ABSTRACT
BACKGROUND: Eczema is usually the first allergic manifestation to appear in life attributed to gene-environment interactions. IL13, IL4, MS4A2 and ILR4A are four key inflammatory genes associated with atopy. This study aimed to explore gene-environment interactions on eczema in early life among the above four genes and environmental factors in Chinese Han children. METHODS: Five hundred ninety-seven children from a birth cohort who completed two-year follow-up were enrolled and their cord blood was collected. Subjects were genotyped for six polymorphisms in the aforementioned four genes. The children were followed at 6, 12 and 24 months, with epidemiologic information and medical history of eczema collected by questionnaire and eczema assessed by dermatologists. RESULTS: Among the 597 children, 168 were diagnosed with eczema and the others were not after 2 years of follow-up. MS4A2 rs569108 GG genotype (P = 1.68E-02, odds ratio (OR) = 4.66) and antibiotic use (P = 3.75E-4, OR = 2.02) were found independently associated with development of childhood eczema. Children with both antibiotic use and MS4A2 rs569108 GG genotype were more likely to develop eczema than those with only antibiotic use or GG homozygote (OR = 6.24 VS. 2.04 or 4.68). CONCLUSIONS: MS4A2 rs569108 polymorphism and antibiotic use were solely associated with eczema, and they interacted with each other to increase the risk of developing the disease in Chinese Han toddlers. Long-term follow-up along with functional and replication studies are still needed.
Subject(s)
Dermatitis, Atopic , Eczema , Receptors, IgE/genetics , Anti-Bacterial Agents , Cohort Studies , Dermatitis, Atopic/genetics , Eczema/genetics , Humans , Infant , Polymorphism, Genetic , Prospective StudiesABSTRACT
BACKGROUND: Neu-Laxova syndrome (NLS) is a rare hereditary disorder featuring intrauterine growth retardation, remarkable oedema with skin restriction, limb contracture, ichthyosis, and craniofacial anomaly. NLS shares multiple overlapping characteristics with several other inheritable refractory diseases: for example, harlequin foetus and restrictive dermopathy. To date, many NLS patients have been described, although the number of NLS cases with clear genetic aetiology remains limited. OBJECTIVES: To characterize the clinical and genetic features of NLS in two Chinese families. MATERIALS AND METHODS: Relevant skin tissue samples, blood specimens, and follow-up data from two unrelated Chinese families with perinatal fatal disorders were collected. To obtain a definitive diagnosis, six genes (ABCA12, LMNA, ZMPSTE24, PHGDH, PSAT1 and PSPH), previously implicated in the pathogenesis of inheritable refractory diseases with similar phenotypic expression to that of the affected members in the two pedigrees, were sequenced. We also performed tandem mass spectrometry, structural protein modelling, and immunohistochemical analysis to further support the genetic findings. RESULTS: New and recurrent missense mutations were identified in two genes (PHGDH and PSAT1) associated with NLS, which further supports the recent findings that NLS is genetically heterogeneous and could result from mutations in genes encoding enzymes of the L-serine biosynthesis pathway. Structural changes in PHGDH and PSAT1 proteins were revealed by molecular modelling. Finally, a tandem mass spectrometry assay and immunohistochemical analysis further corroborated the diagnosis of NLS. CONCLUSION: This study is the first description of PHGDH and PSAT1 mutations in Chinese NLS patients, which strongly implicates them in the pathogenesis of NLS.
Subject(s)
Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/genetics , Brain Diseases/diagnosis , Brain Diseases/genetics , Fetal Growth Retardation/diagnosis , Fetal Growth Retardation/genetics , Ichthyosis/diagnosis , Ichthyosis/genetics , Limb Deformities, Congenital/diagnosis , Limb Deformities, Congenital/genetics , Microcephaly/diagnosis , Microcephaly/genetics , Phosphoglycerate Dehydrogenase/genetics , Transaminases/genetics , Asian People , Humans , Mutation, Missense , Protein ConformationABSTRACT
BACKGROUND: Atopic dermatitis (AD) is one of the most common inflammatory cutaneous diseases. Thymic stromal lymphopoietin (TSLP) has been demonstrated to be an important immunologic factor in the pathogenesis of AD. The production of TSLP can be induced by a high level of intracellular calcium concentration and activation of the receptor-interacting protein 2/caspase-1/NF-κB pathway. Andrographolide (ANDRO), a natural bicyclic diterpenoid lactone, has been found to exert anti-inflammatory effects in gastrointestinal inflammatory disorders through suppressing the NF-κB pathway. OBJECTIVE: To explore the effect of ANDRO on the production of TSLP in human mast cells and AD mice model. METHODS: We utilized enzyme-linked immunosorbent assay, real-time reverse transcription polymerase chain reaction analysis, Western blot analysis, and immunofluorescence staining assay to investigate the effects of ANDRO on AD. RESULTS: ANDRO ameliorated the increase in the intracellular calcium, protein, and messenger RNA levels of TSLP induced by phorbol myristate acetate/calcium ionophore A23187, through the blocking of the receptor-interacting protein 2/caspase-1/NF-κB pathway in human mast cell line 1 cells. ANDRO, via oral or local administration, also attenuated clinical symptoms in 2,4-dinitrofluorobenzene-induced AD mice model and suppressed the levels of TSLP in lesional skin. CONCLUSION: Taken together, ANDRO may be a potential therapeutic agent for AD through suppressing the expression of TSLP.
