A large population-based association study between HLA and KIR genotypes and measles vaccine antibody responses

Human antibody response to measles vaccine is highly variable in the population. Host genes contribute to inter-individual antibody response variation. The killer cell immunoglobulin-like receptors (KIR) are recognized to interact with HLA molecules and possibly influence humoral immune response to viral antigens. To expand on and improve our previous work with HLA genes, and to explore the genetic contribution of KIR genes to the inter-individual variability in measles vaccine-induced antibody responses, we performed a large population-based study in 2,506 healthy immunized subjects (ages 11 to 41 years) to identify HLA and KIR associations with measles vaccine-induced neutralizing antibodies. After correcting for the large number of statistical tests of allele effects on measles-specific neutralizing antibody titers, no statistically significant associations were found for either HLA or KIR loci. However, suggestive associations worthy of follow-up in other cohorts include B*57:01, DQB1*06:02, and DRB1*15:05 alleles. Specifically, the B*57:01 allele (1,040 mIU/mL; p = 0.0002) was suggestive of an association with lower measles antibody titer. In contrast, the DQB1*06:02 (1,349 mIU/mL; p = 0.0004) and DRB1*15:05 (2,547 mIU/mL; p = 0.0004) alleles were suggestive of an association with higher measles antibodies. Notably, the associations with KIR genotypes were strongly nonsignificant, suggesting that KIR loci in terms of copy number and haplotypes are not likely to play a major role in antibody response to measles vaccination. These findings refine our knowledge of the role of HLA and KIR alleles in measles vaccine-induced immunity.

人群对麻疹疫苗的抗体应答存在高度异质性。宿主基因是导致个体间抗体应答差异的重要因素。杀伤细胞免疫球蛋白样受体（killer cell immunoglobulin-like receptors, KIR）已被证实可与人类白细胞抗原（human leukocyte antigen, HLA）分子结合，并可能影响针对病毒抗原的体液免疫应答。为拓展并完善我们此前针对HLA基因的研究，同时探究KIR基因对麻疹疫苗诱导抗体应答个体差异的遗传贡献，我们针对2506名年龄介于11至41岁的健康免疫接种受试者开展了一项大规模人群队列研究，以鉴定与麻疹疫苗诱导中和抗体相关的HLA及KIR位点。在对大量针对等位基因影响麻疹特异性中和抗体滴度的统计学检验进行校正后，未发现HLA或KIR位点存在具有统计学意义的关联。不过，有若干值得在其他队列中开展后续验证的提示性关联位点，包括B*57:01、DQB1*06:02及DRB1*15:05等位基因。具体而言，B*57:01等位基因（抗体滴度1040 mIU/mL；p=0.0002）提示与较低的麻疹抗体滴度存在关联。与之相反，DQB1*06:02（抗体滴度1349 mIU/mL；p=0.0004）与DRB1*15:05（抗体滴度2547 mIU/mL；p=0.0004）等位基因则提示与较高的麻疹抗体水平存在关联。值得注意的是，与KIR基因型相关的关联均无统计学显著性，这表明从拷贝数和单倍型来看，KIR位点不太可能在麻疹疫苗接种后的抗体应答中发挥主要作用。本研究结果进一步明确了HLA与KIR等位基因在麻疹疫苗诱导免疫中的作用。