Journal
ONCOTARGET
Volume 7, Issue 27, Pages 42216-42224Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.9916
Keywords
cervical intraepithelial neoplasia 3; genome-wide association study; genetic variants; expression quantitative trait locus; human leukocyte antigen
Categories
Funding
- National Natural Science Foundation of China (NSFC) [81401212, 91331204, 31501011]
- Pujiang Talent Project [15PJ1405500]
- Strategic Priority Research Program of the Chinese Academy of Sciences (CAS) [XDB13040100]
- National Science Fund for Distinguished Young Scholars [31525014]
- Program of Shanghai Academic Research Leader [16XD1404700]
- National Program for Top-notch Young Innovative Talents of the Wanren Jihua Project
- [QD 2015006]
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Recent genome-wide association studies (GWASs) in subjects of European descent have identified associations between cervical cancer risk and three independent loci as well as multiple classical human leukocyte antigen (HLA) alleles at 6p21.3. To search for novel loci associated with development of cervical cancer, we performed a pooled analysis of data from two GWASs by imputing over 10 million genetic variants and 424 classical HLA alleles, for 1,553 intraepithelial neoplasia 3 (CIN3), 81 cervical cancer and 4,442 controls from the Swedish population. Notable findings were validated in an independent study of 961 patients (827 with CIN3 and 123 with cervical cancer) and 1,725 controls. Our data provided increased support for previously identified loci at 6p21.3 (rs9271898, P = 1.2 x 10(-24); rs2516448, 1.1 x 10(-15); and rs3130196, 2.3 x 10(-9), respectively) and also confirmed associations with reported classical HLA alleles including HLA-B*07:02, -B*15:01, -DRB1*13:01, -DRB1*15:01, -DQA1*01:03, -DQB1*06:03 and -DQB1*06:02. In addition, we identified and subsequently replicated an independent signal at rs73730372 at 6p21.3 (odds ratio = 0.60, 95% confidence interval = 0.54-0.67, P = 3.0 x 10(-19)), which was found to be an expression quantitative trait locus (eQTL) of both HLA-DQA1 and HLA-DQB1. This is one of the strongest common genetic protective variants identified so far for CIN3. We also found HLA-C*07:02 to be associated with risk of CIN3. The present study provides new insights into pathogenesis of CIN3.
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