RESUMO
Folate and vitamin B12 are needed for the proper embryo-fetal development possibly through their interacting role in the 1-carbon metabolism. Folate fortification reduces the prevalence of complex birth defects, and more specifically neural tube defects (NTDs). GIF and FUT2 are 2 genes associated with the uptake and blood level of vitamin B12. We evaluated GIF and FUT2 as predictors of severe birth defects, in 183 aborted fetuses compared with 375 healthy newborns. The GIF290C allele frequency was estimated to 0.4% in healthy newborns and to 8.1% in NTD fetuses (odds ratio 17.8 [95% confidence interval CI: 4.0-77.6]). The frequency of FUT2 rs601338 secretor variant was not different among groups. The GIF 290C heterozygous/FUT2 rs601338 secretor variant combined genotype was reported in 6 of the 37 NTD fetuses, but not in other fetuses and healthy newborns (P < .0001). This GIF/FUT2 combined genotype has been previously reported in children with congenital gastric intrinsic factor (GIF) deficiency, with respective consequences on B12 binding activity and GIF secretion. In conclusion, a genotype reported in congenital GIF deficiency produces also severe forms of NTD. This suggests that vitamin B12 delivery to neural tissue by the CUBN/GIF pathway could play a role in the neural tube closure mechanisms.
Assuntos
Fucosiltransferases/genética , Predisposição Genética para Doença/genética , Fator Intrínseco/genética , Mutação , Defeitos do Tubo Neural/genética , Polimorfismo de Nucleotídeo Único , Estudos de Coortes , Feto/metabolismo , Frequência do Gene , Genótipo , Heterozigoto , Humanos , Recém-Nascido , Análise de Sequência de DNA/métodos , Galactosídeo 2-alfa-L-FucosiltransferaseRESUMO
Genetic predictors of beta-lactam (BL) allergy are mostly related to Immunoglobulin E (IgE) synthesis and atopy. Despite this context, little attention has been devoted to genes of IgE/FcÉRI pathway, such as galectin-3, a ß-galactoside-binding lectin, which binds to IgE. We evaluated the association of LGALS3 polymorphisms with BL allergy in 395 Spanish and 198 Italian cases, compared with 310- and 339-matched controls, respectively. The rs11125 predicted BL allergy with an odds ratio of 4.0 in Spanish population (P<0.0001). This association was replicated with an odds ratio of 5.1 in Italian population (P<0.0001); rs11125 predicted also increased serum level of total IgE in Spanish controls. These data are consistent with the predicted deleterious influence of Gln>His substitution produced by rs11125 on galactose-binding activity of galectin-3. In conclusion, LGALS3 is the strongest genetic predictor of BL allergy reported so far. This association reflects the influence of genes of IgE/FcÉRI pathway in this pathology.
Assuntos
Antibacterianos/efeitos adversos , Hipersensibilidade a Drogas/genética , Galectina 3/genética , beta-Lactamas/efeitos adversos , Adulto , Proteínas Sanguíneas , Estudos de Casos e Controles , Éxons , Feminino , Galectinas , Humanos , Hipersensibilidade Imediata/genética , Imunoglobulina E/sangue , Itália , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estrutura Terciária de Proteína , EspanhaRESUMO
BACKGROUND: Betalactam (BL) immediate-type allergy is influenced by environmental and genetic determinants, as illustrated by differences in worldwide prevalence and ethnicity from a same area and by associations with genes related to atopy. AIMS: To evaluate the association of atopy with BL allergy. MATERIALS AND METHODS: We measured specific Immunoglobulin E (IgE) against prevalent allergens and genetic predictors of atopy, IL13, IL4, IL4RA, IL4, and TNFA, in 340 patients and 340 controls from South of Spain. RESULTS: Total IgE and IgE against mites were at higher concentration in patients. Patients with high total IgE and IgE against prevalent allergens had a slower decrease in BL IgE than nonatopic patients. IL4RA I50V and Q551R were associated with IgE against prevalent allergens and total IgE, respectively, and were also predictors of BL allergy. CONCLUSION: Interacting determinants of atopy, total IgE, IgE against prevalent allergens, and IL4RA polymorphisms, contribute to the high prevalence of BL allergy in South of Spain.
Assuntos
Hipersensibilidade a Drogas/epidemiologia , Hipersensibilidade a Drogas/genética , Hipersensibilidade Imediata/epidemiologia , Hipersensibilidade Imediata/genética , Subunidade alfa de Receptor de Interleucina-4/genética , Ácaros/imunologia , beta-Lactamas/efeitos adversos , Adulto , Alérgenos/imunologia , Animais , Hipersensibilidade a Drogas/etiologia , Hipersensibilidade a Drogas/imunologia , Feminino , Genótipo , Humanos , Hipersensibilidade Imediata/etiologia , Hipersensibilidade Imediata/imunologia , Imunoglobulina E/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Valor Preditivo dos Testes , Prevalência , Espanha/epidemiologia , beta-Lactamas/imunologiaRESUMO
Tumor necrosis factor-alpha (TNF-alpha) is released from mast cells via an immunoglobulin E (IgE)-dependent mechanism. The variant G>A at -308 of TNFA is part of an extended haplotype HLA-A1-B8-DR3-DQ2 and influences the gene expression. We evaluated this variant in relation to IgE-mediated reactions to betalactams, in 427 subjects, including 167 cases and 260 age- and gender-paired controls. TNFA GG genotype was a significant independent predictor of the primary risk of betalactam allergy, concurrently with total IgE level, with an age- and sex-adjusted odds ratio estimated at 2.45 (95% confidence interval: 1.18-5.08, P=0.0163). Cases with -308AA genotype had a higher serum level of specific IgE than those with -308GA/GG genotype, with median levels (relative units) of 4.6 (inter-quartiles: 3.9-10.6) and 2.2 (1.4-4.3), respectively (P=0.0046). In conclusion, our results suggest an ambivalent influence of a genetic determinant of pro-inflammatory pathways on IgE-mediated hypersensitivity to betalactams.