Abstract
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. To determine whether the HLA-B*52:01 allele is associated with CC in Japanese women. 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. Loci within the MHC region associated with CC risk, and the direction and size of association. 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). 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.
Highlights
Cervical cancer (CC) is the fourth most frequently diagnosed cancer and the fourth-leading cause of cancer death in women worldwide in 2018.1 environmental factors such as smoking, parity, and oral contraceptive use are known to be associated with CC,2 it is well established that persistent infection with high-risk human papillomaviruses (HPVs) has a major carcinogenic role.3 Generally, exposure to HPVs is highly prevalent, most women infected with HPVs do not acquire persistent infection.4,5 Because persistent infection is supposed to be mediated by individuals’ immune responses, CC can be considered as an immune-related disease
Allele frequency spectra of human leukocyte antigen (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 major histocompatibility complex (MHC) risk associated with CC because no other HLA alleles remained significant after conditioning on the HLA-B*52:01
Summary
Cervical cancer (CC) is the fourth most frequently diagnosed cancer and the fourth-leading cause of cancer death in women worldwide in 2018.1 environmental factors such as smoking, parity, and oral contraceptive use are known to be associated with CC, it is well established that persistent infection with high-risk human papillomaviruses (HPVs) has a major carcinogenic role. Generally, exposure to HPVs is highly prevalent, most women infected with HPVs do not acquire persistent infection. Because persistent infection is supposed to be mediated by individuals’ immune responses, CC can be considered as an immune-related disease. Cervical cancer (CC) is the fourth most frequently diagnosed cancer and the fourth-leading cause of cancer death in women worldwide in 2018.1 environmental factors such as smoking, parity, and oral contraceptive use are known to be associated with CC, it is well established that persistent infection with high-risk human papillomaviruses (HPVs) has a major carcinogenic role.. The major histocompatibility complex (MHC) region, which regulates immune responses to pathogens, is expected to have an essential role in controlling HPV infection. Because the genetic structure of the MHC region is highly complex and diverse among populations, more detailed and population-specific analysis is required for fine mapping of the CC causal variant embedded within MHC. A new computational method has been developed for detailed fine-mapping analysis of the MHC region, which is called the HLA imputation.. By using the population-specific reference panel, application of HLA imputation can achieve fine mapping of the causal HLA variants of the human complex traits. Because the previous candidate gene-based reports have mainly focused on the class II human leukocyte antigen (HLA) alleles, comprehensive fine-mapping analyses assessing both class I and II HLA alleles, nonclassical HLA alleles, and amino acid variations are warranted. Recently, a new computational method has been developed for detailed fine-mapping analysis of the MHC region, which is called the HLA imputation. By using the population-specific reference panel, application of HLA imputation can achieve fine mapping of the causal HLA variants of the human complex traits.
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