Faulty gene links vitamin deficiency to coronary artery disease
doi:10.1038/nindia.2012.47 Published online 30 March 2012
A diet rich in vegetables is short on vitamin B12 and this has already been linked to coronary artery disease (CAD). Now, a new study explains the mechanism of a gene that links this vitamin B12 deficiency with CAD1. The gene codes for a protein that helps the absorption of vitamin B12, whose deficiency leads to CAD.
The study has identified a few variations in the gene that codes for transcobalamin II (TCII), a protein to which vitamin B12 binds in order to get delivered inside cells. The gene called TCII with its defects hinders the binding of vitamin B12 to TCII protein, thus depleting the vitamin inside cells, the study reported.
Deficiency of vitamin B12 increases the levels of homocysteine and cysteine, two thiol amino acids. Both the amino acids increase the risk of CAD since they are toxic to the endothelium, the thin layer of cells that line the interior surface of blood vessels.
"This study points out that measuring the levels of vitamin B12 or vitamin B12 bound to TCII in blood should be included as a routine test along with other prescribed tests to assess the risk of CAD," lead researcher Shantanu Sengupta told Nature India.
CAD is probably the largest cause of mortality and morbidity worldwide. In India, mortality due to CAD increased from 1.17 million in 1990 to 1.59 million in 2000. For 2010, the figures might be as high as 2.03 million. This is quite surprising as as a majority of Indians are vegetarian and do not consume fat-rich animal food usually linked to heart diseases.
Intrigued, the research group launched a study to find that a strict vegetarian diet lacks vitamin B12, an important micronutrient that is sourced only from animal products. Deficiency of Vitamin B12 leads to elevated levels of homocysteine and cysteine, which have been associated with CAD.
Studies have identified anomalies in TCII gene that codes for transcobalamin II protein which binds to and ferries vitamin B12 inside the cells. Only about one third of Vitamin B12 is bound to TCII (the biologically active fraction) and this fraction of vitamin B12 is delivered to the cells.
However, no studies have explored the role of such genetic defects in vitamin B12 deficiency and CAD among Indian populations. To find out such defects in the TCII gene among Indians, the researchers scanned the genotype of 1398 individuals comprising 589 CAD patients and 809 healthy individuals at the Department of Cardiology, All Indian Institute of Medical Sciences, New Delhi. Participants were also asked to fill out a questionnaire on their diet, height and weight. The vitamin B12 levels in their blood were also measured.
Like other genes, TCII gene contains several single nucleotide polymorphisms (SNPs), a change in a single base. However, the researchers screened eight SNPs located in the coding part of TCII gene. They narrowed their search to four SNPs in TCII gene of CAD patients and controls and analysed their link with vitamin B12 levels and CAD.
Of the four, three SNPs (G1196A, C776G and C1043T) showed significant association with CAD. Even after controlling various confounding factors like age, sex, diet and diabetes, all the three SNPs remained significant.
"The genetic variations in TCII gene could affect the binding of vitamin B12 to TCII protein or intracellular uptake of TCII-vitamin B12 by the receptor, resulting in lower concentration of intracellular Vitamin B12," says Sengupta. This, in turn, increases the levels of homocysteine and cysteine enhancing the risk of CAD, he adds.
Besides assessing the risk of CAD by measuring the levels of free vitamin B12 or vitamin B12 bound to TCII protein, policies should be framed for targeted supplementation of vitamin B12, the researchers contend.
The authors of this work are from: Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, and India and Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India.