Chronic alcohol consumption is reported to be associated with increase in plasma homocysteine levels which is further influenced by the polymorphism in methylenetetrahydrofolate reductase (MTHFR) gene. The present study aims to understand the extent of the MTHFR C677T polymorphism in alcohol dependent (AD) cases of Meiteis of Manipur, a Mendelian population of India. MTHFR C677T polymorphism was screened in 313 controls and 139 alcohol dependent (AD) cases who all met DSM-IV criteria for alcohol dependence. Both AD cases and controls were unrelated up to 1st cousin. Among the control group, different drinking patterns like abstainer/nondrinkers (NDs), occasional drinkers (ODs), and moderate drinkers (MDs) are included. Both the groups were found to be in Hardy-Weinberg equilibrium (). Genotypic and allelic frequency distribution of MTHFR C677T polymorphism did not differ significantly between AD cases and controls (). However, individuals carrying mutant (T) allele show more than 1-fold increased risk for AD though not significant (OR？=？1.43; 95% CI 0.41–5.01, ). In conclusion, MTHFR C677T polymorphism is not found to be risk marker for AD in present studied population. However, higher prevalence of the mutant T allele may exacerbate deleterious health risk in future especially among alcohol drinkers. 1. Introduction Alcoholism or alcohol dependence (AD) is a complex trait characterized by a cluster of physiological, behavioural, and cognitive phenomena in which the use of alcohol takes on a much higher priority for a given individual than other behaviours that once had greater value [1]. The World Health Organization (WHO) estimates that about 140 million people throughout the world suffer from AD [2]. Moreover, it is one of the leading health risks and is likely to become world’s third largest risk factor for disease and disability. Approximately 2.5 million deaths each year are attributable to alcohol, resulting in 4% of all deaths worldwide [3]. Several studies show significance of genetic influences in substance abuse and dependence [4, 5]. However, comprehensive molecular and pathophysiological mechanism associated with AD is not completely revealed yet. As genetic predisposition to AD and its related morbidity and mortality is undebatable, the emerging research has picked up momentum targeting various pathways involved in alcohol consumption and metabolism for deeper understanding of the pathophysiology of AD. Recent studies revealed association of gene that encodes the methylenetetrahydrofolate reductase (MTHFR C677T) with AD. However, findings
References
[1]
WHO, The ICD-10: Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines, World Health Organisation, Geneva, Switzerland, 1992.
[2]
WHO, Global Status Report on Alcohol, WHO, Geneva, Switzerland, 2004.
[3]
WHO, Global Status Report on Alcohol and Health, WHO, Geneva, Switzerland, 2011.
[4]
M.-A. Enoch, “Genetic and environmental influences on the development of alcoholism: resilience vs. risk,” Annals of the New York Academy of Sciences, vol. 1094, pp. 193–201, 2006.
[5]
D. M. Dick and A. Agrawal, “The genetics of alcohol and other drug dependence,” Alcohol Research and Health, vol. 31, no. 2, pp. 111–118, 2008.
[6]
U. C. Lutz, A. Batra, W. Kolb, F. MacHicao, S. Maurer, and M. D. K？hnke, “Methylenetetrahydrofolate reductase C677T-polymorphism and its association with alcohol withdrawal seizure,” Alcoholism: Clinical and Experimental Research, vol. 30, no. 12, pp. 1966–1971, 2006.
[7]
R. Saffroy, A. Benyamina, P. Pham et al., “Protective effect against alcohol dependence of the thermolabile variant of MTHFR,” Drug and Alcohol Dependence, vol. 96, no. 1-2, pp. 30–36, 2008.
[8]
A. Benyamina, R. Saffroy, L. Blecha et al., “Association between MTHFR 677C-T polymorphism and alcohol dependence according to Lesch and Babor typology,” Addiction Biology, vol. 14, no. 4, pp. 503–505, 2009.
[9]
P. Frosst, H. J. Blom, R. Milos et al., “A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase,” Nature Genetics, vol. 10, no. 1, pp. 111–113, 1995.
[10]
L. L. N. Husemoen, T. F. Thomsen, M. Fenger, H. L. J？rgensen, and T. J？rgensen, “Contribution of thermolabile methylenetetrahydrofolate reductase variant to total plasma homocysteine levels in healthy men and women. Inter99 (2),” Genetic Epidemiology, vol. 24, no. 4, pp. 322–330, 2003.
