OBJECTIVETo assess the associations of death receptor DR4 and DR5 gene polymorphisms with Crohn's disease (CD).

METHODSA total of 295 CD patients and 490 healthy controls were recruited. Three single nucleotide polymorphisms (SNPs) of the DR4 (rs13278062, rs20575) and DR5 (rs1047266) genes were determined with a SNaPshot method. Unconditional logistic regression analysis was carried out for determining the allelic and genotypic differences of the three SNPs between CD patients and the controls, as well as the influence of the DR4 and DR5 gene polymorphisms on the clinical features of CD patients. Linkage disequilibrium and haplotype analysis were calculated by haplotype 4.2 and R language software. A gene-gene interaction model was established to analyze whether the three SNPs can exert a synergistic effect on the susceptibility to CD.

RESULTSThe mutant allele (T) and genotype (GT+TT) of DR4 (rs13278062) were increased among CD patients compared to the controls (37.12% vs. 32.04%, P = 0.040, 95%CI: 1.010-1.550; 62.71% vs. 54.90%, P = 0.032, 95%CI: 1.028-1.855, respectively). However, the allelic and genotypic frequencies of DR4 (rs20575) and DR5 (rs1047266) did not differ between the two groups (all P > 0.05). Based on the Montreal Classification Standards, the CD patients were stratified by locations and behaviors of the disease. After multiple comparison correction (P < 0.0125), compared to ileocolonic CD patients respectively, the mutant allele (T) and genotype (GT+TT) of the rs13278062 polymorphism were significantly increased in colonic CD patients (41.04% vs. 25.64%, P = 0.002, 95%CI: 0.315-0.778; 66.04% vs. 41.03%, P = 0.001, 95%CI: 0.196-0.655, respectively) and terminal ileum CD patients (41.44% vs. 25.64%, P = 0.002, 95%CI: 0.311-0.762; 74.77% vs. 41.03%, P < 0.001, 95%CI: 0.126-0.437, respectively). In comparison to penetrating CD patients, the mutant allele (T) and genotype (GT+TT) of DR4 (rs13278062) were significantly decreased in stricturing CD patients (32.29% vs. 48.91%, P = 0.007, 95%CI: 0.300-0.828; 57.29% vs. 86.96%, P = 0.001, 95%CI: 0.078-0.520, respectively). A similar conclusion was drawn for the mutant genotype (GT+TT) of DR4 (rs13278062) in non-stricturing, non-penetrating CD patients (58.82% vs. 86.96%, P = 0.001, 95%CI: 0.086-0.536). Haplotype analysis indicated that the CT haplotype formed by rs20575 and rs13278062 was increased in CD patients compared to the controls (37.1% vs. 31.8%, P = 0.029, OR=1.279, 95%CI: 1.022-1.600). The outcome of a gene-gene interaction model indicated that the mutant genotype (GT+TT) of DR4 (rs13278062) and mutant genotype (CT+TT) of DR5 (rs1047266) may play a negatively synergistic role in CD patients (B = - 0.483, OR = 0.617, P = 0.030).

CONCLUSIONThe rs13278062 polymorphism of the DR4 gene not only can confer an increased risk for CD, but may also influence the location of the lesions and the disease behaviors. The CT haplotype formed by rs20575 and rs13278062 may be an independent risk factor for CD. Furthermore, the mutant genotype (GT+TT) of DR4 (rs13278062) and mutant genotype (CT+TT) of DR5 (rs1047266) may exert a negative synergistic effect on CD.

Adult ; Crohn Disease ; genetics ; Epistasis, Genetic ; Female ; Genetic Predisposition to Disease ; Genotype ; Haplotypes ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Receptors, TNF-Related Apoptosis-Inducing Ligand ; genetics

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Based on the viewpoint of "sweat pore-qi and liquid-kidney collaterals"， it is believed that children's nephrotic syndrome is caused by the core mechanism of sweat pore constraint and closure， qi and liquid imbalance， and kidney collaterals impairment， and it is proposed that the treatment principle is to nourish the sweat pore， regulate qi and fluid， and supplement the kidney and unblock the collaterals. In clinic， guided by sequential therapy and according to the different disease mechanism characteristics of the four stages， including early stage of the disease， hormone induction stage， hormone reduction stage， hormone maintenance stage， the staged dynamic identification and treatment was applied. For early stage of the disease with edema due to yang deficiency， modified Zhenwu Decoction （真武汤） was applied to warm yang and drain water； for hormone induction stage with yin deficiency resulting in effulgent fire， modified Zhibai Dihuang Pill （知柏地黄丸） plus Erzhi Pill （二至丸） was used to enrich yin and reduce fire； for hormone reduction stage with qi and yin deficiency， modified Shenqi Dihuang Decoction （参芪地黄汤） was used to boost qi and nourish yin； for hormone maintenance stage， modified Shenqi Pill （肾气丸） was used to supplement yin and yang. Meanwhile， the treatment also attaches importance to the combination of vine-based or worm medicinals to dredge collaterals， so as to providing ideas for clinical treatment.

The main pathogenesis of chronic cough in children is the disorder of ascending and descending of qi movement caused by healthy qi deficiency and pathogenic qi retention. The deficiency of lung， spleen， and kidney is the root of the disease， and the retention of phlegm-fluid， food accumulation， and fire from constraint is the branch pathogenesis of the disease. In the treatment， we should reinforce and tonify healthy qi， dispel pathogen and regulate qi， with Yupingfeng Powder （玉屏风散） as the basic prescription. For lung qi deficiency syndrome， modified Yupingfeng Powder could be used for supplementing lung to consolidate the exterior； for lung and spleen qi deficiency syndrome， modified Yupingfeng Powder plus Shenling Baizhu Powder （参苓白术散） could be used for supplementing lung and fortifying the spleen， treating with both supplementation and transformation； for lung kidney qi deficiency syndrome， modified Yupingfeng Powder combined with Suzi Jiangqi Decoction （苏子降气汤） could be used for supplementing lung and replenishing kidneys， absorbing qi to the root. All the above prescriptions could combine the method of dispelling phlegm， promoting digestion and guiding out food stagnation， soothing the liver and draining fire to remove the solid pathogens， in order to treat the root and branch simultaneously， and the cough will stop if the ascending and descending of qi movement recover as usual.