Fine Mapping of the Major Histocompatibility Complex Region and Association of the HLA-B*52:01 Allele With Cervical Cancer in Japanese Women

IMPORTANCE: Understanding the genetic contribution of the major histocompatibility complex (MHC) region to the risk of cervical cancer (CC) will help understand how immune responses to infection with human papillomaviruses are associated with CC. OBJECTIVE: To determine whether the HLA-B*52:01 allele is associated with CC in Japanese women. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter genetic association study. Genotype and phenotype data were obtained from BioBank Japan Project. Additional patients with CC were enrolled from the Aichi Cancer Center Research Institute. An MHC fine-mapping study was conducted on CC risk in the Japanese population by applying a human leukocyte antigen (HLA) imputation method to the large-scale CC genome-wide association study data of using the Japanese population-specific HLA reference panel. Participants included 540 women in BioBank Japan Project with CC or 39 829 women without gynecologic diseases, malignant neoplasms, and MHC-related diseases as controls. An additional 168 patients with CC were recruited from Aichi Cancer Center Research Institute. Histopathological subtypes and clinical stages were not considered. Participants with low genotype call rate, closely related participants, and outliers in the principal component analysis were excluded. Data analysis was performed from August 2018 to January 2020. MAIN OUTCOMES AND MEASURES: Loci within the MHC region associated with CC risk, and the direction and size of association. RESULTS: A total of 704 CC cases and 39 556 controls were analyzed. All participants were Japanese women with a median (range) age of 67 (18 to 100) years. One of the class I HLA alleles of HLA-B*52:01 was significantly associated with CC risk (odds ratio, 1.60; 95% CI, 1.38-1.86; P = 7.4 × 10(−10)). Allele frequency spectra of HLA-B*52:01 are heterogeneous among worldwide populations with high frequency in Japanese populations (0.109 in controls), suggesting its population–specific risk associated with CC. The conditional analysis suggested that HLA-B*52:01 could explain most of the MHC risk associated with CC because no other HLA alleles remained significant after conditioning on the HLA-B*52:01. The HLA amino acid residue–based analysis suggested that HLA-B p.Tyr171His located in the peptide-binding groove was associated with the most significant CC risk (odds ratio, 1.47; 95% CI, 1.30-1.66; P = 1.2 × 10(−9)). CONCLUSIONS AND RELEVANCE: The results of this study contribute to understanding of the genetic background of CC. The results suggest that immune responses mediated by class I HLA molecules are associated with susceptibility to CC.