Genome-Wide Meta-Analysis of Homocysteine and Methionine Metabolism Identifies Five One Carbon Metabolism Loci and a Novel Association of with Ischemic Stroke

English version České info

Elevated homocysteine (tHcy) is strongly associated with risk for common disorders such as stroke, cardiovascular disease and Alzheimer disease. Lowering tHcy levels has proven to have variable success in reducing clinical risk, so the question remains, “Are we correctly targeting these disorders by lowering tHcy?” Understanding folate one-carbon metabolism pathway (FOCM) genetic variation will aid us in developing new targets for therapy. The FOCM is essential in regulation of the epigenome, which controls genes in ways beyond nucleotide sequence. We present data generated from stroke-only and general populations where we identify strong association of genetic risk factors for variation in one-carbon metabolism function, characterized by the post-methionine load test. We show that GNMT harbors genetic and epigenetic differences that influence gene function, which may have downstream effects on the epigenome of the cell, affecting disease risk. We developed a genetic risk score that predicts post-methionine load homocysteine levels that may be useful in clinic. Finally, we identified a novel association between ischemic stroke and ALDH1L1, which emphasizes the clinical importance of this work. Our results highlight the importance of a concerted effort to target the FOCM (beyond tHcy) and parallel pathways in future pharmacogenetic work using the genetic variation we describe here.

Vyšlo v časopise: Genome-Wide Meta-Analysis of Homocysteine and Methionine Metabolism Identifies Five One Carbon Metabolism Loci and a Novel Association of with Ischemic Stroke. PLoS Genet 10(3): e32767. doi:10.1371/journal.pgen.1004214
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004214

Souhrn

Zdroje

1. FurieKL, KellyPJ (2006) Homocyst(e)ine and stroke. Semin Neurol 26 : 24–32.

2. RefsumH, UelandPM, NygardO, VollsetSE (1998) Homocysteine and cardiovascular disease. Annu Rev Med 49 : 31–62.

3. SeshadriS (2006) Elevated plasma homocysteine levels: risk factor or risk marker for the development of dementia and Alzheimer's disease? J Alzheimers Dis 9 : 393–398.

4. LippiG, PlebaniM (2012) Hyperhomocysteinemia in health and disease: where we are now, and where do we go from here? Clin Chem Lab Med 50 : 2075–80.

5. JiY, TanS, XuY, ChandraA, ShiC, et al. (2013) Vitamin B supplementation, homocysteine levels, and the risk of cerebrovascular disease: A meta-analysis. Neurology 81 : 1298–1307.

6. SpenceJD, StampferMJ (2011) Understanding the complexity of homocysteine lowering with vitamins: the potential role of subgroup analyses. JAMA 306 : 2610–2611.

7. BostomAG, JacquesPF, NadeauMR, WilliamsRR, EllisonRC, et al. (1995) Post-methionine load hyperhomocysteinemia in persons with normal fasting total plasma homocysteine: initial results from the NHLBI Family Heart Study. Atherosclerosis 116 : 147–151.

8. BostomAG, RoubenoffR, DellaripaP, NadeauMR, SutherlandP, et al. (1995) Validation of abbreviated oral methionine-loading test. Clin Chem 41 : 948–949.

9. GalimbertiG, ContiE, ZiniM, PiazzaF, FenaroliF, et al. (2008) Post-methionine load test: A more sensitive tool to reveal hyperhomocysteinemia in Alzheimer patients? Clin Biochem 41 : 914–916.

10. van der GriendR, BiesmaDH, BangaJD (2002) Postmethionine-load homocysteine determination for the diagnosis hyperhomocysteinaemia and efficacy of homocysteine lowering treatment regimens. Vasc Med 7 : 29–33.

11. TraylorM, FarrallM, HollidayEG, SudlowC, HopewellJC, et al. (2012) Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies. Lancet Neurol 11 : 951–62.

12. HollidayEG, MaguireJM, EvansTJ, KoblarSA, JannesJ, et al. (2012) Common variants at 6p21.1 are associated with large artery atherosclerotic stroke. Nat Genet 44 : 1147–1151.

