Vitamin B12 Deficiency

rs526934 is a polymorphism in the haptocorrin protein (R binder) (TCN1) gene. Allelic distribution for TCN1 is signficantly different between gastric cancer and healthy controls, with the minor G allele significantly associated with higher risk (Zhao etal, 2016)

There are 3 common variants in the gene coding for the expression of the serum B12 transporter, transcobalamin, rs1801198 (C755G), rs9606756, and rs961049. Of these rs1801198 is the most common and the best studied. The TCN2 776G allele decreases the transcription of transcobalamin and as such also decreases the cellular and plasma concentration of transcobalamin. The polymorphism has been associated with an increased risk of spontaneous abortion (Gueant et al, 2007). Curiously the frequency of the allele varies dramatically from country to country, with frequency ranging from as high as 35% in China down to 1.9% in Benin and 2.3 % in West Africa. The reduced level of the GG allele has been postulated as being selected for by the malaria parasite Plasmodium falciparum as the parasite has a huge demand for one-carbon metabolism as supplied by the host. The GG allele has also been associated with increased peripheral neuropathy following high folate intake, for reasons that are unclear (Swaengsri etal, (2016), and is more prevalent in ulcerative colitis with elevation of homocysteine, and deficiency in vitamin B12 and folate being common (Zheng etal, 2017a).

Similarly to rs1801198, rs9606756 GG allele was higher in Crohn's disease patients and was associated with lower folate and vitamin B12 levels (Zheng etal 2017b; 2016). Lower levels of vitamin B12 have been associated with lower production of CoQ10, creatine, and lower activity of iron-sulphur proteins. This could potentially explain the association of the GG allele with obesity as seen in a study in the Arab population (Hebbar et al. 2017)

rs2336573 and rs8425 are rare polymorphisms in the TCbl-receptor gene that have been associated with neural tube defects (Pangilinan et al. 2010) and lower serum vitamin B12 (Kurnat-Thoma et al, 2015).

References

Zhao etal. Association study between genome-wider significant variants of vitamin B12 metabolism and gastric cancer in a han Chinese population. IUBMB Life 2016 68: 303-10

Gueant etal, Environmental influence on the worldwide prevalence of a 776C->G variant in the transcobablamin gene (TCN2). J Med Genet 2007 44: 363-367

Sawaengsri et al. Transcobalamin 776C->G polymorphism is associated with peripheral neuropathy in elderly individuals with high folate intake. Am J Clin Nutr. 2016 104: 1665-1670

Zheng et al. Association of ulcerative colitis with transcobalamin II gene polymorphisms and serum homocysteine, vitamin B12, and folate levels in Chinese patients. Immunogenetics 2017 69: 421-428

Zheng et al. An analysis of transcobalamin II gene polymorphisms and serum levels of homocysteine, folate and vitamin B12 in Chinese Patients with Crohn's disease. Dig Dis 2017b 35: 453-471

Zheng et al. Association of Crohn's disease with transcobalamin II gene polymorphisms and serum homocysteine, folate and vitamin B12 levels in Chinese patientsl Zhonghua Ye Zue ZaXhi 2016 96: 2390-7

Hebbar et al. The TCN2 variant of rs9606756[Ile23Val] acts as a risk loci for obesity-related traits and mediates by interacting with Apo-A1. Obesity 2017 25P1098-11108.

Pangilinan et al. Transcobalamin II receptor polymorphisms are associated with increased risk for neural tube defects. J Med Genet 2010 47: 677-85.

Kurnat-Thoma et al. Association of transcobalamin II (TCN2) and transcobalamin II-receptor (TCblR) genetic variations with cobalamin deficiency parameters in elderly women. Biol Res. Nurs 2015 17:444-54