body mass but not fat body mass

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

Along with aging, human body composition undergoes notable changes and may incur sarcopenia, obesity or osteoporosis. Sarcopenia is related to a wide series of human health problems and can be largely characterized by loss of lean body mass (LBM). Studies have showed relevance of methylenetetrahydrofolate reductase (MTHFR) with variation in LBM and fat body mass (FBM). To test if polymorphism of the MTHFR gene is underlying the pathology of sarcopenia and obesity, we concurrently tested five single nucleotide polymorphisms (SNPs) of the MTHFR gene for association with LBM, FBM and body mass index (BMI) in 405 Caucasian nuclear families comprising 1,873 individuals. After correction for multiple testing, we detected significant associations for LBM with rs2066470 (P = 0.0006), rs4846048 (P = 0.0007) and with rs3737964 (P = 0.004), as well as for BMI with rs4846048 (P = 0.009). Polymorphism of rs2066470 explains 3.67% of LBM variation in this sample. The association between BMI and rs4846048 diminished after adjusting for LBM, suggesting that the association between BMI and rs4846048 is largely due to LBM instead of the fat component. In concert, no significant associations were identified for FBM with any of the studied SNPs. The results of single-locus association analyses were corroborated by haplotype-based analyses. In summary, the MTHFR gene polymorphism is associated with LBM, suggesting that MTHFR may play an important role in LBM variation. In addition, the MTHFR gene polymorphism is not associated with FBM or obesity in this sample.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Abecasis GR, Cardon LR, Cookson WO (2000) A general test of association for quantitative traits in nuclear families. Am J Hum Genet 66:279–292

    Article  PubMed  CAS  Google Scholar 

  • Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101

    Article  PubMed  CAS  Google Scholar 

  • Albanese CV, Diessel E, Genant HK (2003) Clinical applications of body composition measurements using DXA. J Clin Densitom 6:75–85

    Article  PubMed  Google Scholar 

  • Allison DB, Faith MS, Heo M, Kotler DP (1997) Hypothesis concerning the U-shaped relation between body mass index and mortality. Am J Epidemiol 146:339–349

    PubMed  CAS  Google Scholar 

  • Arden NK, Spector TD (1997) Genetic influences on muscle strength, lean body mass, and bone mineral density: a twin study. J Bone Miner Res 12:2076–2081

    Article  PubMed  CAS  Google Scholar 

  • Ashurst JL, Chen CK, Gilbert JG, Jekosch K, Keenan S, Meidl P, Searle SM, Stalker J, Storey R, Trevanion S, Wilming L, Hubbard T (2005) The vertebrate genome annotation (Vega) database. Nucleic Acids Res 33:D459–D465

    Article  PubMed  CAS  Google Scholar 

  • Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265

    Article  PubMed  CAS  Google Scholar 

  • Baumgartner RN, Waters DL, Gallagher D, Morley JE, Garry PJ (1999) Predictors of skeletal muscle mass in elderly men and women. Mech Ageing Dev 107:123–136

    Article  PubMed  CAS  Google Scholar 

  • Chen Z, Karaplis AC, Ackerman SL, Pogribny IP, Melnyk S, Lussier-Cacan S, Chen MF, Pai A, John SW, Smith RS, Bottiglieri T, Bagley P, Selhub J, Rudnicki MA, James SJ, Rozen R (2001) Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet 10:433–443

    Article  PubMed  CAS  Google Scholar 

  • Deng HW, Deng H, Liu YJ, Liu YZ, Xu FH, Shen H, Conway T, Li JL, Huang QY, Davies KM, Recker RR (2002a) A genomewide linkage scan for quantitative-trait loci for obesity phenotypes. Am J Hum Genet 70:1138–1151

    Article  PubMed  CAS  Google Scholar 

  • Deng HW, Shen H, Xu FH, Deng HY, Conway T, Zhang HT, Recker RR (2002b) Tests of linkage and/or association of genes for vitamin D receptor, osteocalcin, and parathyroid hormone with bone mineral density. J Bone Miner Res 17:678–686

