The Association Between End-Stage Diabetic Nephropathy and Methylenetetrahydrofolate Reductase Genotype with Macroangiopathy in Type 2 Diabetes Mellitus

G. Hasegawa; H. Obayashi; K. Kamiuchi; M. Nakai; T. Kanatsuna; M. Yamaguchi; T. Tanaka; H. Shigeta; M. Fujii; T. Yoshikawa; N. Nakamura

doi:10.1055/s-2003-39785

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2003; 111(3): 132-138
DOI: 10.1055/s-2003-39785

Article

J. A. Barth Verlag in Georg Thieme Verlag Stuttgart · New York

The Association Between End-Stage Diabetic Nephropathy and Methylenetetrahydrofolate Reductase Genotype with Macroangiopathy in Type 2 Diabetes Mellitus

G. Hasegawa¹ , H. Obayashi² , K. Kamiuchi¹ , M. Nakai³ , T. Kanatsuna³ , M. Yamaguchi⁴ , T. Tanaka⁴ , H. Shigeta⁴ , M. Fujii⁵ , T. Yoshikawa¹ , N. Nakamura¹

¹The First Department of Internal Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
²The Department of Clinical Research, Kyoto Microbiological Institute, Kyoto, Japan
³The Department of Internal Medicine, Nishijin Hospital, Kyoto, Japan
⁴The Department of Internal Medicine, Kyoto First Red Cross Hospital, Kyoto, Japan
⁵The Department of Internal Medicine, Kobe Central Hospital, Kobe, Japan

Abstract

The T/T genotype of the methylenetetrahydrofolate reductase C677 T gene polymorphism is associated with elevated homocysteine levels and presumably with increased atherosclerotic risk. We evaluated the interaction between this gene polymorphism and end-stage diabetic nephropathy on the observed prevalence of macroangiopathy in type 2 diabetes mellitus. The methylenetetrahydrofolate reductase 677 C/T genotypes were determined in 174 type 2 diabetic patients: 80 with and 94 without renal failure due to diabetic nephropathy. In the patients with renal failure, the T/T genotype and T allele were significantly associated with macroangiopathy (T/T; 31 % vs. 2 %, P = 0.0001 T allele; 59 % vs. 29 %, P = 0.00014), whereas the associations were not significant in the patients without renal failure. In the multiple logistic regression analysis, age (10 years OR 4.05 [1.79 - 9.31], P < 0.0005) and 677 T allele (6.84 [2.12 - 22.05], P = 0.0013) were significantly associated with macroangiopathy in the patients with renal failure. In conclusion, this study demonstrated that the 677 T/T genotype and T allele of MTHFR were significantly associated with macroangiopathy in type 2 diabetic patients with renal failure. The MTHFR 677 T allele, together with renal dysfunction due to diabetic nephropathy, could be a strong risk factor for atherosclerotic disease.

Key words

Atherosclerosis - polymorphism - methylenetetrahydrofolate reductase - renal failure

