Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, China.
Department of Gynecologic Oncology, No. 3 Affiliated Hospital of Kunming Medical University, Kunming, China.
HLA. 2024 Jan;103(1):e15340. doi: 10.1111/tan.15340.
Cervical cancer (CC) is one of the leading causes of cancer-related death in females worldwide. Genome-wide association studies (GWASs) have identified CC-related susceptibility loci in HLA regions. To investigate the associations between HLA genes and cervical intraepithelial neoplasia (CIN) or cervical cancer (CC), six loci of HLA class I (HLA-A, -B, and -C) and II (HLA-DRB1, -DPB1, and -DQB1) were selected for genotyping, and the associations between these alleles or their haplotypes with CIN or CC risk or protection from disease were evaluated. In total, 2193 participants, including 909 healthy individuals in the control group, 769 patients with CC, and 515 patients with CIN2+ (CIN II and III), were enrolled in the current study. HLA genes were genotyped using the NGSgo Illumina MiSeq workflow, and the associations between these loci and CIN2+ or CC at the allele and haplotype levels were analyzed. The allele frequencies of HLA-A33:03, B58:01, C03:02, DPB105:01, and DRB112:01 were lower in both the CC and CIN2+ groups than in the control group, whereas those of B55:02, C04:03, and DPB103:01 were higher in the CC group than in the control group. In the histologic CC type analysis, the differences in the frequencies of these alleles in squamous cell carcinoma (SCC) of the cervix and stage I CC showed a consistent trend. In the haplotype analysis, the frequency of A33:03-C03:02-B58:01 was lower in the CC and CIN2+ groups than in the control group, and that of A24:02-C04:03-B15:25 was higher in the CC group than in both the control and CIN2+ groups. These three different haplotype frequencies were also identified in the FIGO CC stage analysis. In addition, in human papilloma virus (HPV) genotype analyses, the frequencies of HLA-C03:02 and DPB105:01 were significantly lower in the CC and CIN2+ groups than in the control group, and in SCC subgroup, the frequencies of HLA-DQB104:01 and DRB104:05 were higher in the HPV other genotype infection group than in the HPV16 infection group. In both HPV16 single infection and coinfection with other HPVs, the frequency of haplotype A33:03-C03:02-B58:01 was lower in both CC and CIN2+ than in the control group, while the frequencies of A11:01-C14:02-B51:01 and A24:02-C03:04-B13:01 were higher in the CIN2+ than in CC and the control group. In the HPV16 and other HPV infection comparisons, the frequencies of DRB104:05-DQB104:01-DPB102:01 and DRB111:01-DQB103:01-DPB1*05:01 were lower in the HPV16 infection group than in the other HPV infection group. Our results suggest that the HLA class I and II genes may affect the risk of CIN and CC as well as the histologic CC types and FIGO stages of CC in the Han Chinese population. In addition, HLA genes were associated with HPV16 infection at both the allelic and haplotype levels.
宫颈癌（CC）是全球女性癌症相关死亡的主要原因之一。全基因组关联研究（GWAS）已经确定了 HLA 区域与 CC 相关的易感性位点。为了研究 HLA 基因与宫颈上皮内瘤变（CIN）或宫颈癌（CC）之间的关联，选择了 HLA Ⅰ类（HLA-A、-B 和 -C）和Ⅱ类（HLA-DRB1、-DPB1 和 -DQB1）的六个基因座进行基因分型，并评估了这些等位基因或其单倍型与 CIN 或 CC 风险或疾病保护之间的关联。本研究共纳入 2193 名参与者，包括对照组 909 名健康个体、769 名 CC 患者和 515 名 CIN2+（CIN II 和 III）患者。使用 NGSgo Illumina MiSeq 工作流程对 HLA 基因进行基因分型，并分析了这些基因座与 CIN2+或 CC 在等位基因和单倍型水平上的关联。HLA-A33:03、B58:01、C03:02、DPB105:01 和 DRB112:01 的等位基因频率在 CC 和 CIN2+组中均低于对照组，而 B55:02、C04:03 和 DPB103:01 的等位基因频率在 CC 组中高于对照组。在组织学 CC 类型分析中，这些等位基因在宫颈鳞状细胞癌（SCC）和 I 期 CC 中的频率差异表现出一致的趋势。在单倍型分析中，CC 和 CIN2+组中 A33:03-C03:02-B58:01 的频率低于对照组，而 CC 组中 A24:02-C04:03-B15:25 的频率高于对照组和 CIN2+组。在 FIGO CC 分期分析中也发现了这三种不同的单倍型频率。此外，在人乳头瘤病毒（HPV）基因型分析中，CC 和 CIN2+组中 HLA-C03:02 和 DPB105:01 的频率明显低于对照组，在 SCC 亚组中，HPV 其他基因型感染组中 HLA-DQB104:01 和 DRB104:05 的频率高于 HPV16 感染组。在 HPV16 单一感染和与其他 HPV 共同感染中，CC 和 CIN2+组中 A33:03-C03:02-B58:01 的单倍型频率均低于对照组，而 CIN2+组中 A11:01-C14:02-B51:01 和 A24:02-C03:04-B13:01 的频率高于 CC 和对照组。在 HPV16 和其他 HPV 感染比较中，HPV16 感染组中 DRB104:05-DQB104:01-DPB102:01 和 DRB111:01-DQB103:01-DPB1*05:01 的频率低于其他 HPV 感染组。我们的研究结果表明，HLA Ⅰ类和Ⅱ类基因可能影响汉族人群中 CIN 和 CC 的风险以及 CC 的组织学类型和 FIGO 分期。此外，HLA 基因与 HPV16 感染在等位基因和单倍型水平上均相关。