    Article  PubMed  CAS  Google Scholar 

  • Di Renzo L, Bigioni M, Bottini FG, Del Gobbo V, Premrov MG, Cianci R, De Lorenzo A (2006) Normal weight obese syndrome: role of single nucleotide polymorphism of IL-1 5Ralpha and MTHFR 677C–>T genes in the relationship between body composition and resting metabolic rate. Eur Rev Med Pharmacol Sci 10:235–245

    PubMed  CAS  Google Scholar 

  • Dirks AJ, Hofer T, Marzetti E, Pahor M, Leeuwenburgh C (2006) Mitochondrial DNA mutations, energy metabolism and apoptosis in aging muscle. Ageing Res Rev 5:179–195

    Article  PubMed  CAS  Google Scholar 

  • Doherty TJ (2003) Invited review: aging and sarcopenia. J Appl Physiol 95:1717–1727

    PubMed  CAS  Google Scholar 

  • Edwalds-Gilbert G, Veraldi KL, Milcarek C (1997) Alternative poly(A) site selection in complex transcription units: means to an end? Nucleic Acids Res 25:2547–2561

    Article  PubMed  CAS  Google Scholar 

  • Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247

    Article  PubMed  CAS  Google Scholar 

  • Gaughan DJ, Barbaux S, Kluijtmans LA, Whitehead AS (2000) The human and mouse methylenetetrahydrofolate reductase (MTHFR) genes: genomic organization, mRNA structure and linkage to the CLCN6 gene. Gene 257:279–289

    Article  PubMed  CAS  Google Scholar 

  • Gorlova OY, Amos CI, Wang NW, Shete S, Turner ST, Boerwinkle E (2003) Genetic linkage and imprinting effects on body mass index in children and young adults. Eur J Hum Genet 11:425–432

    Article  PubMed  CAS  Google Scholar 

  • Hansen RD, Raja C, Aslani A, Smith RC, Allen BJ (1999) Determination of skeletal muscle and fat-free mass by nuclear and dual-energy X-ray absorptiometry methods in men and women aged 51–84 y (1–3). Am J Clin Nutr 70:228–233

    PubMed  CAS  Google Scholar 

  • Hsu FC, Lenchik L, Nicklas BJ, Lohman K, Register TC, Mychaleckyj J, Langefeld CD, Freedman BI, Bowden DW, Carr JJ (2005) Heritability of body composition measured by DXA in the diabetes heart study. Obes Res 13:312–319

    Article  PubMed  Google Scholar 

  • Jackson-Grusby L, Beard C, Possemato R, Tudor M, Fambrough D, Csankovszki G, Dausman J, Lee P, Wilson C, Lander E, Jaenisch R (2001) Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Nat Genet 27:31–39

    Article  PubMed  CAS  Google Scholar 

  • Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J (2001) Determinants of plasma total homocysteine concentration in the Framingham offspring cohort. Am J Clin Nutr 73:613–621

    PubMed  CAS  Google Scholar 

  • Janssen I, Shepard DS, Katzmarzyk PT, Roubenoff R (2004) The healthcare costs of sarcopenia in the United States. J Am Geriatr Soc 52:80–85

    Article  PubMed  Google Scholar 

  • Karakelides H, Sreekumaran Nair K (2005) Sarcopenia of aging and its metabolic impact. Curr Top Dev Biol 68:123–148

    Article  PubMed  CAS  Google Scholar 

  • Karolchik D, Baertsch R, Diekhans M, Furey TS, Hinrichs A, Lu YT, Roskin KM, Schwartz M, Sugnet CW, Thomas DJ, Weber RJ, Haussler D, Kent WJ (2003) The UCSC Genome Browser Database. Nucleic Acids Res 31:51–54