13. BarrettJC, FryB, MallerJ, DalyMJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21 : 263–265.

14. LeeCM, ShihYP, WuCH, ChenYM (2009) Characterization of the 5′ regulatory region of the human Glycine N-methyltransferase gene. Gene 443 : 151–157.

15. ClarkeR, DalyL, RobinsonK, NaughtenE, CahalaneS, et al. (1991) Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 324 : 1149–1155.

16. BoersGH (2000) Mild hyperhomocysteinemia is an independent risk factor of arterial vascular disease. Semin Thromb Hemost 26 : 291–295.

17. TooleJF (2002) Vitamin intervention for stroke prevention. J Neurol Sci 203–204 : 121–124.

18. GuillandJC, FavierA, Potier de CourcyG, GalanP, HercbergS (2003) [Hyperhomocysteinemia: an independent risk factor or a simple marker of vascular disease? 2. Epidemiological data]. Pathol Biol (Paris) 51 : 111–121.

19. StankovicS, Majkic-SinghN (2010) Genetic aspects of ischemic stroke: coagulation, homocysteine, and lipoprotein metabolism as potential risk factors. Crit Rev Clin Lab Sci 47 : 72–123.

20. BersanoA, BallabioE, BresolinN, CandeliseL (2008) Genetic polymorphisms for the study of multifactorial stroke. Hum Mutat 29 : 776–795.

21. ChristensenB, ArbourL, TranP, LeclercD, SabbaghianN, et al. (1999) Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. Am J Med Genet 84 : 151–157.

22. AlluriRV, MohanV, KomandurS, ChawdaK, ChaudhuriJR, et al. (2005) MTHFR C677T gene mutation as a risk factor for arterial stroke: a hospital based study. Eur J Neurol 12 : 40–44.

23. TheodoratouE, MontazeriZ, HawkenS, AllumGC, GongJ, et al. (2012) Systematic meta-analyses and field synopsis of genetic association studies in colorectal cancer. J Natl Cancer Inst 104 : 1433–1457.

24. DongLM, PotterJD, WhiteE, UlrichCM, CardonLR, et al. (2008) Genetic susceptibility to cancer: the role of polymorphisms in candidate genes. JAMA 299 : 2423–2436.

25. CookRJ, WagnerC (1984) Glycine N-methyltransferase is a folate binding protein of rat liver cytosol. Proc Natl Acad Sci U S A 81 : 3631–3634.

26. BaccarelliA, WrightR, BollatiV, LitonjuaA, ZanobettiA, et al. (2010) Ischemic heart disease and stroke in relation to blood DNA methylation. Epidemiology 21 : 819–828.

27. KrishnaSM, DearA, CraigJM, NormanPE, GolledgeJ (2013) The potential role of homocysteine mediated DNA methylation and associated epigenetic changes in abdominal aortic aneurysm formation. Atherosclerosis 228 : 295–305.

28. TeslovichTM, MusunuruK, SmithAV, EdmondsonAC, StylianouIM, et al. (2010) Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466 : 707–713.

29. GiustiB, SaraciniC, BolliP, MagiA, MartinelliI, et al. (2010) Early-onset ischaemic stroke: analysis of 58 polymorphisms in 17 genes involved in methionine metabolism. Thromb Haemost 104 : 231–242.

30. LefaucheurR, Triquenot-BaganA, QuillardM, GenevoisO, HannequinD (2008) [Stroke and iridodonesis revealing a homocystinuria caused by a compound heterozygous mutation of cystathionine beta-synthase]. Rev Neurol (Paris) 164 : 728–732.

31. MuddSH (2011) Hypermethioninemias of genetic and non-genetic origin: A review. Am J Med Genet C Semin Med Genet 157 : 3–32.

32. KluijtmansLA, BoersGH, KrausJP, van den HeuvelLP, CruysbergJR, et al. (1999) The molecular basis of cystathionine beta-synthase deficiency in Dutch patients with homocystinuria: effect of CBS genotype on biochemical and clinical phenotype and on response to treatment. Am J Hum Genet 65 : 59–67.

33. KrausJP (1994) Komrower Lecture. Molecular basis of phenotype expression in homocystinuria. J Inherit Metab Dis 17 : 383–390.

