Genome-wide association study identifies TPH2 variant as a novel locus for severe CV-A6-associated hand, foot, and mouth disease in Han Chinese

Int J Infect Dis. 2020 Sep:98:268-274. doi: 10.1016/j.ijid.2020.06.104. Epub 2020 Jul 4.


Background: Little is known about the association between genetic susceptibility and the severity of hand, foot, and mouth disease (HFMD) infected with coxsackievirus A6 (CV-A6).

Methods: Three hundred and sixty-four CV-A6 HFMD patients were enrolled, including 115 severe and 249 mild patients. A genome-wide association study (GWAS) was performed involving eight DNA pools of 115 severe and 115 mild CV-A6 HFMD patients pair-matched by age and gender. Differences in relative allele signal scores of SNPs in Illumina Human OmniZhongHua-8 BeadChips were compared between the two groups. The tag SNPS for potentially functional SNPs or their high linked SNPs were selected for individual genotyping in all 364 patients and assessed for their associations with severe CV-A6 HFMD using multivariable logistic regression analyses.

Results: The top 30 significant SNPs obtained from pooled DNA GWAS analysis were checked for biological functions and their high linkage disequilibrium (LD) SNPs. Four tag SNPs (rs1558206, rs6927647, rs9375728 and rs10879355) were selected for further individual genotyping in 364 CV-A6 patients. Only SNP rs10879355 was associated with severe CV-A6 HFMD, with CC genotype having a greater risk of severe illness than TT+TC genotypes (OR=2.48, 95%CI: 1.34, 4.56). SNP rs4290270 is in complete LD with rs10879355 in Chinese Han children.

Conclusions: This is the first report that one potentially functional SNP rs4290270 in the TPH2 gene may be associated with the risk of severe CV-A6 HFMD.

Keywords: Coxsackievirus 6; Genome-wide association study; Hand, foot, and mouth disease; Severe; Susceptibility.

MeSH terms

  • Alleles
  • Child
  • Child, Preschool
  • China / epidemiology
  • China / ethnology
  • Enterovirus B, Human / genetics
  • Enterovirus B, Human / isolation & purification
  • Enterovirus B, Human / physiology
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Hand, Foot and Mouth Disease / epidemiology
  • Hand, Foot and Mouth Disease / ethnology
  • Hand, Foot and Mouth Disease / genetics*
  • Hand, Foot and Mouth Disease / virology
  • Humans
  • Infant
  • Male
  • Polymorphism, Single Nucleotide
  • Tryptophan Hydroxylase / genetics*


  • TPH2 protein, human
  • Tryptophan Hydroxylase