Full Text

References

1 Alberti K GMM, Zimmet (for the consultation) P ZWHO. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus. Provisional report of a WHO consultation. Diabetic Med. 1998; 15 539-553
2 Anderson J L, King G J, Thomson M J, Todd M, Bair T L, Muhlestein J B, Carlquist J F. A mutation in the methylenetetrahydrofolate reductase gene is not associated with increased risk for coronary artery disease or myocardial infarction. J Am Coll Cardiol. 1997; 30 1206-1211
3 Arai K, Yamasaki Y, Kajimoto Y, Watada H, Umayahara Y, Kodama M, Sakamoto K, Hori M. Association of methylenetetrahydrofolate reductase gene polymorphism with carotid arterial wall thickening and myocardial infarction risk in NIDDM. Diabetes. 1997; 46 2102-2104
4 Araki A, Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr. 1987; 422 43-52
5 Bachmann J, Tepel M, Raidt H, Riezler R, Graefe U, Langer K, Zidek W. Hyperhomocysteinemia and the risk for vascular disease in hemodialysis patients. J Am Soc Nephrol. 1995; 6 121-125
6 Bostom A G, Shemin D, Verhoef P, Nadeau M R, Jacques P F, Selhub J, Dworkin L, Rosenberg I H. Elevated fasting total plasma homocysteine levels and cardiovascular disease outcomes in maintenance dialysis patients. A prospective study. Arterioscler Thromb Vasc Biol. 1997; 17 2554-2558
7 Bostom A G, Brosnan J T, Hall B, Nadeau M R, Selhub J. Net uptake of plasma homocysteine by the rat kidney in vivo. Atherosclerosis. 1995; 116 59-62
8 Bostom A G, Gohh R Y, Bausserman L, Hakas D, Jacques P F, Selhub J. Serum cystatin C as a determinant of fasting total homocysteine levels in renal transplant recipients with a normal serum creatinine. J Am Soc Nephrol. 1999; 10 164-166
9 Chambers J C, Obeid O A, Kooner J S. Physiological increments in plasma homocysteine induce vascular endothelial dysfunction in normal human subjects. Arterioscler Thromb Vasc Biol. 1999; 19 2922-2927
10 Cheung A K, Sarnak M J, Yan G, Dwyer J T, Heyka R J, Rocco M V, Teehan B P, Levey A S. The hemodialysis (HEMO) study. Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients. Kidney Int. 2000; 58 353-362
11 Chico A, Perez A, Cordoba A, Arcelus R, Carreras G, de Leiva A, Gonzalez-Sastre F, Blanco-Vaca F. Plasma homocysteine is related to albumin excretion rate in patients with diabetes mellitus: a new link between diabetic nephropathy and cardiovascular disease. Diabetologia. 1998; 41 684-693
12 Dierkes J, Domrose U, Ambrosch A, Schneede J, Guttormsen A B, Neumann K H, Luley C. Supplementation with vitamin B12 decreases homocysteine and methylmalonic acid but also serum folate in patients with end-stage renal disease. Metabolism. 1999; 48 631-635
13 Franken D G, Boers G HJ, Blom H J, Trijbels J M, Kloppenborg P WC. Effect of various regimens of vitamin B6 and folic acid on mild hyperhomocysteinemia in vascular patients. J Inherited Metab Dis. 1994; 17 159-162
14 Frosst P, Blom H J, Milos R, Goyette P, Sheppard C A, Matthewes R G, Boers G JH, den Heijer M, Kluijtmans L AJ, van den Heuvel L P, Rozan R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995; 10 111-113
15 Födinger M, Mannhalter C, Wölfl G, Pabinger I, Muller E, Schmid R, Horl W H, Sunder-Plassmann G. Mutation (677 C to T) in the methylenetetrahydrofolate reductase gene aggravates hyperhomocysteinemia in hemodialysis patients. Kidney Int. 1997; 52 517-523
16 Gardemann A, Weidemann H, Philipp M, Katz N, Tillmanns H, Hehrlein F W, Haberbosch W. The TT genotype of the methylenetetrahydrofolate reductase C677 T gene polymorphism is associated with the extent of coronary atherosclerosis in patients at high risk for coronary artery disease. Eur Heart J. 1999; 20 584-592
17 Giles W H, Croft J B, Greenlund K J, Ford E S, Kittner S J. Association between total homocyst(e)ine and the likelihood for a history of acute myocardial infarction by race and ethnicity: Results from the third national health and nutrition examination survey. Am Heart J. 2000; 139 446-453
18 Graham I M, Daly L E, Refsum H M, Robinson K, Brattstrom L E, Ueland P M, Palma-Reis R J, Boers G H, Sheahan R G, Israelsson B, Uiterwaal C S, Meleady R, McMaster D, Verhoef P, Witteman J, Rubba P, Bellet H, Wautrecht J C, de Valk H W, Sales L A, Parrot-Rouland F M, Tan K S, Higgins I, Garcon D, Andria G. Plasma homocysteine as a risk factor for vascular disease. The European Concerted Action Project. JAMA. 1997; 277 1775-1781
