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

Circulation: Cardiovascular Genetics

Volumn 2, Issue 2, 2009, Pages 142-150

  Paré, Guillaume ^a   Chasman, Daniel I ^a   Parker, Alexander N ^b   Zee, Robert R Y ^a   Mälarstig, Anders ^c   Seedorf, Udo ^d   Collins, Rory ^e   Watkins, Hugh ^e   Hamsten, Anders ^c   Miletich, Joseph P ^b   Ridker, Paul M ^a  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b AMGEN INC   (United States)

^c KAROLINSKA INSTITUTE   (Sweden)

^d UNIVERSITY OF MÜNSTER   (Germany)

^e UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

Amino acids; Genetics; Metabolism

Indexed keywords

HOMOCYSTEINE; CARBAMOYL PHOSPHATE SYNTHASE; DIPEPTIDASE; METHYLMALONYL COENZYME A MUTASE; NOX4 PROTEIN, HUMAN; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE;

AMINO ACID METABOLISM; ARTICLE; CPS1 GENE; DPEP1 GENE; FEMALE; GENE; GENE CONTROL; GENETIC ASSOCIATION; GENETIC VARIABILITY; GENOTYPE; HUMAN; KARYOTYPE; MOLECULAR GENETICS; MUT GENE; NORMAL HUMAN; NOX4 GENE; PRIORITY JOURNAL; SINGLE NUCLEOTIDE POLYMORPHISM; BLOOD; GENETICS; MIDDLE AGED; POPULATION GENETICS; WOMEN'S HEALTH;

CARBAMOYL-PHOSPHATE SYNTHASE (AMMONIA); DIPEPTIDASES; FEMALE; GENETICS, POPULATION; GENOME-WIDE ASSOCIATION STUDY; HOMOCYSTEINE; HUMANS; METHYLMALONYL-COA MUTASE; MIDDLE AGED; NADPH OXIDASE; POLYMORPHISM, SINGLE NUCLEOTIDE; WOMEN'S HEALTH;

EID: 70449560459     PISSN: 1942325X     EISSN: 19423268     Source Type: Journal    
DOI: 10.1161/CIRCGENETICS.108.829804     Document Type: Article

References (55)