    Article  PubMed  CAS  Google Scholar 

  • Kuriyama S, Ohmori K, Miura C, Suzuki Y, Nakaya N, Fujita K, Sato Y, Tsubono Y, Tsuji I, Fukao A, Hisamichi S (2004) Body mass index and mortality in Japan: the Miyagi Cohort Study. J Epidemiol 14(Suppl 1):S33–S38

    Article  PubMed  Google Scholar 

  • Liu YJ, Xu FH, Shen H, Liu YZ, Deng HY, Zhao LJ, Huang QY, Dvornyk V, Conway T, Davies KM, Li JL, Recker RR, Deng HW (2004) A follow-up linkage study for quantitative trait loci contributing to obesity-related phenotypes. J Clin Endocrinol Metab 89:875–882

    Article  PubMed  CAS  Google Scholar 

  • Liu YJ, Shen H, Xiao P, Xiong DH, Li LH, Recker RR, Deng HW (2006) Molecular genetic studies of gene identification for osteoporosis: a 2004 update. J Bone Miner Res 21:1511–1535

    Article  PubMed  CAS  Google Scholar 

  • Livshits G, Kato BS, Wilson SG, Spector TD (2007) Linkage of genes to total lean body mass in normal women. J Clin Endocrinol Metab 92:3171–3176

    Article  PubMed  CAS  Google Scholar 

  • Norris JM, Langefeld CD, Scherzinger AL, Rich SS, Bookman E, Beck SR, Saad MF, Haffner SM, Bergman RN, Bowden DW, Wagenknecht LE (2005) Quantitative trait loci for abdominal fat and BMI in Hispanic–Americans and African–Americans: the IRAS family study. Int J Obes (Lond) 29:67–77

    Article  CAS  Google Scholar 

  • Nyholt DR (2004) A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet 74:765–769

    Article  PubMed  CAS  Google Scholar 

  • O’Connell JR, Weeks DE (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63:259–266

    Article  PubMed  CAS  Google Scholar 

  • Payette H, Hanusaik N, Boutier V, Morais JA, Gray-Donald K (1998) Muscle strength and functional mobility in relation to lean body mass in free-living frail elderly women. Eur J Clin Nutr 52:45–53

    Article  PubMed  CAS  Google Scholar 

  • Rankinen T, Zuberi A, Chagnon YC, Weisnagel SJ, Argyropoulos G, Walts B, Perusse L, Bouchard C (2006) The human obesity gene map: the 2005 update. Obesity (Silver Spring) 14:529–644

    Google Scholar 

  • Rauh M, Verwied S, Knerr I, Dorr HG, Sonnichsen A, Koletzko B (2001) Homocysteine concentrations in a German cohort of 500 individuals: reference ranges and determinants of plasma levels in healthy children and their parents. Amino Acids 20:409–418

    Article  PubMed  CAS  Google Scholar 

  • Shane B, Picciano MF, Stokstad ER, Gregory JF (1990) Folic acid metabolism in health and disease. Wiley-Liss Press, New York

    Google Scholar 

  • Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, Sirotkin K (2001) dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 29:308–311

    Article  PubMed  CAS  Google Scholar 

  • Shmueli O, Horn-Saban S, Chalifa-Caspi V, Shmoish M, Ophir R, Benjamin-Rodrig H, Safran M, Domany E, Lancet D (2003) GeneNote: whole genome expression profiles in normal human tissues. C R Biol 326:1067–1072

    Article  PubMed  CAS  Google Scholar 

  • Sipila S, Heikkinen E, Cheng S, Suominen H, Saari P, Kovanen V, Alen M, Rantanen T (2006) Endogenous hormones, muscle strength, and risk of fall-related fractures in older women. J Gerontol A Biol Sci Med Sci 61:92–96

    PubMed  Google Scholar 

  • Smith AG, Muscat GE (2006) Orphan nuclear receptors: therapeutic opportunities in skeletal muscle. Am J Physiol Cell Physiol 291:C203–C217

