Polymorphisms in the CBS gene associated with decreased risk of coronary artery disease and increased responsiveness to total homocysteine lowering by folic acid

Elevated total plasma homocysteine (tHcy) is an established risk factor for the development of vascular disease and neural tube defects. Total homocys teine levels can be lowered by folic acid supplements but individual respon se is highly variable, In this case-control study, involving 142 coronary a rtery disease (CAD) patients and 102 controls, we have typed six genetic po lymorphisms in three homocysteine metabolizing genes and examined their rel ationship to the incidence of CAD, tHcy levels, and lowering of tHcy levels in response to folic acid supplementation. We found that two single nucleo tide polymorphisms in the cystathionine beta synthase (CBS) gene, 699C --> T and 1080T --> C, are associated with decreased risk of CAD and increased responsiveness to the tHcy Lowering effects of folic acid. individuals homo zygous for 699T were significantly underrepresented ill CAD patients as com pared to controls (4.9% vs 17.3%, P = 0.0015), as were individuals homozygo us for the 1080C (29.6% vs 44.2%, P = 0.018). Additionally, 699T and 1080C homozygous individuals were the most responsive to folate supplementation. 699T homozygotes lowered tHcy levels 13.6% on average, compared to 4.8% low ering in 699C homozygotes (P = 0.009), while 1080C homozygotes lowered 12.9 % compared to just 2.7% for 1080T homozygotes (P = 0.005), The two polymorp hisms in CBS are third codon changes and would not be predicted to affect t he underlying protein. However, there is strong linkage disequilibrium betw een these two positions, suggesting that they may also be linked to other a s yet unidentified polymorphisms within the CBS gene. These observations su ggest that specific CBS alleles are a risk factor for the development of va scular disease and that genetic information could be predictive of individu al response to folic acid supplementation. (C) 2000 Academic Press.