1. Selhub J. Homocysteine metabolism. Annu Rev Nutr. 1999; 19: 217-246. (Pubitemid 29380603)
2. Upchurch GR Jr, Welch GN, Fabian AJ, Freedman JE, Johnson JL, Keaney JF Jr, Loscalzo J. Homocysteine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. J Biol Chem. 1997; 272: 17012-17017. (Pubitemid 27289806)
3. Weiss N, Zhang YY, Heydrick S, Bierl C, Loscalzo J. Overexpression of cellular glutathione peroxidase rescues homocyst (e) ine-induced endothelial dysfunction. Proc Natl Acad Sci USA. 2001; 98: 12503-12508.
4. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002; 288: 2015-2022.
5. Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 1998; 338: 1042-1050. (Pubitemid 128753793)
6. Mills JL, McPartlin JM, Kirke PN, Lee YJ, Conley MR, Weir DG, Scott JM. Homocysteine metabolism in pregnancies complicated by neural-tube defects. Lancet. 1995; 345: 149-151.
7. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol. 1998; 55: 1449-1455.
8. Souto JC, Blanco-Vaca F, Soria JM, Buil A, Almasy L, Ordonez-Llanos J, Martin-Campos JM, Lathrop M, Stone W, Blangero J, Fontcuberta J. A genomewide exploration suggests a new candidate gene at chromosome 11q23 as the major determinant of plasma homocysteine levels: results from the GAIT project. Am J Hum Genet. 2005; 76: 925-933.
9. Vermeulen SH, van der Vleuten GM, de Graaf J, Hermus AR, Blom HJ, Stalenhoef AF, den Heijer M. A genome-wide linkage scan for homocysteine levels suggests three regions of interest. J Thromb Haemost. 2006; 4: 1303-1307.
10. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995; 10: 111-113.
11. De Stefano V, Dekou V, Nicaud V, Chasse JF, London J, Stansbie D, Humphries SE, Gudnason V. Linkage disequilibrium at the cystathionine beta synthase (CBS) locus and the association between genetic variation at the CBS locus and plasma levels of homocysteine. The Ears II Group European Atherosclerosis Research Study. Ann Hum Genet. 1998; 62: 481-490.
12. Lievers KJ, Kluijtmans LA, Heil SG, Boers GH, Verhoef P, van Oppenraay-Emmerzaal D, den Heijer M, Trijbels FJ, Blom HJ. A 31 bp VNTR in the cystathionine beta-synthase (CBS) gene is associated with reduced CBS activity and elevated post-load homocysteine levels. Eur J Hum Genet. 2001; 9: 583-589.
13. Tsai MY, Bignell M, Yang F, Welge BG, Graham KJ, Hanson NQ. Polygenic influence on plasma homocysteine: association of two prevalent mutations, the 844ins68 of cystathionine beta-synthase and A (2756) G of methionine synthase, with lowered plasma homocysteine levels. Atherosclerosis. 2000; 149: 131-137.
14. Gaughan DJ, Kluijtmans LA, Barbaux S, McMaster D, Young IS, Yarnell JW, Evans A, Whitehead AS. The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations. Atherosclerosis. 2001; 157: 451-456.
15. Ridker PM, Chasman DI, Zee RY, Parker A, Rose L, Cook NR, Buring JE. Rationale, design, and methodology of the Women's Genome Health Study: a genome-wide association study of more than 25, 000 initially healthy american women. Clin Chem. 2008; 54: 249-255. (Pubitemid 351302617)
16. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, Manson JE, Hennekens CH, Buring JE. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005; 352: 1293-1304. (Pubitemid 41002838)
17. Zee RY, Mora S, Cheng S, Erlich HA, Lindpaintner K, Rifai N, Buring JE, Ridker PM. Homocysteine, 5, 10-methylenetetrahydrofolate reductase 6770T polymorphism, nutrient intake, and incident cardiovascular disease in 24, 968 initially healthy women. Clin Chem. 2007; 53: 845-851. (Pubitemid 46744239)
18. Zhang SM, Moore SC, Lin J, Cook NR, Manson JE, Lee IM, Buring JE. Folate, vitamin B6, multivitamin supplements, and colorectal cancer risk in women. Am J Epidemiol. 2006; 163: 108-115. (Pubitemid 43068979)
19. Willett WC, Sampson L, Browne ML, Stampfer MJ, Rosner B, Hennekens CH, Speizer FE. The use of a self-administered questionnaire to assess diet four years in the past. Am J Epidemiol. 1988; 127: 188-199. (Pubitemid 18034380)
20. Salvini S, Hunter DJ, Sampson L, Stampfer MJ, Colditz GA, Rosner B, Willett WC. Food-based validation of a dietary questionnaire: the effects of week-to-week variation in food consumption. Int J Epidemiol. 1989; 18: 858-867. (Pubitemid 20030201)
21. Giovannucci E, Stampfer MJ, Colditz GA, Rimm EB, Trichopoulos D, Rosner BA, Speizer FE, Willett WC. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst. 1993; 85: 875-884. (Pubitemid 23157127)
22. Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD, Colditz GA, Hankinson SE. Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst. 2003; 95: 373-380.
23. Wigginton JE, Cutler DJ, Abecasis GR. A note on exact tests of Hardy-Weinberg equilibrium. Am J Hum Genet. 2005; 76: 887-893.
24. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007; 81: 559-575.
25. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006; 38: 904-909.
26. Gambacciani M, Mannella P. Homocysteine, menopause and cardiovascular disease. Menopause Int. 2007; 13: 23-26.
27. Siri PW, Verhoef P, Kok FJ. Vitamins B6, B12, and folate: association with plasma total homocysteine and risk of coronary atherosclerosis J Am Coll Nutr. 1998; 17: 435-441.
28. O'Callaghan P, Meleady R, Fitzgerald T, Graham I. Smoking and plasma homocysteine. Eur Heart J. 2002; 23: 1580-1586.
29. Mora S, Lee IM, Buring JE, Ridker PM. Association of physical activity and body mass index with novel and traditional cardiovascular biomarkers in women. JAMA. 2006; 295: 1412-1419.
30. Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, Belmont JW, Boudreau A, Hardenbol P, Leal SM, Pasternak S, Wheeler DA, Willis TD, Yu F, Yang H, Zeng C, Gao Y, Hu H, Hu W, Li C, Lin W, Liu S, Pan H, Tang X, Wang J, Wang W, Yu J, Zhang B, Zhang Q, Zhao H, Zhao H, Zhou J, Gabriel SB, Barry R, Blumenstiel B, Camargo A, Defelice M, Faggart M, Goyette M, Gupta S, Moore J, Nguyen H, Onofrio RC, Parkin M, Roy J, Stahl E, Winchester E, Ziaugra L, Altshuler D, Shen Y, Yao Z, Huang W, Chu X, He Y, Jin L, Liu Y, Shen Y, Sun W, Wang H, Wang Y, Wang Y, Xiong X, Xu L, Waye MM, Tsui SK, Xue H, Wong JT, Galver LM, Fan JB, Gunderson K, Murray SS, Oliphant AR, Chee MS, Montpetit A, Chagnon F, Ferretti V, Leboeuf M, Olivier JF, Phillips MS, Roumy S, Sallee C, Verner A, Hudson TJ, Kwok PY, Cai D, Koboldt DC, Miller RD, Pawlikowska L, Taillon-Miller P, Xiao M, Tsui LC, Mak W, Song YQ, Tam PK, Nakamura Y, Kawaguchi T, Kitamoto T, Morizono T, Nagashima A, Ohnishi Y, Sekine A, Tanaka T, Tsunoda T, Deloukas P, Bird CP, Delgado M, Dermitzakis ET, Gwilliam R, Hunt S, Morrison J, Powell D, Stranger BE, Whittaker P, Bentley DR, Daly MJ, de Bakker PI, Barrett J, Chretien YR, Maller J, McCarroll S, Patterson N, Pe'er I, Price A, Purcell S, Richter DJ, Sabeti P, Saxena R, Schaffner SF, Sham PC, Varilly P, Altshuler D, Stein LD, Krishnan L, Smith AV, Tello-Ruiz MK, Thorisson GA, Chakravarti A, Chen PE, Cutler DJ, Kashuk CS, Lin S, Abecasis GR, Guan W, Li Y, Munro HM, Qin ZS, Thomas DJ, McVean G, Auton A, Bottolo L, Cardin N, Eyheramendy S, Freeman C, Marchini J, Myers S, Spencer C, Stephens M, Donnelly P, Cardon LR, Clarke G, Evans DM, Morris AP, Weir BS, Tsunoda T, Mullikin JC, Sherry ST, Feolo M, Skol A, Zhang H, Zeng C, Zhao H, Matsuda I, Fukushima Y, Macer DR, Suda E, Rotimi CN, Adebamowo CA, Ajayi I, Aniagwu T, Marshall PA, Nkwodimmah C, Royal CD, Leppert MF, Dixon M, Peiffer A, Qiu R, Kent A, Kato K, Niikawa N, Adewole IF, Knoppers BM, Foster MW, Clayton EW, Watkin J, Gibbs RA, Belmont JW, Muzny D, Nazareth L, Sodergren E, Weinstock GM, Wheeler DA, Yakub I, Gabriel SB, Onofrio RC, Richter DJ, Ziaugra L, Birren BW, Daly MJ, Altshuler D, Wilson RK, Fulton LL, Rogers J, Burton J, Carter NP, Clee CM, Griffiths M, Jones MC, McLay K, Plumb RW, Ross MT, Sims SK, Willey DL, Chen Z, Han H, Kang L, Godbout M, Wallenburg JC, L'Archeveque P, Bellemare G, Saeki K, Wang H, An D, Fu H, Li Q, Wang Z, Wang R, Holden AL, Brooks LD, McEwen JE, Guyer MS, Wang VO, Peterson JL, Shi M, Spiegel J, Sung LM, Zacharia LF, Collins FS, Kennedy K, Jamieson R, Stewart J. A second generation human haplotype map of over 3.1 million SNPs. Nature. 2007; 449: 851-861.
31. Farrall M, Green FR, Peden JF, Olsson PG, Clarke R, Hellenius ML, Rust S, Lagercrantz J, Franzosi MG, Schulte H, Carey A, Olsson G, Assmann G, Tognoni G, Collins R, Hamsten A, Watkins H. Genome-wide mapping of susceptibility to coronary artery disease identifies a novel replicated locus on chromosome 17. PLoS Genet. 2006; 2: e72.
32. Broadbent HM, Peden JF, Lorkowski S, Goel A, Ongen H, Green F, Clarke R, Collins R, Franzosi MG, Tognoni G, Seedorf U, Rust S, Eriksson P, Hamsten A, Farrall M, Watkins H. Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome p. Hum Mol Genet. 2008; 17: 806-814.
