Published Online
on September 5, 2009

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Original Article

Single nucleotide polymorphisms in homocysteine metabolism pathway genes: Association of CHDH A119C and MTHFR C677T with hyperhomocysteinemia.

Jitender Kumar¹; Gaurav Garg¹; Arun Kumar¹; Elayanambi Sundaramoorthy¹; Krishna Rao Sanapala²; Saurabh Ghosh²; Ganesan Karthikeyan³; Lakshmy Ramakrishnan³; Indian Genome Variation Consortium¹ and Shantanu Sengupta^1,4

¹ Institute of Genomics and Integrative Biology, Delhi, India;
² Indian Statistical Institute, Kolkata, India;
³ All India Institute of Medical Sciences, New Delhi, India

^* Corresponding author; email: shantanus{at}igib.res.in

Background—An elevated level of homocysteine (hyperhomocysteinemia) has been implicated as an independent risk factor for cardiovascular diseases. Deficiency of dietary factors like vitamin B12, folate and/or genetic variations can cause hyperhomocysteinemia. The prevalence of hyperhomocysteinemia in Indian population is likely to be high since a majority of Indians adhere to a vegetarian diet, deficient in vitamin B12. In the background of vitamin B12 deficiency, variations in genes involved in homocysteine metabolism might have a greater impact on homocysteine levels.

Methods and Results—We genotyped 44 non-synonymous single nucleotide polymorphisms (nsSNPs) from 11 genes involved in homocysteine metabolism and found only 14 to be polymorphic. These 14 nsSNPs were genotyped in 546 individuals recruited from a tertiary care centre in New Delhi, India and it was found that choline dehydrogenase (CHDH A119C) and methylenetetrahydrofolate reductase (MTHFR C677T) were significantly associated with plasma total homocysteine levels (p=0.009 and p=0.001 respectively). These 2 SNPs were further genotyped in 330 individuals recruited from the same centre and the association remained significant even after increasing the sample size. Further, we found the possibility of a significant interaction between vegetarian diet and the two polymorphisms that could explain the variation of homocysteine levels. We also genotyped all the polymorphic nsSNPs in apparently healthy individuals recruited from 24 different sub-populations (based on their linguistic lineage) spread across the country to determine their basal frequencies. The frequencies of these SNPs varied significantly between linguistic groups.

Conclusion—Vegetarian diet along with CHDH A119C and MTHFR C677T play an important role in modulating the homocysteine levels in Indian population.

Key Words: genetics • CHDH • homocysteine • MTHFR • polymorphism • Indian population