Complement-related gene polymorphisms and severity of Coxsackievirus A6-induced hand, foot, and mouth disease in chinese han children: a candidate-gene association study

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Severe hand, foot, and mouth disease (HFMD) remains an important threat to child health. Host genetic factors, particularly those involved in complement activation, may contribute to HFMD susceptibility, but the role of complement-related gene polymorphisms in disease severity remains unclear. We enrolled 189 children with Coxsackievirus A6 (CVA6)-induced HFMD from Henan Children’s Hospital, including 94 severe and 95 mild cases. Genomic DNA was extracted from peripheral blood leukocytes using a modified phenol-chloroform method, and SNP genotyping was performed by PCR-RFLP. Crude and multivariable logistic regression models adjusted for age group and sex were used to evaluate associations between SNP genotypes and severe HFMD. In models adjusted for age group and sex, nominal associations with severe CVA6-induced HFMD were observed for C5 rs3761847 GA versus GG (adjusted OR = 2.523, 95% CI: 1.036–6.143), C3 rs2250656 TC versus TT (adjusted OR = 1.982, 95% CI: 1.061–3.704), and CFH rs1065489 TT versus GG (adjusted OR = 3.125, 95% CI: 1.249–7.818) and GT versus GG (adjusted OR = 2.499, 95% CI: 1.118–5.588). However, none of these associations remained statistically significant after Bonferroni correction for multiple testing. The combined SNP model showed limited discriminatory performance, with an apparent AUC of 0.653 and a bootstrap optimism-corrected AUC of 0.631. Exploratory genotype-related differences were also observed in selected laboratory parameters. C5, C3, and CFH variants showed nominal associations with severe CVA6-induced HFMD in this exploratory candidate-gene study, but these findings did not remain statistically significant after correction for multiple comparisons. Further validation in larger independent cohorts is required.