Genetic polymorphisms modulate the folate metabolism of Brazilian individuals with Down syndrome

Abstract

Individuals with Down syndrome (DS) carry three copies of the Cystathionine b-synthase (CbS) gene. The increase in the dosage of this gene results in an altered profile of metabolites involved in the folate pathway, including reduced homocysteine (Hcy), methionine, S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM). Furthermore, previous studies in individuals with DS have shown that genetic variants in genes involved in the folate pathway influence the concentrations of this metabolism's products. The purpose of this study is to investigate whether polymorphisms in genes involved in folate metabolism affect the plasma concentrations of Hcy and methylmalonic acid (MMA) along with the concentration of serum folate in individuals with DS. Twelve genetic polymorphisms were investigated in 90 individuals with DS (median age 1.29 years, range 0.07-30.35 years; 49 male and 41 female). Genotyping for the polymorphisms was performed either by polymerase chain reaction (PCR) based techniques or by direct sequencing. Plasma concentrations of Hcy and MMA were measured by liquid chromatography-tandem mass spectrometry as previously described, and serum folate was quantified using a competitive immunoassay. Our results indicate that the MTHFR C677T, MTR A2756G, TC2 C776G and BHMT G742A polymorphisms along with MMA concentration are predictors of Hcy concentration. They also show that age and Hcy concentration are predictors of MMA concentration. These findings could help to understand how genetic variation impacts folate metabolism and what metabolic consequences these variants have in individuals with trisomy 21.

DHFR 19-bp Deletion and SHMT C1420T Polymorphisms and Metabolite Concentrations of the Folate Pathway in Individuals with Down Syndrome

“…The presence of three copies of the CBS gene, located on chromosome 21, and Methylenetetrahydrofolate reductase (MTHFR) C677T, Methionine synthase (MTR) A2756G, Transcobalamin 2 (TC2) C776G, and Betaine homocysteine methyltransferase (BHMT) G742A polymorphisms, involved in folate/Hcy metabolism, have been associated with variations on the concentrations of metabolites of this pathway (Pogribna et al, 2001;Fillon-Emery et al, 2004;Guéant et al, 2005;Licastro et al, 2006;Coppus et al, 2007;Biselli et al, 2008;Meguid et al, 2010;Biselli et al, 2012). Guéant et al (2005) observed that individuals with DS who present the MTHFR 677T allele and an elevated Hcy concentration had a low intelligence quotient and Licastro et al (2006) found that the MTHFR 677TT genotype increases the concentrations of Hcy in these individuals.…”

“…Studies have shown that, in addition to overexpression of the CBS gene, polymorphisms in genes involved in folate/ Hcy metabolism may also influence metabolite concentrations of this pathway (Fillon-Emery et al, 2004;Guéant et al, 2005;Licastro et al, 2006;Biselli et al, 2008;Biselli et al, 2012). A 19-base pair (bp) deletion polymorphism in intron-1 of the Dihydrofolate reductase (DHFR) gene, located on chromosome 5q11.2, has been identified ( Johnson et al, 2004) and Kalmbach et al (2008) demonstrated that this is a functional polymorphism.…”

Systematic review and meta-analysis shows a specific micronutrient profile in people with Down Syndrome: Lower blood calcium, selenium and zinc, higher red blood cell copper and zinc, and higher salivary calcium and sodium

“…We reviewed the remaining 117 publications. Based on detail review, we excluded 40 additional publications: eight articles were excluded because they did not report adequate data [29–36] another eight because a healthy control group lacked [37–44]. One was a duplicate record [45].…”

A pilot clinical trial assessing the efficacy and safety of supplementation with a B complex vitamin to reduce the incidence of chemotherapy induced peripheral neuropathy in patients diagnosed with a malignancy

“…Four studies addressing various samples was conducted on vitamin B complexes [346][347][348][349], a review on folate, vitamin B6 and B12 was conducted on methods for analysis in humans [350], four studies were conducted on vitamin B6 [351][352][353][354], two on folate [355,356], five on vitamin B12 [357][358][359][360][361] and one on betaine (from choline) [362]. These studies have been outlined below in Table 3-2.…”

“…It was determined that both were fast, reliable and sensitive for folate vitamers, homocysteine and methyl malonic acid [355,356].…”