34. PareG, ChasmanDI, ParkerAN, ZeeRR, MalarstigA, et al. (2009) Novel associations of CPS1, MUT, NOX4, and DPEP1 with plasma homocysteine in a healthy population: a genome-wide evaluation of 13 974 participants in the Women's Genome Health Study. Circ Cardiovasc Genet 2 : 142–150.

35. LangeLA, Croteau-ChonkaDC, MarvelleAF, QinL, GaultonKJ, et al. (2010) Genome-wide association study of homocysteine levels in Filipinos provides evidence for CPS1 in women and a stronger MTHFR effect in young adults. Hum Mol Genet 19 : 2050–2058.

36. CaiuloA, BardoniB, CamerinoG, GuioliS, MinelliA, et al. (1989) Cytogenetic and molecular analysis of an unbalanced translocation (X;7) (q28;p15) in a dysmorphic girl. Hum Genet 84 : 51–54.

37. Veiga-da-CunhaM, ColletJF, PrieurB, JaekenJ, PeeraerY, et al. (2004) Mutations responsible for 3-phosphoserine phosphatase deficiency. Eur J Hum Genet 12 : 163–166.

38. LocasaleJW (2013) Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer 13 : 572–583.

39. TibbettsAS, ApplingDR (2010) Compartmentalization of Mammalian folate-mediated one-carbon metabolism. Annu Rev Nutr 30 : 57–81.

40. GalanP, BrianconS, BlacherJ, CzernichowS, HercbergS (2008) The SU.FOL.OM3 Study: a secondary prevention trial testing the impact of supplementation with folate and B-vitamins and/or Omega-3 PUFA on fatal and non fatal cardiovascular events, design, methods and participants characteristics. Trials 9 : 35.

41. LonnE, YusufS, ArnoldMJ, SheridanP, PogueJ, et al. (2006) Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 354 : 1567–1577.

42. TooleJF, MalinowMR, ChamblessLE, SpenceJD, PettigrewLC, et al. (2004) Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 291 : 565–575.

43. DawberTR, KannelWB, LyellLP (1963) An approach to longitudinal studies in a community: the Framingham Study. Ann N Y Acad Sci 107 : 539–556.

44. FeinleibM, KannelWB, GarrisonRJ, McNamaraPM, CastelliWP (1975) The Framingham Offspring Study. Design and preliminary data. Prev Med 4 : 518–525.

45. ArakiA, SakoY (1987) Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr 422 : 43–52.

46. CarandangR, SeshadriS, BeiserA, Kelly-HayesM, KaseCS, et al. (2006) Trends in incidence, lifetime risk, severity, and 30-day mortality of stroke over the past 50 years. JAMA 296 : 2939–2946.

47. SeshadriS, BeiserA, Kelly-HayesM, KaseCS, AuR, et al. (2006) The lifetime risk of stroke: estimates from the Framingham Study. Stroke 37 : 345–350.

48. WolfPA, KannelWB, DawberTR (1978) Prospective investigations: the Framingham study and the epidemiology of stroke. Adv Neurol 19 : 107–120.

49. ChenMH, YangQ (2010) GWAF: an R package for genome-wide association analyses with family data. Bioinformatics 26 : 580–581.

50. TherneauTM, GrambschPM (2000) Modeling Survival Data: Extending the Cox Model. Springer-Verlag 170–172.

51. AltshulerD, GibbsR, PeltonenL, DermitzakisE, SchaffnerS, et al. (2010) Integrating common and rare genetic variation in diverse human populations. Nature 467 : 52–58.

52. BrowningB, BrowningS (2009) A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals. Am J Hum Genet 84 : 210–223.

53. ManichaikulA, MychaleckyjJC, RichSS, DalyK, SaleM, et al. (2010) Robust relationship inference in genome-wide association studies. Bioinformatics 26 : 2867–2873.

54. WillerCJ, LiY, AbecasisGR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26 : 2190–2191.

55. JackA, ConnellyJJ, MorrisJP (2012) DNA methylation of the oxytocin receptor gene predicts neural response to ambiguous social stimuli. Front Hum Neurosci 6 : 280.