[11]
S. Bleich, M. Carl, K. Bayerlein et al., “Evidence of increased homocysteine levels in alcoholism: the Franconian alcoholism research studies (FARS),” Alcoholism: Clinical and Experimental Research, vol. 29, no. 3, pp. 334–336, 2005.
[12]
Homocysteine Studies Collaboration, “Homocysteine and risk of ischemic heart disease and stroke a meta-analysis,” Journal of American Medical Association, vol. 288, no. 16, pp. 2015–2022, 2002.
[13]
S. Seshadri, A. Beiser, J. Selhub et al., “Plasma homocysteine as a risk factor for dementia and Alzheimer's disease,” The New England Journal of Medicine, vol. 346, no. 7, pp. 476–483, 2002.
[14]
S. Ningombam, Y. Hutin, and M. V. Murhekar, “Prevalence and pattern of substance use among the higher secondary school students of Imphal, Manipur, India,” National Medical Journal of India, vol. 24, no. 1, pp. 11–15, 2011.
[15]
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (DSM-IV), American Psychiatric Press, Washington, DC, USA, 1994.
[16]
V. R. Arruda, P. M. von Zuben, L. C. Chiaparini, J. M. Annichino-Bizzacchi, and F. F. Costa, “The mutation Ala 677> Val in the methylene tetrahydrofolate reductase gene: a risk factor for arterial disease and venous thrombosis,” Thrombosis and Haemostasis, vol. 77, no. 5, pp. 818–821, 1997.
[17]
S. A. Miller, D. D. Dykes, and H. F. Polesky, “A simple salting out procedure for extracting DNA from human nucleated cells,” Nucleic Acids Research, vol. 16, no. 3, p. 1215, 1988.
[18]
F. C. Yeh and R. Yang, Popgene Version 1.31. Microsoft Window Based Freeware for Population Genetic Analysis, University of Alberta and Tim Boyle, Centre for International Forestry Research, Alberta, Canada, 1999.
[19]
http://vassarstats.net/odds2x2.html.
[20]
L. B. Bailey, “Folate , methyl-related nutrients, alcohol, and the MTHFR 677C>T polymorphism affect cancer risk: intake recommendations,” Journal of Nutrition, vol. 133, supplement 1, no. 11, pp. 3748–3753, 2003.
[21]
R. Saffroy, P. Pham, F. Chiappini et al., “The MTHFR 677C>T polymorphism is associated with an increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis,” Carcinogenesis, vol. 25, no. 8, pp. 1443–1448, 2004.
[22]
K. N. Saraswathy, M. Asghar, R. Samtani et al., “Spectrum of MTHFR gene SNPs C677T and A1298C: a study among 23 population groups of India,” Molecular Biology Reports, vol. 39, no. 4, pp. 5025–5031, 2012.
[23]
S. Kabita, H. S. Singh, D. S. Chongtham, and K. N. Saraswathy, “MTHFR C677T polymorphism among Meiteis of Manipur (India),” Ethnicity and Disease, vol. 23, no. 3, pp. 379–381, 2013.
[24]
S. Bleich, D. Degner, K. Javaheripour, C. Kurth, and J. Kornhuber, “Homocysteine and alcoholism,” Journal of Neural Transmission, vol. 60, pp. 187–196, 2000.
[25]
M. P. Mattson and T. B. Shea, “Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders,” Trends in Neurosciences, vol. 26, no. 3, pp. 137–146, 2003.
[26]
A. Fuso, L. Seminara, R. A. Cavallaro, F. D'Anselmi, and S. Scarpa, “S-adenosylmethionine/homocysteine cycle alterations modify DNA methylation status with consequent deregulation of PS1 and BACE and beta-amyloid production,” Molecular and Cellular Neuroscience, vol. 28, no. 1, pp. 195–204, 2005.
[27]
D. B？nsch, B. Lenz, J. Kornhuber, and S. Bleich, “DNA hypermethylation of the alpha synuclein promoter in patients with alcoholism,” NeuroReport, vol. 16, no. 2, pp. 167–170, 2005.
