XIAP Q423P polymorphism and susceptibility to childhood hemophagocytic lymphohistiocytosis.

To the Editor: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory disease due to cytokine overproduction from excessively activated lymphocytes and macrophages [1]. It primarily affects children and has a varied genetic background [1]. Rigaud et al. [2] reported for the first time that mutations in the X-linked inhibitor of apoptosis (XIAP) gene affect the risk for HLH in X-linked lymphoproliferative disorder (XLP) patients. The Q423P polymorphism of XIAP gene was reported to be associated with the susceptibility to idiopathic periodic fever (IPF)[3]. XIAP 423Q influences monocyte function and possibly activates pro-inflammatory cytokines such as TNFa [3]. The purpose of this study was to investigate the relationship of XIAP Q423P (rs5956583, 123034511A>C) polymorphism and the risk for childhood HLH. The study was approved by the hospital-based ethic committee. The XIAP Q423P polymorphism was genotyped in 100 pediatric patients diagnosed with HLH based on the HLH-2004 guideline [4] and 100 healthy children matched in age and gender by polymerase chain reaction–restriction fragment length polymorphism (PCR– RFLP). After informed consent, peripheral blood specimens were collected from all the patients and controls. Genomic DNA was extracted using DNA Purification Kit (Tiangen Biotech, Beijing, China) according to the manufacturer’s directions. The forward primer (50-CCTTGCATCGTTTCAAACAC-30) and the reverse primer (50-GAGCCTCCAAAACTGTCAGAA-30) were used for PCR. The PCR products were digested for 1 hour with HpyCH4V (New England Biolabs, Beverly, MA) at 37 ̊C and separated on the 2% agarose gels. Ten percentages of the products were randomly selected for DNA sequence. Statistical analysis was performed with the chi-square test or Fisher’s exact test when one or more variables were <5 (SPSS 17.0). P< 0.05 was considered as statistically significant. Odds ratios and 95% confidence intervals were used for estimating the relative risk for genotypes. The Q423PA/A, C/C, and A/C genotypes were discovered both in the HLH patients and the controls. The genotyping by PCR– RFLP analysis was completely confirmed by DNA sequencing analysis (Fig. 1). In the patients with HLH, the frequencies of A/A, C/C, and A/C genotypes and A and C alleles were 84.0%, 13.0%, 3.0%, 85.5%, and 14.5%, respectively. The frequencies of A/A, C/ C, and A/C genotypes and A and C alleles in the healthy controls were 86.0%, 12.0%, 2.0%, 87.0%, and 13.0%, respectively. There was no significant difference in genotype and allele distribution between the two groups (P1⁄4 0.692 and 0.705, respectively). The incidence of HLH in XLP is 90% in XIAP deficiency [5]. It was hypothesized that the Q423P polymorphism in XIAP gene alters the protein sequences and may be involved in the pathogenesis of HLH. However, no significant difference was shown in the genotype and allele distribution between the pediatric patients with HLH and the healthy controls. It suggested that the Q423P polymorphism may not contribute to the pathogenesis of childhood HLH and may not be used as a stratification marker to predict the susceptibility to childhood HLH. Discovery of other polymorphisms in XIAP gene may facilitate further exploration of associations between genetic alteration and pathogenesis of childhood HLH.