    Article  PubMed  CAS  Google Scholar 

  • Song MY, Ruts E, Kim J, Janumala I, Heymsfield S, Gallagher D (2004) Sarcopenia and increased adipose tissue infiltration of muscle in elderly African American women. Am J Clin Nutr 79:874–880

    PubMed  CAS  Google Scholar 

  • Stone S, Abkevich V, Hunt SC, Gutin A, Russell DL, Neff CD, Riley R, Frech GC, Hensel CH, Jammulapati S, Potter J, Sexton D, Tran T, Gibbs D, Iliev D, Gress R, Bloomquist B, Amatruda J, Rae PM, Adams TD, Skolnick MH, Shattuck D (2002) A major predisposition locus for severe obesity, at 4p15-p14. Am J Hum Genet 70:1459–1468

    Article  PubMed  CAS  Google Scholar 

  • Thawnashom K, Tungtrongchitr R, Petmitr S, Pongpaew P, Phonrat B, Tungtrongchitr A, Schelp FP (2005) Methylenetetrahydrofolate reductase (MTHFR) polymorphism (C677T) in relation to homocysteine concentration in overweight and obese Thais. Southeast Asian J Trop Med Public Health 36:459–466

    PubMed  CAS  Google Scholar 

  • Waters DL, Brooks WM, Qualls CR, Baumgartner RN (2003) Skeletal muscle mitochondrial function and lean body mass in healthy exercising elderly. Mech Ageing Dev 124:301–309

    Article  PubMed  CAS  Google Scholar 

  • Wilcken DE, Wang XL, Sim AS, McCredie RM (1996) Distribution in healthy and coronary populations of the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Arterioscler Thromb Vasc Biol 16:878–882

    PubMed  CAS  Google Scholar 

  • Xiong DH, Shen H, Zhao LJ, Xiao P, Yang TL, Guo Y, Wang W, Guo YF, Liu YJ, Recker RR, Deng HW (2006) Robust and comprehensive analysis of 20 osteoporosis candidate genes by very high-density single-nucleotide polymorphism screen among 405 white nuclear families identified significant association and gene-gene interaction. J Bone Miner Res 21:1678–1695

    Article  PubMed  CAS  Google Scholar 

  • Yan LJ, Levine RL, Sohal RS (1997) Oxidative damage during aging targets mitochondrial aconitase. Proc Natl Acad Sci USA 94:11168–11172

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was partially funded by NIH (R01 AR050496, K01 AR02170-01, R01 AR45349-01, R01 GM60402-01A1, R21 AG027110-01A1 and R01 AG026564-01A2), and an LB595 grant from the State of Nebraska. The study benefited from National Science Foundation of China (30570875), Huo YingDong Education Foundation, Hunan Province, Xi’an Jiaotong University and the Ministry of Education of China. Xiaogang Liu was partially supported by Doctoral Foundation of Xi’an Jiaotong University (DFXJTU2004-11).

Author information

Authors and Affiliations

  1. The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an Shaanxi, 710049, People’s Republic of China

    Xiaogang Liu & Hong-Wen Deng

  2. Departments of Orthopedic Surgery and Basic Medical Sciences, School of Medicine, University of Missouri-Kansas City, Kansas City, MO, 64108, USA

    Xiaogang Liu, Lan-Juan Zhao, Yong-Jun Liu & Hong-Wen Deng

  3. Osteoporosis Research Center and Department of Biomedical Sciences, Creighton University, Omaha, NE, 68131, USA

    Dong-Hai Xiong & Robert R. Recker

  4. Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha Hunan, 410081, People’s Republic of China

    Hong-Wen Deng

Authors
  1. Xiaogang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lan-Juan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yong-Jun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dong-Hai Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Robert R. Recker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hong-Wen Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hong-Wen Deng.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, X., Zhao, LJ., Liu, YJ. et al. The MTHFR gene polymorphism is associated with lean body mass but not fat body mass. Hum Genet 123, 189–196 (2008). https://doi.org/10.1007/s00439-007-0463-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-007-0463-7

Keywords

Search

Navigation