Homocysteine 

• Elevated blood  level of homocysteine is a risk factor for thrombogenesis (blood clots), atherogenesis (plaque buildup), and CAD (coronary artery disease).¹ Since several homocysteine lowering trials have consistently failed to produce any beneficial outcome, measuring and or treating homocysteine cannot be recommended at this time.^{2, 3}  However, the value of homocysteine lowering in people without heart disease (primary prevention) has not been ascertained.

• High homocysteine level may be a risk marker, rather than causal risk factor, allowing many intermediate risk individuals to be reclassified as high-risk qualifying for more aggressive medical management.^1-4

• Several classes of drugs, such as biguanides, fibrates and hydrochlorothiazide have been reported to raise circulating homocysteine levels. On the other hand beta-blockers, calcium channel blockers, statins, sulphonylureas, TZDs, biguanide, and meglitinide reduce homocysteine level.⁵

• Homocysteine augments the deposition of Lp(a)on fibrin surfaces and its pathological effects are exponentially increased with the concomitant presence of elevated Lp(a) (30-fold) and Factor V Leiden (20-fold).^{6, 7} Homocysteine, even at low concentration markedly increases the affinity of Lp(a) for fibrin.⁸ 

• Raised homocysteine and serum Lp(a) levels were found to be independently associated with ischemic stroke with a significant positive correlation between the two parameters in Indians.⁹ Elevated homocysteine levels may modulate the toxicity of Lp(a) in ischemic stroke.

• Homocysteine levels are higher among Asian Indians than Europids in several countries.^10-16 Homocysteine levels > 15 mmol/L are found in 75-84% of subjects in India.^{12, 17} High homocysteine levels in Asian Indians in India and the Diasporas appear to be related more to subnormal levels of vitamin B12 rather than folic acid deficiency.^{12, 16, 17} Overall, 47%- 67% of Indian men had low vitamin B12 concentration (<150 pmol/L)^{12, 17} Low vitamin B12 concentration contributed 28% to the risk of hyperhomocysteinemia (population attributable risk) while low red cell folate contributed 2%.¹⁷

• Many experts believe that intrauterine growth retardation (IUGR) is a risk factor for insulin resistance and premature cardiometabolic risk. High maternal levels of homocysteine associated with low maternal and cord folate levels) have been implicated in IUGR warranting further studies.¹⁸

• High homocysteine level is now considered the single best measure of poor dietary habits such as not eating fresh fruits and vegetables as well as overcooking and deep-frying which destroy most of the nutrients, especially folate. It appears that widespread B12 deficiency is another perhaps more important risk factor for Indians.

• In India, most people adhere to a vegetarian diet, which may lead to cobalamin deficiency. Vegetarians have 3.0 times higher risk of hyperhomocysteinemia compared to those who ate non-vegetarian foods frequently.¹⁷ Vegetarians also had 4 times higher risk of low vitamin B12 concentrations¹⁷Thus, impaired cobalamin status appears more important than folate deficiency among Asian Indians.

• Some reports have suggested that higher homocysteine levels in South Asians are due to high levels amongst Hindus many of whom are vegtarians.¹⁹  Only 2.5% of the Asian Indians are homozygous for the MTHFR 677C–>T polymorphism and thus genetic abnormalities plays no significant role in elevated homocysteine levels in Asian Indians.

Sources

1. Veeranna V. Z, S. K., Niraj A, Pradhan J, et al. Homocysteine and reclassification of cardiovascular disease risk. J Am Coll Cardiol. Aug 30 2011;58(10):1025-1033.

2. Smulders YM, Blom HJ. The homocysteine controversy. J Inherit Metab Dis. Feb 2011;34(1):93-99.

3. Miller ER, 3rd, Juraschek S, Pastor-Barriuso R, Bazzano LA, Appel LJ, Guallar E. Meta-analysis of folic acid supplementation trials on risk of cardiovascular disease and risk interaction with baseline homocysteine levels. Am J Cardiol. Aug 15 2010;106(4):517-527.

4. Hlatky MA, Greenland P, Arnett DK, et al. Criteria for evaluation of novel markers of cardiovascular risk: a scientific statement from the American Heart Association. Circulation. May 5 2009;119(17):2408-2416.

5. Ntaios G, Savopoulos C, Chatzopoulos S, Mikhailidis D, Hatzitolios A. Iatrogenic hyperhomocysteinemia in patients with metabolic syndrome: a systematic review and metaanalysis. Atherosclerosis. Jan 2011;214(1):11-19.

6. Enas EA, Mehta JL. Lipoprotein (a): an important risk factor in coronary artery disease. J Am Coll Cardiol. Oct 1998;32(4):1132-1134.

7. Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Williams RR. Lipoprotein(a) interactions with lipid and nonlipid risk factors in early familial coronary artery disease. Arterioscler Thromb Vasc Biol. 1997;17(11):2783-2792.

8. Harpel PC, Chang VT, Borth W. Homocysteine and other sulfhydryl compounds enhance the binding of lipoprotein(a) to fibrin: a potential biochemical link between thrombosis, atherogenesis, and sulfhydryl compound metabolism. Proc Natl Acad Sci U S A. 1992;89(21):10193-10197.

9. Dhamija R. K., Gaba P, Arora S, Kaintura A, Kumar M, Bhattacharjee J. Homocysteine and lipoprotein (a) correlation in ischemic stroke patients. J Neurol Sci. Mar 12 2009.

10. Chambers JC, Kooner JS. Homocysteine: a novel risk factor for coronary heart disease in UK Indian Asians. Heart. 2001;86(2):121-122.

11. Anand SS, Yusuf S, Vuksan V, et al. Differences in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE). Lancet. 2000;356(9226):279-284.

12. Refsum H, Yajnik CS, Gadkari M, et al. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr. 2001;74(2):233-241.

13.Superko HR, Enas EA, Kotha P, Bhat N. Impaired cholesterol transport in Asian Indians. J Am Coll Cardiol. 2001;37:300A.

14. Heng DM, Lee J, Chew SK, Tan BY, Hughes K, Chia KS. Incidence of ischaemic heart disease and stroke in Chinese, Malays and Indians in Singapore: Singapore Cardiovascular Cohort Study. Ann Acad Med Singapore. 2000;29(2):231-236.

15. Chambers JC, Obeid OA, Refsum H, et al. Plasma homocysteine concentrations and risk of coronary heart disease in UK Indian Asian and European men. Lancet. 2000;355(9203):523-527.

16. Chandalia M, Abate N, Cabo-Chan AV, Jr., Devaraj S, Jialal I, Grundy SM. Hyperhomocysteinemia in Asian Indians living in the United States. J Clin Endocrinol Metab. 2003;88(3):1089-1095.

17. Yajnik CS, Deshpande SS, Lubree HG, et al. Vitamin B12 deficiency and hyperhomocysteinemia in rural and urban Indians. J Assoc Physicians India. Oct 2006;54:775-782.

18. Lindblad B, Zaman S, Malik A, et al. Folate, vitamin B12, and homocysteine levels in South Asian women with growth-retarded fetuses. Acta Obstet Gynecol Scand. Nov 2005;84(11):1055-1061.

19. Cappuccio FP, Bell R, Perry IJ, et al. Homocysteine levels in men and women of different ethnic and cultural background living in England. Atherosclerosis. Sep 2002;164(1):95-102.