title: Association of HLA-G 3' untranslated region variants with type 1 diabetes mellitus.
abstract: Besides the well recognized association of HLA-DRB1 and DQB1 alleles with type 1 diabetes mellitus (T1D), linkage studies have identified a gene region close to the non-classical class I HLA-G gene as an independent susceptibility marker. HLA-G is constitutively expressed in the endocrine compartment of the human pancreas and may play a role in controlling autoimmune responses. We evaluated the genetic diversity of the 3' untranslated region (3'UTR) of HLA-G, which have been associated with HLA-G mRNA post-transcriptional regulation, in 120 Brazilian T1D patients and in 120 healthy controls. We found the +3001 T allele was observed only in T1D patients. Notably, the +3001 T allele was in linkage disequilibrium with polymorphic sites associated with low production of HLA-G mRNA or soluble HLA-G levels. Moreover, T1D patients showed a low frequency of the HLA-G 3'UTR-17 (14bpINS/+3001T/+3003T/+3010C/+3027C/+3035T/+3142G/+3187A/+3196C). The +3010 CC genotype and the UTR-3 haplotype (14bpDEL/+3001C/+3003T/+3010C/+3027C/+3035C/+3142G/+3187A/+3196C), associated with low and moderate soluble HLA-G expression, respectively, were underrepresented in patients. The decreased expression of HLA-G at the pancreas level should be detrimental in individuals genetically prone to produce less HLA-G.
authors.affiliation: Faculty of Medicine of Ribeirão Preto, University of São Paulo, Departament of Genetics, Ribeirão Preto, SP, Brazil; Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Rafael S
authors.initials: RS
authors.lastname: de Albuquerque
authors.affiliation: Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil. Electronic address: ctmendes@ffclrp.usp.br.
authors.forename: Celso Teixeira
authors.initials: CT
authors.lastname: Mendes-Junior
authors.affiliation: Aggeu Magalhães Research Center, Department of Immunology, Oswaldo Cruz Fundation (Fiocruz), Recife, PE, Brazil.
authors.forename: Norma
authors.initials: N
authors.lastname: Lucena-Silva
authors.affiliation: Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Camila Leal Lopes
authors.initials: CL
authors.lastname: da Silva
authors.affiliation: Faculty of Medicine of Ribeirão Preto, University of São Paulo, Department of Medicine, Ribeirão Preto, SP, Brazil.
authors.forename: Diane Meire
authors.initials: DM
authors.lastname: Rassi
authors.affiliation: Faculty of Medicine of Ribeirão Preto, University of São Paulo, Department of Medicine, Ribeirão Preto, SP, Brazil.
authors.forename: Luciana C
authors.initials: LC
authors.lastname: Veiga-Castelli
authors.affiliation: Faculty of Medicine of Ribeirão Preto, University of São Paulo, Department of Medicine, Ribeirão Preto, SP, Brazil.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Foss-Freitas
authors.affiliation: Faculty of Medicine of Ribeirão Preto, University of São Paulo, Department of Medicine, Ribeirão Preto, SP, Brazil.
authors.forename: Milton César
authors.initials: MC
authors.lastname: Foss
authors.affiliation: Faculty of Medicine of Ribeirão Preto, University of São Paulo, Department of Medicine, Ribeirão Preto, SP, Brazil.
authors.forename: Neifi Hassan Saloum
authors.initials: NH
authors.lastname: Deghaide
authors.affiliation: UMR Commissariat à l'Energie Atomique et aux Energies Alternatives/Université Paris Diderot-Paris 7, Sorbonne Paris-Cité/iMETI/Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, IUH, Hôpital Saint-Louis, 1, avenue Claude Vellefaux, 75475 Paris cedex 10, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
authors.affiliation: Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Gregori
authors.affiliation: Departamento de Patologia, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista Júlio de Mesquita Filho, Botucatu, SP, Brazil.
authors.forename: Erick C
authors.initials: EC
authors.lastname: Castelli
authors.affiliation: Faculty of Medicine of Ribeirão Preto, University of São Paulo, Department of Medicine, Ribeirão Preto, SP, Brazil.
authors.forename: Eduardo Antônio
authors.initials: EA
authors.lastname: Donadi
mesh_terms: D020413:3' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D059951:HLA-G Antigens / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; D059951:HLA-G Antigens
keywords: 3′ untranslated region; Brazilians; Gene regulation; HLA-G; Type 1 diabetes mellitus