RESUMO
Adequate responses by our innate immune system toward invading pathogens were of vital importance for surviving infections, especially before the antibiotic era. Recently, a polymorphism in Mal (Ser180Leu, TIRAP rs8177374), an important adaptor protein downstream of the Toll-like receptor (TLR) 2 and 4 pathways, has been described to provide protection against a broad range of infectious pathogens. We assessed the functional effects of this polymorphism in human experimental endotoxemia, and we demonstrate that individuals bearing the TIRAP 180L allele display an increased, innate immune response to TLR4 and TLR2 ligands, but not to TLR9 stimulation. This phenotype has been related to an increased resistance to infection. However, an overshoot in the release of proinflammatory cytokines by TIRAP 180L homozygous individuals suggests a scenario of balanced evolution. We have also investigated the worldwide distribution of the Ser180Leu polymorphism in 14 populations around the globe to correlate the genetic makeup of TIRAP with the local infectious pressures. Based on the immunological, clinical, and genetic data, we propose that this mutation might have been selected in West Eurasia during the early settlement of this region after the out-of-Africa migration of modern Homo sapiens. This combination of functional and genetic data provides unique insights to our understanding of the pathogenesis of sepsis.
Assuntos
Endotoxemia/genética , Endotoxemia/imunologia , Glicoproteínas de Membrana/fisiologia , Receptores de Interleucina-1/fisiologia , Seleção Genética , Choque Séptico/genética , Choque Séptico/imunologia , Alelos , Humanos , Imunidade Inata/genética , Leucina/genética , Glicoproteínas de Membrana/genética , Polimorfismo Genético , Receptores de Interleucina-1/genética , Serina/genéticaRESUMO
BACKGROUND/AIMS: Tropical calcific pancreatitis (TCP) refers to a type of idiopathic pancreatitis prevalent in Asia. The trypsin inhibitor (SPINK1) N34S variant partially explains the genetic susceptibility to TCP. As anionic trypsinogen (PRSS2) G191R protects against chronic pancreatitis in Europeans, we investigated whether this variant protects from TCP in Indians. METHODS: We enrolled 174 patients and 794 controls from two Indian tertiary care referral hospitals. We analyzed PRSS2 and SPINK1 variants by melting curve analysis, allele-specific discrimination assay, and sequencing. RESULTS: G191R was detected in 1 TCP patient (0.6%) compared to 13 controls (1.6%; OR 0.27, 95% CI 0.03-2.1; p = 0.33). SPINK1 N34S was enriched in the TCP population 67/174 (38.5%) compared to controls 10/234 (4.3%; OR 14, 95% CI 6.9-28.3; p < 0.001). CONCLUSION: G191R PRSS2 is a rare allele in the Indian population and the data suggest a nonsignificant trend towards a protective effect. N34S SPINK1 represents the major genetic risk factor in TCP.
Assuntos
Calcinose/genética , Proteínas de Transporte/genética , Proteínas de Transporte/fisiologia , Pancreatite Crônica/genética , Tripsina/genética , Tripsina/fisiologia , Tripsinogênio/genética , Tripsinogênio/fisiologia , Adulto , Substituição de Aminoácidos , Calcinose/epidemiologia , Feminino , Predisposição Genética para Doença , Variação Genética , Heterozigoto , Homozigoto , Humanos , Índia/epidemiologia , Masculino , Pancreatite Crônica/epidemiologia , Inibidor da Tripsina Pancreática de KazalRESUMO
BACKGROUND: Wilson's disease (WD) is an autosomal recessive disorder leading to copper overload, mainly in the liver and brain, due to mutations in the ATP7B gene. About 10% of heterozygous carriers of ATP7B gene mutations have decreased serum ceruloplasmin, posing diagnostic difficulties. CASE REPORT: We report a four-member family wherein the 11-year-old daughter was diagnosed as having WD based on standard biochemical tests and the presence of Kayser Fleischer rings. On screening the entire family for WD, both parents and her eight-year-old brother had no clinical evidence of WD. However, serum ceruloplasmin was markedly decreased in the brother and was borderline low in the father, raising the possibility that the brother also had WD. We used conformation-sensitive gel electrophoresis (CSGE) to screen for mutations in the ATP7B gene in this family. Using CSGE we found that the patient's father and brother had an aberrant pattern in exon 8 of the ATP7B gene, the mother an aberrant pattern in exon 13, while the daughter (the index patient) had aberrant patterns in exons 8 and 13 of the ATP7B gene. DNA sequencing revealed that the index patient was a compound heterozygote with 2292-2312de121bp (a novel mutation) and Arg969Gln mutations, while the father and brother were heterozygous for the 2292-2312de121bp mutation and the mother for the Arg969Gln mutation. CONCLUSIONS: This case report illustrates the utility of CSGE in analyzing mutations in the ATP7B gene to resolve diagnostic dilemmas arising in heterozygous carriers with low serum ceruloplamin.