Abstract
BackgroundHyperhomocysteinemia (>15 µmol/L) is highly prevalent in South Asian populations including Pakistan. In order to investigate the genetic determinants of this condition, we studied 6 polymorphisms in genes of 3 enzymes - methylenetetrahydrofolate reductase (MTHFR; C677T; A1298C), methionine synthase (MS; A2756G), cystathionine-β-synthase (CBS; T833C/844ins68, G919A) involved in homocysteine metabolism and investigated their interactions with nutritional and environmental factors in a Pakistani population.Methodology/Principal FindingsIn a cross-sectional survey, 872 healthy adults (355 males and 517 females; age 18–60 years) were recruited from a low-income urban population in Karachi. Fasting venous blood was obtained and assessed for plasma/serum homocysteine; folate, vitamin B12, pyridoxal phosphate and blood lead. DNA was isolated and genotyping was performed by PCR-RFLP (restriction-fragment-length- polymorphism) based assays. The average changes in homocysteine levels for MTHFR 677CT and TT genotypes were positive [β(SE β), 2.01(0.63) and 16.19(1.8) µmol/L, respectively]. Contrary to MTHFR C677T polymorphism, the average changes in plasma homocysteine levels for MS 2756AG and GG variants were negative [β(SE β), −0.56(0.58) and −0.83(0.99) µmol/L, respectively]. The average change occurring for CBS 844ins68 heterozygous genotype (ancestral/insertion) was −1.88(0.81) µmol/L. The combined effect of MTHFR C677T, MS A2756G and CBS 844ins68 genotypes for plasma homocysteine levels was additive (p value <0.001). Odds of having hyperhomocysteinemia with MTHFR 677TT genotype was 10-fold compared to MTHFR 677CC genotype [OR (95%CI); 10.17(3.6–28.67)]. Protective effect towards hyperhomocysteinemia was observed with heterozygous (ancestral/insertion) genotype of CBS 844ins68 compared to homozygous ancestral type [OR (95% CI); 0.58 (0.34–0.99)]. Individuals with MTHFR 677CT or TT genotypes were at a greater risk of hyperhomocysteinemia in folate and vitamin B12 deficiencies and high blood lead (p value <0.05) level.ConclusionsGene polymorphism (especially MTHFR C677T transition), folate and vitamin B12 deficiencies, male gender and high blood lead level appear to be contributing towards the development of hyperhomocysteinemia in a Pakistani population.
Highlights
Cardiovascular disease (CVD) which is defined as diseases of the heart and blood vessels of the body, has reached epidemic proportions in South Asia [1]
Gene polymorphism, folate and vitamin B12 deficiencies, male gender and high blood lead level appear to be contributing towards the development of hyperhomocysteinemia in a Pakistani population
While deficiency of folate and vitamin B12 have been found to be associated with high levels of plasma homocysteine, the role of polymorphisms in combination of genes of enzymes involved in homocysteine metabolism need to be explored in the South Asian general population
Summary
Cardiovascular disease (CVD) which is defined as diseases of the heart and blood vessels of the body, has reached epidemic proportions in South Asia [1]. A recent study carried out in Singapore indicates that nationals of Indian descent had the highest frequency of CBS 844ins allele and MS 2756G allele, while Singaporean Chinese had the highest frequency of MTHFR 677T allele [5] This indicates that genetic determinants of plasma homocysteine in Asians vary to a great extent. In order to investigate the genetic determinants of this condition, we studied 6 polymorphisms in genes of 3 enzymes methylenetetrahydrofolate reductase (MTHFR; C677T; A1298C), methionine synthase (MS; A2756G), cystathionine-bsynthase (CBS; T833C/844ins, G919A) involved in homocysteine metabolism and investigated their interactions with nutritional and environmental factors in a Pakistani population
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