33. McVean GA, Myers SR, Hunt S, Deloukas P, Bentley DR, Donnelly P. The fine-scale structure of recombination rate variation in the human genome. Science. 2004; 304: 581-584.
34. Winckler W, Myers SR, Richter DJ, Onofrio RC, McDonald GJ, Bontrop RE, McVean GA, Gabriel SB, Reich D, Donnelly P, Altshuler D. Comparison of fine-scale recombination rates in humans and chimpanzees. Science. 2005; 308: 107-111. (Pubitemid 40471008)
35. Habib GM, Barrios R, Shi ZZ, Lieberman MW. Four distinct membrane-bound dipeptidase RNAs are differentially expressed and show discordant regulation with gamma-glutamyl transpeptidase. J Biol Chem. 1996; 271: 16273-16280.
36. Kozak EM, Tate SS. Glutathione-degrading enzymes of microvillus membranes. J Biol Chem. 1982; 257: 6322-6327.
37. Finkelstein JD. Inborn errors of sulfur-containing amino acid metabolism. J Nutr. 2006; 136: 1750S-1754S.
38. Mayatepek E, Badiou S, Bellet H, Lehmann WD. A patient with neurological symptoms and abnormal leukotriene metabolism: a new defect in leukotriene biosynthesis. Ann Neurol. 2005; 58: 968-970.
39. Scaglia F, Brunetti-Pierri N, Kleppe S, Marini J, Carter S, Garlick P, Jahoor F, O'Brien W, Lee B Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism. J Nutr. 2004; 134: 2775S-2782S.
40. Summar ML, Hall L, Christman B, Barr F, Smith H, Kallianpur A, Brown N, Yadav M, Willis A, Eeds A, Cermak E, Summar S, Wilson A, Arvin M, Putnam A, Wills M, Cunningham G. Environmentally determined genetic expression: clinical correlates with molecular variants of carbamyl phosphate synthetase I. Mol Genet Metab. 2004; 81: S12-S19.
41. Summar ML, Gainer JV, Pretorius M, Malave H, Harris S, Hall LD, Weisberg A, Vaughan DE, Christman BW, Brown NJ. Relationship between carbamoyl-phosphate synthetase genotype and systemic vascular function. Hypertension. 2004; 43: 186-191.
42. Pearson DL, Dawling S, Walsh WF, Haines JL, Christman BW, Bazyk A, Scott N, Summar ML. Neonatal pulmonary hypertension-urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med. 2001; 344: 1832-1838.
43. Summar ML, Scott N, Cummings E, Hutcheson H, Dawling S, Christman B. Analysis of 200 patients undegoing bone marrow transplant shows allelic disequilibrium between drug related toxicity and a common exonic polymorphism in the CPS1 gene and correlates with disruption of urea cycle intermediates. Am J Hum Genet. 1999; 65: A25.
44. Deacon R, Lumb M, Perry J, Chanarin I, Minty B, Halsey MJ, Nunn JF. Selective inactivation of vitamin B12 in rats by nitrous oxide. Lancet. 1978; 2: 1023-1024.
45. Ng J, Frith R. Nanging. Lancet. 2002; 360: 384.
46. Waclawik AJ, Luzzio CC, Juhasz-Pocsine K, Hamilton V. Myeloneuropathy from nitrous oxide abuse: unusually high methylmalonic acid and homocysteine levels. WMJ. 2003; 102: 43-45.
47. Drummond JT, Matthews RG. Nitrous oxide degradation by cobalamindependent methionine synthase: characterization of the reactants and products in the inactivation reaction. Biochemistry. 1994; 33: 3732-3741.
48. Kondo H, Osborne ML, Kolhouse JF, Binder MJ, Podell ER, Utley CS, Abrams RS, Allen RH. Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian cobalamin-dependent enzymes in rats. J Clin Invest. 1981; 67: 1270-1283.
49. Rask H, Olesen AS, Mortensen JZ, Freund LG. N2O and urine methylmalonic acid in man. Scand J Haematol. 1983; 31: 45-48.
50. Loscalzo J. Adverse effects of supplemental L-arginine in atherosclerosis: consequences of methylation stress in a complex catabolism? Arterioscler Thromb Vasc Biol. 2003; 23: 3-5.
51. Okada M, Cheeseman IM, Hori T, Okawa K, McLeod IX, Yates JR III, Desai A, Fukagawa T. The CENP-H-I complex is required for the efficient incorporation of newly synthesized CENP-A into centromeres. Nat Cell Biol. 2006; 8: 446-457.
52. Murray R, Granner D, Mayes P, Rodwell V. Harper's Illustrated Biochemistry. New York, NY: Lange Medical Books/McGraw-Hill; 2003.
53. Selhub J, Morris MS, Jacques PF. In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations. Proc Natl Acad Sci USA. 2007; 104: 19995-20000.
54. Geiszt M, Kopp JB, Varnai P, Leto TL. Identification of renox, an NAD (P) H oxidase in kidney. Proc Natl Acad Sci USA. 2000; 97: 8010-8014.
55. Sharma K, Ramachandrarao S, Qiu G, Usui HK, Zhu Y, Dunn SR, Ouedraogo R, Hough K, McCue P, Chan L, Falkner B, Goldstein BJ. Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest. 2008; 118: 1645-1656.