Association of TCN2 rs1801198 c.776G>C polymorphism with markers of one-carbon metabolism and related diseases: a systematic review and meta-analysis of genetic association studies

Abstract

Background: Vitamin B-12 (cobalamin) deficiency may produce severe neurologic and hematologic manifestations. Approximately 20-25% of circulating cobalamin binds to transcobalamin 2 (TCN2), which is referred to as active vitamin B-12. The G allele of the TCN2 c.776G.C (rs1801198) polymorphism has been associated with a lower plasma concentration of holotranscobalamin. However, genotype association studies on rs1801198 have led to conflicting results regarding its influence on one-carbon metabolism (OCM) markers or its association with pathologic conditions. Objective: We assessed the association of rs1801198 genotypes with OCM marker concentrations and primary risks of congenital abnormalities, cancer, and Alzheimer disease. Design: We conducted a systematic review of the literature that was published from January 1966 to February 2017 and included all studies that assessed the association between rs1801198 and OCM markers or a pathologic condition. Results: Thirty-four studies met the inclusion criteria. Subjects with the rs1801198 GG genotype had significantly lower concentrations of holotranscobalamin [standardized mean difference (SMD): 20.445 (95% CI: 20.673, 20.217; P , 0.001); I 2 = 48.16% (95% CI: 0.00%, 78.10%; P = 0.07)] and higher concentrations of homocysteine (European descent only) [SMD: 0.070 (95% CI: 0.020, 0.120; P = 0.01); I 2 = 0.00% (95% CI: 0.00%, 49.59%; P = 0.73)] than did subjects with the rs1801198 CC genotype. The meta-analysis on the association between rs1801198 and methylmalonic acid (MMA) lacked statistical power. No significant difference was observed regarding cobalamin, folate, and red blood cell folate. No significant association was observed between rs1801198 and primary risks of congenital abnormalities, cancer, or Alzheimer disease. Conclusions: Meta-analysis results indicate an influence of rs1801198 on holotranscobalamin and homocysteine concentrations in Europeandescent subjects. In addition, well-designed and -powered studies should be conducted for assessing the association between rs1801198 and MMA and clinical manifestations that are linked to a decreased availability of cobalamin. This review was registered at www.crd.york.ac.uk/prospero as CRD42017058504.

Maternal folate, one‐carbon metabolism and pregnancy outcomes

“…Transcobalamin 2 (TCN2) is a protein that is essential for binding circulating vitamin B12 for its transport into cells (Oussalah, Levy, Filhine-Tresarrieu, Namour, & Gueant, 2017). TCN2 polymorphism affects not only its expression but ultimately its plasma concentration and thus the availability of vitamin B12 to aid in re-methylation of Hcy (Oussalah et al, 2017). The C > G substitution alters the structure of the TCN2 protein affecting its affinity for vitamin B12, resulting in easier release from the bound TCN2 transporter (Afman, Lievers, van der Put, Trijbels, & Blom, 2002;Joslin, Green, German, & Lange, 2014) (Furness et al, 2013;Furness, Yasin, Dekker, Thompson, & Roberts, 2012).…”

“…We also found an association between the maternal TCN2 C776G (GG) genotype and a decreased risk for sPTB. Transcobalamin 2 (TCN2) is a protein that is essential for binding circulating vitamin B12 for its transport into cells (Oussalah, Levy, Filhine‐Tresarrieu, Namour, & Gueant, 2017). TCN2 polymorphism affects not only its expression but ultimately its plasma concentration and thus the availability of vitamin B12 to aid in re‐methylation of Hcy (Oussalah et al, 2017).…”

The Effect of Interactions between Folic Acid Supplementation and One Carbon Metabolism Gene Variants on Small-for-Gestational-Age Births in the Screening for Pregnancy Endpoints (SCOPE) Cohort Study

“…Six SNPs were included in this study: MTHFR 677 (rs1801133), MTHFR 1298 (rs1801131), MTHFD1 1958 (rs2236225), MTR 2756 (rs1805087), MTRR 66 (rs1801394), TCN2 776 (rs1801198). Supplementary Table S1 describes the chromosomal location of each SNP, the enzyme encoded by the associated gene, enzyme function and effect of the polymorphism [ 6 , 22 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ].…”

Disturbed homocysteine metabolism is associated with cancer

“…TCN-2 has ~8291 polymorphisms, out of which 1183 are deletions, 02 are multiple base substitutions, 146 are repeat variations, and 6960 are SNPs 107 . One common polymorphism in the TCN 2 gene is a G to C substitution (776 G > C, rs1801198) that results in replacement of a proline with an arginine 108 In a recent meta-analysis, it was shown that subjects with the rs1801198 GG genotype had significantly lower concentrations of holotranscobalamin and higher Hcy levels compared to subjects with the rs1801198 CC genotype. This polymorphism has also been shown to be associated with different cancers, including colorectal cancer, ovarian cancer, glioblastoma, among others.…”