Bibiana Sgorla de Almeida1, Yara Costa Netto Muniz2, Alice Heidrich Prompt3, Erick C Castelli4, Celso Teixeira Mendes-Junior5, Eduardo Antonio Donadi6. 1. Divisão de Imunologia Clínica, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), 14049-900 Ribeirão Preto, SP, Brazil; Laboratório Multiusuário de Estudos em Biologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil. Electronic address: bibiana.sgorla@ufsc.br. 2. Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil. Electronic address: yara.muniz@ufsc.br. 3. Departamento de Biologia Celular, Embriologia e Genética, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Brazil. Electronic address: prompt.a@ufsc.br. 4. Departamento de Patologia, Faculdade de Medicina de Botucatu, Unesp - Univ. Estadual Paulista, 18618-970 Botucatu, SP, Brazil. Electronic address: castelli@fmb.unesp.br. 5. Faculdade de Filosofia Ciências e Letras de Ribeirão Preto (FFCLRP), Universidade de São Paulo (USP), 14049-900 Ribeirão Preto, SP, Brazil. Electronic address: ctmendes@ffclrp.usp.br. 6. Divisão de Imunologia Clínica, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), 14049-900 Ribeirão Preto, SP, Brazil. Electronic address: eadonadi@fmrp.usp.br.
Abstract
BACKGROUND: HLA-G is an immune checkpoint molecule. Since a differential molecule expression has been reported even for healthy individuals, many studies have focused on polymorphisms at HLA-G regulatory regions, particularly the 3' untranslated region (3'UTR). The presence/absence of a 14-bp sequence was the first polymorphism described and it is the most studied in association between HLA-G and disorders. METHODS: In this study, we performed a systematic review and meta-analysis of all association studies published regarding the HLA-G 14-bp. RESULTS: We verified association between 14-bp alleles and diseases in the following situations: (1) presence of 14-bp (insertion) conferred susceptibility to preeclampsia (child alleles evaluated) and systemic lupus erythematosus (OR = 1.42; 95%CI = 1.04-1.93; p = 0.026 and OR = 1.13; 95%CI = 1.01-1.27, p = 0.028); (2) 14-bp absence (deletion) was associated with increased risk to breast cancer (OR = 1.23; 95%CI = 1.06-1.43; p = 0.006) and human Cytomegalovirus infection (OR = 2.06; 95%CI = 1.60-2.64; p < 0.0001); and (3) a risk association was observed between the group of reproductive disorders and the 14-bp insertion (OR = 1.12; 95%CI = 1.01-1.24; p = 0.034). CONCLUSIONS: Considering that others 14-bp associations were inconclusive and that other variation sites observed at HLA-G 3'UTR exhibit a proven role on post-transcriptional regulation of HLA-G expression, the complete 3'UTR segment should be analyzed in terms of disease susceptibility, instead of a single polymorphism.
BACKGROUND:HLA-G is an immune checkpoint molecule. Since a differential molecule expression has been reported even for healthy individuals, many studies have focused on polymorphisms at HLA-G regulatory regions, particularly the 3' untranslated region (3'UTR). The presence/absence of a 14-bp sequence was the first polymorphism described and it is the most studied in association between HLA-G and disorders. METHODS: In this study, we performed a systematic review and meta-analysis of all association studies published regarding the HLA-G 14-bp. RESULTS: We verified association between 14-bp alleles and diseases in the following situations: (1) presence of 14-bp (insertion) conferred susceptibility to preeclampsia (child alleles evaluated) and systemic lupus erythematosus (OR = 1.42; 95%CI = 1.04-1.93; p = 0.026 and OR = 1.13; 95%CI = 1.01-1.27, p = 0.028); (2) 14-bp absence (deletion) was associated with increased risk to breast cancer (OR = 1.23; 95%CI = 1.06-1.43; p = 0.006) and human Cytomegalovirus infection (OR = 2.06; 95%CI = 1.60-2.64; p < 0.0001); and (3) a risk association was observed between the group of reproductive disorders and the 14-bp insertion (OR = 1.12; 95%CI = 1.01-1.24; p = 0.034). CONCLUSIONS: Considering that others 14-bp associations were inconclusive and that other variation sites observed at HLA-G 3'UTR exhibit a proven role on post-transcriptional regulation of HLA-G expression, the complete 3'UTR segment should be analyzed in terms of disease susceptibility, instead of a single polymorphism.
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