Association of CARD10 rs6000782 and TNF rs1799724 variants with paediatric-onset autoimmune hepatitis

Abstract

Although the pathogenesis of paediatric-onset autoimmune hepatitis (pAIH) remains incompletely understood, genetic variants and environmental factors are known to be involved. Caspase recruitment domain family member 10 (CARD10) is a scaffold protein that participates in a complex pathway activating nuclear factor kappa-B (NFκB) and tumour necrosis factor alpha (TNF-α). This study aimed to investigate the association of CARD10 rs6000782 (g.37928186A > C) and TNF gene promoter rs1799724 (c.-1037C > T) variants with pAIH susceptibility in a cohort of Egyptian children. The research was also extended to assess the relationship of these variants with levels of NFκB-p65 and TNF-α. Fifty-six pAIH patients and 44 age- and sex-matched healthy controls were included. Variant genotyping was performed by polymerase chain reaction (PCR). Serum NFκB-p65 and TNF-α levels were measured using enzyme-linked immunosorbent assays (ELISAs). rs6000782 C and rs1799724 T alleles, separate or in combination, were significantly increased in pAIH patients compared to controls. Serum levels of NFκB-p65 and TNF-α were higher in pAIH differentiating both groups. Moreover, the recessive model of rs6000782 revealed a significant association with the levels of both NFκB-p65 and TNF-α. In conclusion, rs6000782 and rs1799724 variants are potential genetic risk factors for pAIH predisposition, with the former affecting NFκB-p65 and TNF-α levels. Overall, the inflammatory cascade was associated with the degree of liver cell destruction. Clinically, screening and genetic counselling are recommended for relatives of pAIH patients.

Keywords: Autoimmune; Cytokines; Hepatitis; Paediatrics; Tumour necrosis factor; Variants.

Graphical abstract

Fig. 1

Genotype distribution according to the full genotype model of (A) CARD10 rs6000782 and (B) TNF rs1799724 in pAIH patients and controls. P was calculated using the χ² test. Statistical significance was considered at P < 0.05.

Fig. 2

Serum levels of NFκB-p65 and TNF-α. (A) NFκB-p65 in cases and controls. (B) TNF-α among cases and controls. (C) Correlation of NFκB-p65 and TNF-α levels. (D) NFκB-p65 among different rs6000782 genotypes. (E) TNF-α among different rs6000782 genotypes. (F) TNF-α among different rs1799724 genotypes. Values are expressed as the mean ± standard deviation (SD). P values in boxes were calculated by ANOVA. Statistical significance at P < 0.05.