title: Gastric intrinsic factor deficiency with combined GIF heterozygous mutations and FUT2 secretor variant.
abstract: Several genome-wide association studies (GWAS) have identified a strong association between serum vitamin B12 and fucosyltransferase 2 (FUT2), a gene associated with susceptibility to Helicobacter pylori infection. Hazra et al. conducted a meta-analysis of three GWAS and found three additional loci in MUT, CUBN and TCN1. Other GWAS conducted in Italy and China confirmed the association for FUT2 gene. Alpha-2-fucosyltransferase (FUT2) catalyzes fucose addition to form H-type antigens in exocrine secretions. FUT2 non-secretor variant produces no secretion of H-type antigens and is associated with high-plasma vitamin B12 levels. This association was explained by the influence of FUT2 on H. pylori, which is a risk factor of gastritis, a main cause of vitamin B12 impaired absorption. However, we recently showed that H. pylori serology had no influence on FUT2 association with vitamin B12, in a large sample population, suggesting the involvement of an alternative mechanism. GIF is another gene associated with plasma levels of vitamin B12 and gastric intrinsic factor (GIF) is a fucosylated protein needed for B12 absorption. Inherited GIF deficiency produces B12 deficiency unrelated with gastritis. We report 2 families with heterozygous GIF mutation, 290T>C, M97T, with decreased binding affinity of GIF for vitamin B12 and one family with heterozygous GIF mutation 435_437delGAA, K145_N146delinsN and no B12 binding activity of mutated GIF. All cases with vitamin B12 deficit carried the FUT2 rs601338 secretor variant. Ulex europeus binding to GIF was influenced by FUT2 genotypes and GIF concentration was lower, in gastric juice from control subjects with the secretor genotype. GIF290C allele was reported in 5 European cases and no Africans among 1282 ambulatory subjects and was associated with low plasma vitamin B12 and anaemia in the single case bearing the FUT2 secretor variant. We concluded that FUT2 secretor variant worsens B12 status in cases with heterozygous GIF mutations by impairing GIF secretion, independently from H. pylori-related gastritis.
authors: Inserm-U954, National reference centre for inherited metabolic diseases, University Hospital Center, Nancy-Université, 54500 Vandoeuvre lès Nancy, France.
authors: Celine
authors: C
authors: Chery
authors: Alain
authors: A
authors: Hehn
authors: Nadir
authors: N
authors: Mrabet
authors: Abderrahim
authors: A
authors: Oussalah
authors: Elise
authors: E
authors: Jeannesson
authors: Cyril
authors: C
authors: Besseau
authors: Jean-Marc
authors: JM
authors: Alberto
authors: Isabelle
authors: I
authors: Gross
authors: Thomas
authors: T
authors: Josse
authors: Philippe
authors: P
authors: Gérard
authors: Rosa Maria
authors: RM
authors: Guéant-Rodriguez
authors: Jean-Noel
authors: JN
authors: Freund
authors: Jean
authors: J
authors: Devignes
authors: Frédérique
authors: F
authors: Bourgaud
authors: Laurent
authors: L
authors: Peyrin-Biroulet
authors: François
authors: F
authors: Feillet
authors: Jean-Louis
authors: JL
authors: Guéant
mesh_terms: D000328:Adult; D000752:Anemia, Pernicious / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005647:Fucosyltransferases / Q000235:genetics*; D055106:Genome-Wide Association Study; D016481:Helicobacter Infections / Q000235:genetics / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007437:Intrinsic Factor / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D014805:Vitamin B 12 / Q000378:metabolism; D055815:Young Adult; D000097631:Galactoside 2-alpha-L-fucosyltransferase
chemical_list: D005647:Fucosyltransferases; D007437:Intrinsic Factor; D014805:Vitamin B 12; D000097631:Galactoside 2-alpha-L-fucosyltransferase