Dataset Information

Fine-mapping of HLA class I and class II genes identified two independent novel variants associated with nasopharyngeal carcinoma susceptibility.

ABSTRACT:

Background

Several genome-wide association studies (GWASs) have identified strong associations between genetic variants in the human leukocyte antigen (HLA) region and nasopharyngeal carcinoma (NPC). However, given the complex LD pattern in this region, the causal variants and the underlying mechanism of how genetic variants in HLA contribute to NPC development is yet to be understood.

Methods

To systematically characterize the HLA variants and their relationship to NPC susceptibility, we fine-mapped the HLA genes based on the GWAS data of 1583 NPC cases and 972 healthy controls, using SNP2HLA with the Pan-Asian panel as references. Stepwise conditional regression was used to identify independent association loci.

Results

Interestingly, the most significant association was the presence of Gln in HLA-A amino acid position 62 (OR = 0.57, P = 1.41 × 10^-16 ). The G allele of rs2894207 located between HLA-B and HLA-C showed protective effect of NPC development (OR = 0.52, P = 2.23 × 10^-13 ). Additionally, amino acid Phe-67 located in the peptide-binding pocket of HLA-DRB1 was identified as a novel functional variant with OR = 0.64 and P = 9.64 × 10^-11 . Another novel variant, Glu-45 in HLA-B pocket B, conferred a protective effect on NPC susceptibility (OR = 0.64, P = 5.23 × 10^-8 ). These four variants explained 2.07% of the phenotypic variance for NPC risk.

Conclusion

In summary, by fine-mapping the HLA region in south Chinese population, we reported additional loci missed in the GWAS studies and provided a better understanding of the relationship between HLA and NPC susceptibility.

SUBMITTER: Wang TM

PROVIDER: S-EPMC6308056 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Publications

Fine-mapping of HLA class I and class II genes identified two independent novel variants associated with nasopharyngeal carcinoma susceptibility.

Wang Tong-Min TM Zhou Ting T He Yong-Qiao YQ Xue Wen-Qiong WQ Zhang Jiang-Bo JB Zheng Xiao-Hui XH Li Xi-Zhao XZ Zhang Shao-Dan SD Zeng Yi-Xin YX Jia Wei-Hua WH

Cancer medicine 20181030 12

<h4>Background</h4>Several genome-wide association studies (GWASs) have identified strong associations between genetic variants in the human leukocyte antigen (HLA) region and nasopharyngeal carcinoma (NPC). However, given the complex LD pattern in this region, the causal variants and the underlying mechanism of how genetic variants in HLA contribute to NPC development is yet to be understood.<h4>Methods</h4>To systematically characterize the HLA variants and their relationship to NPC susceptibi ...[more]

PMID: 30378292

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Project description:Background & aimsAssociation studies have greatly refined the important role of the major histocompatibility complex (MHC) region in autoimmune hepatitis (AIH). However, the effects of human leucocyte antigen (HLA) polymorphisms on AIH are not well established. The aim of this study is to systematically characterise the association of MHC variants with AIH in our well-defined cohort of patients.MethodsWe performed an imputation-based analysis on the extensive association observed within the MHC region using the Han-MHC reference panel, and tested the comprehensive associations of HLA polymorphisms with AIH in 1622 Chinese AIH type 1 patients and 10,466 population controls.ResultsA total of 588 HLA variants were significantly associated with AIH, with HLA-B∗35:01 (p = 8.17 × 10-304; odds ratio [OR] = 7.32) contributing the strongest signal. Stepwise conditional analysis revealed additional independent signals at HLA-B∗08:01 (p = 1.35 × 10-33; OR = 4.26) and rs7765379 (p = 5.08 × 10-18; OR = 1.66). A strong link between the lead HLA variant and clinical phenotypes of AIH was observed: patients with HLA-B∗35:01 were less frequently positive for ANA and tended to have higher serum AST and ALT levels at diagnosis, but lower serum IgG levels.ConclusionsOur study reveals three novel and independent variants at HLA-B∗35:01, HLA-B∗08:01, and rs7765379 associated with AIH across the whole MHC region in the Han Chinese population. The findings illustrate the value of the MHC region in AIH and provide a new perspective for the immunogenetics of AIH.Impact and implicationsThis study revealed three novel and independent variants associated with autoimmune hepatitis across the whole major histocompatibility complex region in the Han Chinese population. These findings are significant in identifying autoantigens, providing insights into the activation of the autoimmune processes, and further advancing our understanding of the immunogenetic basis underlying autoimmune hepatitis.

Project description:Recent genome-wide association studies have identified 78 loci associated with Parkinson's disease susceptibility but the underlying mechanisms remain largely unclear. To identify likely causal variants for disease risk, we fine-mapped these Parkinson's-associated loci using four different fine-mapping methods. We then integrated multi-assay cell type-specific epigenomic profiles to pinpoint the likely mechanism of action of each variant, allowing us to identify Consensus single nucleotide polymorphism (SNPs) that disrupt LRRK2 and FCGR2A regulatory elements in microglia, an MBNL2 enhancer in oligodendrocytes, and a DYRK1A enhancer in neurons. This genome-wide functional fine-mapping investigation of Parkinson's disease substantially advances our understanding of the causal mechanisms underlying this complex disease while avoiding focus on spurious, non-causal mechanisms. Together, these results provide a robust, comprehensive list of the likely causal variants, genes and cell-types underlying Parkinson's disease risk as demonstrated by consistently greater enrichment of our fine-mapped SNPs relative to lead GWAS SNPs across independent functional impact annotations. In addition, our approach prioritized an average of 3/85 variants per locus as putatively causal, making downstream experimental studies both more tractable and more likely to yield disease-relevant, actionable results. Large-scale studies comparing individuals with Parkinson's disease to age-matched controls have identified many regions of the genome associated with the disease. However, there is widespread correlation between different parts of the genome, making it difficult to tell which genetic variants cause Parkinson's and which are simply co-inherited with causal variants. We therefore applied a suite of statistical models to identify the most likely causal genetic variants (i.e. fine-mapping). We then linked these genetic variants with epigenomic and gene expression signatures across a wide variety of tissues and cell types to identify how these variants cause disease. Therefore, this study provides a comprehensive and robust list of cellular and molecular mechanisms that may serve as targets in the development of more effective Parkinson's therapeutics.

Dataset Information

Fine-mapping of HLA class I and class II genes identified two independent novel variants associated with nasopharyngeal carcinoma susceptibility.

Background

Methods

Results

Conclusion

Publications

Fine-mapping of HLA class I and class II genes identified two independent novel variants associated with nasopharyngeal carcinoma susceptibility.

Similar Datasets

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