19 Harker L A, Ros R, Slichter S, Scott R C. Homocystine-induced arteriosclerosis: the role of endothelial cell injury and platelet response in its genesis. J Clin Invest. 1976; 58 731-741
20 Hultberg B, Anderson A, Sterner G. Plasma homocysteine in renal failure. Clin Nephrol. 1993; 40 230-235
21 Jacques P F, Bostom A G, Williams R R, Ellison R C, Eckfeld J H, Rosenberg I H, Selhub J, Rozen R. Relationship between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation. 1996; 93 7-9
22 Jager A, Kostense P J, Nijpels G, Dekker J M, Heine R J, Bouter L M, Donker A JM, Stehouwer C DA. Serum homocysteine levels are associated with the development of (micro)albuminuria: The Hoorn study. Arterioscler Thromb Vasc Biol. 2001; 21 74-81
23 Kitiyakara C, Gonin J, Massy Z, Wilcox C S. Non-traditional cardiovascular disease risk factors in end-stage renal disease: oxidative stress and hyperhomocysteinemia. Curr Opin Nephrol Hypertens. 2000; 9 477-487
24 London G M, Drueke T B. Atherosclerosis and arteriosclerosis in chronic renal failure. Kidney Int. 1997; 51 1678-1695
25 Ma J, Stampfer M J, Hennekens C H, Frosst P, Selhub J, Horsford J, Malinow M R, Willett W C, Rozen R. Methylenetetrahydrofolate reductase polymorphism, plasma folate, homocysteine, and risk of myocardial infarction in US physicians. Circulation. 1996; 94 2410-2416
26 Mazza A, Motti C, Nulli A, Marra G, Gnaso A, Pastore A, Federici G, Cortese C. Lack of association between carotid intima-media thickness and methylenetetrahydrofolate reductase gene polymorphism or serum homocysteine in non-insulin-dependent diabetes mellitus. Metabolism. 2000; 49 718-723
27 Morita H, Taguchi J I, Kurihara H, Kitaoka M, Kaneda H, Kurihara Y, Maemura K, Shindo T, Minamino T, Ohno M, Yamaoki K, Ogasawara K, Aizawa T, Suzuki S, Yazaki Y. Genetic polymorphism of 5, 10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation. 1997; 95 2032-2036
28 Moustapha A, Naso A, Nahlawi M, Gupta A, Arheart K L, Jacobsen D W, Robinson K, Dennis V W. Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease. Circulation. 1998; 97 138-141
29 Selhub J, Jacques P F, Wilson P W, Rush D, Rosenberg I H. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA. 1993; 270 2693-2698
30 Stanford J L, Molina H, Phillips J, Kohlman-Trigoboff D, Moore J, Smith B M. Oral folate reduces plasma homocyst(e)ine levels in hemodialysis patients with cardiovascular disease. Cardiovasc Surg. 2000; 8 567-571
31 Sunder-Plassmann G, Födinger M, Buchmayer H, Papagiannopoulos M, Wojcik J, Kletzmayr J, Enzenberger B, Janata O, Winkelmayer W C, Paul G, Auinger M, Barnas U, Horl W H. Effect of high dose folic acid therapy on hyperhomocysteinemia in hemodialysis patients: results of the Vienna multicenter study. J Am Soc Nephrol. 2000; 11 1106-1116
32 Vychytil A, Födinger M, Wölfl G, Enzenberger B, Auinger M, Prischl F, Buxbaum M, Wiesholzer M, Mannhalter C, Höri W H, Sunder-Plassmann G. Major determinants of hyperhomocycteinemia in peritoneal dialysis patients. Kidney Int. 1998; 53 1775-1782
33 Wall R T, Harlan J M, Harker L A, Striker G E. Homocysteine-induced endothelial cell injury in vitro: A model for the study of vascular injury. Thromb Res. 1980; 18 113-121
34 Weisberg I, Tran P, Christensen B, Sibani S, Rozen R. A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab. 1998; 64 169-172
35 Wilcken D EL, Wang X L, Adachi T, Hara H, Duarte N, Green K, Wilcken B. Relationship between homocysteine and superoxide dismutase in homocystinuria. Possible relevance to cardiovascular risk. Arterioscler Thromb Vasc Biol. 2000; 20 1199-1202
36 Wollesen F, Brattström L, Refsum H, Ueland P M, Berglund L, Berne C. Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int. 1999; 55 1028-1035

M. D. Goji Hasegawa

First Department of Internal Medicine, Kyoto Prefectural University of Medicine

465 kajii-cho, Kawaramachi-Hirokoji, kamikyo-ku,

Kyoto 602-8566

Japan

Phone: + 81752515505

Fax: + 81752523721

Email: goji@koto.kpu-m.ac.jp