RESUMO
Celiac disease (CeD) is a common immune-mediated disease of the small intestine that is triggered by exposure to dietary gluten. While the HLA locus plays a major role in disease susceptibility, 39 non-HLA loci were also identified in a study of 24,269 individuals. We now build on this earlier study by adding 4125 additional Caucasian samples including an Argentinian cohort. In doing so, we not only confirm the previous associations, we also identify two novel independent genome-wide significant associations at loci: 12p13.31 and 22q13.1. By applying a genomics approach and differential expression analysis in CeD intestinal biopsies, we prioritize potential causal genes at these novel loci, including LTBR, CYTH4, and RAC2. Nineteen prioritized causal genes are overlapping known drug targets. Pathway enrichment analysis and expression of these genes in CeD biopsies suggest that they have roles in regulating multiple pathways such as the tumor necrosis factor (TNF) mediated signaling pathway and positive regulation of I-κB kinase/NF-κB signaling.
Assuntos
Doença Celíaca/genética , Loci Gênicos , Polimorfismo de Nucleotídeo Único , Argentina , Doença Celíaca/patologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 22/genética , Europa (Continente) , Estudo de Associação Genômica Ampla , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Receptor beta de Linfotoxina/genética , Receptor beta de Linfotoxina/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas rac de Ligação ao GTP/genética , Proteínas rac de Ligação ao GTP/metabolismo , Proteína RAC2 de Ligação ao GTPRESUMO
We analyzed LTßR mRNA expression in piglets from birth to weaning and compared the differential expression between Escherichia coli F18-resistant and sensitive populations to determine whether this gene could be used as a genetic marker for E. coli F18 resistance. Sutai piglets of different age groups (8, 18, 30, and 35 days; N = 4 each) and piglets demonstrating resistance/sensitivity to E. coli F18 were used. LTßR expression levels were determined by real-time PCR. The LTßR expression levels in the lymph node, duodenum, and jejunum were significantly higher in 8-day-old piglets than in the other age groups (P < 0.01), and the expression levels were significantly higher in the lungs of 8-day-old piglets than in 35-day-old piglets (P < 0.01) and 30 day-old piglets (P < 0.05). In liver tissue, the expression level was significantly higher in the 35-day-old piglets than in other age groups (P < 0.01). In the stomach tissue, the expression level was significantly higher in 35-day-old piglets than in 18-day-old piglets (P < 0.05). LTßR expression in the lymph nodes was significantly higher in the resistant group than in the sensitive group (P < 0.01), but there was no significant difference in the other tissues (P > 0.05). These results indicate that 8 days after birth is a crucial stage in the formation of mesentery lymph nodes and immune barriers in pigs, and increased expression of LTßR may be beneficial for developing resistance to E. coli F18.
Assuntos
Infecções por Escherichia coli/veterinária , Receptor beta de Linfotoxina/biossíntese , Doenças dos Suínos/patologia , Suínos/genética , Animais , Peptídeos Catiônicos Antimicrobianos/biossíntese , Peptídeos Catiônicos Antimicrobianos/genética , Biomarcadores , Resistência à Doença , Duodeno/metabolismo , Escherichia coli/fisiologia , Infecções por Escherichia coli/genética , Expressão Gênica , Jejuno/metabolismo , Receptor beta de Linfotoxina/genética , Doenças dos Suínos/genética , Doenças dos Suínos/microbiologia , DesmameRESUMO
The lymphotoxin-ß receptor (LTßR) gene is involved in autoimmune disease and inflammatory disorder development, but the relationship between LTßR and benign prostatic hyperplasia (BPH) is unclear. In total, 222 with BPH were examined for 3 single nucleotide polymorphisms [rs3759333 (-1387C/T), rs3759334 (-1326A/G), and rs2364480 (Ala172Ala)] located in the promoter and coding regions of LTßR using direct sequencing. The genotype distributions of rs3759334 were associated with prostate volume larger than 40 g. There were significant differences between the small (<40 g) and large (≥40 g) group subjects [codominant 1 model: odds ratio (OR) = 4.65, 95% confidence interval (CI) = 1.95-11.09, P = 0.001; dominant model: OR = 4.91, 95%CI = 2.07-11.63, P = 0.0002; log-additive model: OR = 4.81, 95%CI = 2.05-11.24, P = 0.0001]. The allele distributions of rs3759334 were significantly associated with BPH (OR = 4.87, 95%CI = 2.16-10.99, P = 0.0001). The distribution of rs2364480 was significantly different between groups (codominant 1 model: OR = 2.17, 95%CI = 1.11-4.26, P = 0.028; dominant model: OR = 2.16, 95%CI = 1.13-4.12, P = 0.019; log-additive model: OR = 1.86, 95%CI = 1.07-3.24, P = 0.027). The allele distribution of rs2364480 was significantly associated with BPH (OR = 1.88, 95%CI = 1.08-3.30, P = 0.027). We found that LTßR polymorphisms caused severe BPH. Thus, LTßR may contribute to the risk of BPH development.
Assuntos
Predisposição Genética para Doença , Receptor beta de Linfotoxina/genética , Polimorfismo de Nucleotídeo Único , Hiperplasia Prostática/genética , Hiperplasia Prostática/patologia , Idoso , Alelos , Biomarcadores , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Tamanho do Órgão , Hiperplasia Prostática/metabolismo , República da CoreiaRESUMO
The lymphotoxin beta receptor (LTßR) is a member of the tumor necrosis factor family of receptors (TNFR). It plays a role in regulating lymphoid organogenesis and homeostasis of the immune system. In the present study, the full coding region of a putative LTßR gene of Sus scrofa was amplified by reverse transcription-polymerase chain reaction (RT-PCR) and cloned for the first time (accession Nos. JX457347 and AFU74012). In addition, analysis of the tissue expression profile was carried out via RT-PCR. The full-length coding region of porcine LTßR had 1266 nucleotides (molecular weight, 45.61 kDa; pI, 5.71) and encoded 421 amino acids. Bioinformatic prediction indicates that LTßR belongs to the TNFR superfamily and contains a TNFR domain. The sequence homology analysis revealed that the amino acid sequences of S. scrofa LTßR had 82.9, 82.4, 81.3, 80.5, 78.7, 74.6, and 73.0% identity with those of Equus caballus, Canis lupus, Ailuropoda melanoleuca, Oryctolagus cuniculus, Bos taurus, Mus musculus, and Homo sapiens, respectively. The phylogenetic tree based on the amino acid sequences of LTßR from 8 species revealed that S. scrofa was more closely related to E. caballus, C. lupus, and A. melanoleuca. RT-PCR analysis showed that the porcine LTßR gene was differentially expressed (e.g., high, moderate, low, or nonexistent) in various tissues (e.g., prostate, pituitary, brainstem, and esophagus, respectively). This may be related to differences in the regulation of LTßR in the different tissues.