HLA-A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese
Nasopharyngeal carcinoma (NPC) arises from the mucosal epithelium of the nasopharynx and is constantly associated with Epstein-Barr virus type 1 (EBV-1) infection. We carried out a genome-wide association study (GWAS) of 575,247 autosomal SNPs in 184 NPC patients and 236 healthy controls of Malaysia...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
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John Wiley & Sons
2015
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| _version_ | 1825720055437983744 |
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| author | Chin, Yoon-Ming Mushiroda, T. Takahashi, A. Kubo, M. Krishnan, G. Yap, Lee-Fah Teo, Soo-Hwang Lim, P.Vey-Hong Yap, Yoke-Yeow Pua, Kin-Choo Kamatani, N. Nakamura, Y. Sam, Choon-Kook Khoo, Alan Soo-Beng Ng, Ching-Ching Grp, Malaysian NPC Study |
| author_facet | Chin, Yoon-Ming Mushiroda, T. Takahashi, A. Kubo, M. Krishnan, G. Yap, Lee-Fah Teo, Soo-Hwang Lim, P.Vey-Hong Yap, Yoke-Yeow Pua, Kin-Choo Kamatani, N. Nakamura, Y. Sam, Choon-Kook Khoo, Alan Soo-Beng Ng, Ching-Ching Grp, Malaysian NPC Study |
| author_sort | Chin, Yoon-Ming |
| collection | UM |
| description | Nasopharyngeal carcinoma (NPC) arises from the mucosal epithelium of the nasopharynx and is constantly associated with Epstein-Barr virus type 1 (EBV-1) infection. We carried out a genome-wide association study (GWAS) of 575,247 autosomal SNPs in 184 NPC patients and 236 healthy controls of Malaysian Chinese ethnicity. Potential association signals were replicated in a separate cohort of 260 NPC patients and 245 healthy controls. We confirmed the association of HLA-A to NPC with the strongest signal detected in rs3869062 (p=1.73 x 10(-9)). HLA-A fine mapping revealed associations in the amino acid variants as well as its corresponding SNPs in the antigen peptide binding groove (p(HLA-A-aa-site-99)=3.79 x 10(-8), p(rs1136697)=3.79 x 10(-8)) and T-cell receptor binding site (p(HLA-A-aa-site-145)=1.41 x 10(-4), p(rs1059520)=1.41 x 10(-4)) of the HLA-A. We also detected strong association signals in the 5-UTR region with predicted active promoter states (p(rs41545520)=7.91 x 10(-8)). SNP rs41545520 is a potential binding site for repressor ATF3, with increased binding affinity for rs41545520-G correlated with reduced HLA-A expression. Multivariate logistic regression diminished the effects of HLA-A amino acid variants and SNPs, indicating a correlation with the effects of HLA-A*11:01, and to a lesser extent HLA-A*02:07. We report the strong genetic influence of HLA-A on NPC susceptibility in the Malaysian Chinese. What's new? Certain variants of the HLA-A gene are linked to either resistance or susceptibility in nasopharyngeal carcinoma (NPC). But which variants are most strongly associated with effects in NPC remains unclear. Here, high resolution fine-mapping of the HLA-A region was used to better understand the effects of variants on peptide loading or HLA-A expression in a Malaysian Chinese population. Variants showing potential epigenetic, peptide-loading function and T-cell immune response were correlated with the effects of HLA-A*11:01, a protective HLA-A allele. Most other HLA-A variants did not appear to possess any potential function. |
| first_indexed | 2024-03-06T05:29:10Z |
| format | Article |
| id | um.eprints-11619 |
| institution | Universiti Malaya |
| last_indexed | 2024-03-06T05:29:10Z |
| publishDate | 2015 |
| publisher | John Wiley & Sons |
| record_format | dspace |
| spelling | um.eprints-116192015-01-02T02:28:47Z http://eprints.um.edu.my/11619/ HLA-A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese Chin, Yoon-Ming Mushiroda, T. Takahashi, A. Kubo, M. Krishnan, G. Yap, Lee-Fah Teo, Soo-Hwang Lim, P.Vey-Hong Yap, Yoke-Yeow Pua, Kin-Choo Kamatani, N. Nakamura, Y. Sam, Choon-Kook Khoo, Alan Soo-Beng Ng, Ching-Ching Grp, Malaysian NPC Study Nasopharyngeal carcinoma (NPC) arises from the mucosal epithelium of the nasopharynx and is constantly associated with Epstein-Barr virus type 1 (EBV-1) infection. We carried out a genome-wide association study (GWAS) of 575,247 autosomal SNPs in 184 NPC patients and 236 healthy controls of Malaysian Chinese ethnicity. Potential association signals were replicated in a separate cohort of 260 NPC patients and 245 healthy controls. We confirmed the association of HLA-A to NPC with the strongest signal detected in rs3869062 (p=1.73 x 10(-9)). HLA-A fine mapping revealed associations in the amino acid variants as well as its corresponding SNPs in the antigen peptide binding groove (p(HLA-A-aa-site-99)=3.79 x 10(-8), p(rs1136697)=3.79 x 10(-8)) and T-cell receptor binding site (p(HLA-A-aa-site-145)=1.41 x 10(-4), p(rs1059520)=1.41 x 10(-4)) of the HLA-A. We also detected strong association signals in the 5-UTR region with predicted active promoter states (p(rs41545520)=7.91 x 10(-8)). SNP rs41545520 is a potential binding site for repressor ATF3, with increased binding affinity for rs41545520-G correlated with reduced HLA-A expression. Multivariate logistic regression diminished the effects of HLA-A amino acid variants and SNPs, indicating a correlation with the effects of HLA-A*11:01, and to a lesser extent HLA-A*02:07. We report the strong genetic influence of HLA-A on NPC susceptibility in the Malaysian Chinese. What's new? Certain variants of the HLA-A gene are linked to either resistance or susceptibility in nasopharyngeal carcinoma (NPC). But which variants are most strongly associated with effects in NPC remains unclear. Here, high resolution fine-mapping of the HLA-A region was used to better understand the effects of variants on peptide loading or HLA-A expression in a Malaysian Chinese population. Variants showing potential epigenetic, peptide-loading function and T-cell immune response were correlated with the effects of HLA-A*11:01, a protective HLA-A allele. Most other HLA-A variants did not appear to possess any potential function. John Wiley & Sons 2015 Article PeerReviewed Chin, Yoon-Ming and Mushiroda, T. and Takahashi, A. and Kubo, M. and Krishnan, G. and Yap, Lee-Fah and Teo, Soo-Hwang and Lim, P.Vey-Hong and Yap, Yoke-Yeow and Pua, Kin-Choo and Kamatani, N. and Nakamura, Y. and Sam, Choon-Kook and Khoo, Alan Soo-Beng and Ng, Ching-Ching and Grp, Malaysian NPC Study (2015) HLA-A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese. International Journal of Cancer, 136 (3). pp. 678-687. ISSN 0020-7136, |
| spellingShingle | Chin, Yoon-Ming Mushiroda, T. Takahashi, A. Kubo, M. Krishnan, G. Yap, Lee-Fah Teo, Soo-Hwang Lim, P.Vey-Hong Yap, Yoke-Yeow Pua, Kin-Choo Kamatani, N. Nakamura, Y. Sam, Choon-Kook Khoo, Alan Soo-Beng Ng, Ching-Ching Grp, Malaysian NPC Study HLA-A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese |
| title | HLA-A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese |
| title_full | HLA-A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese |
| title_fullStr | HLA-A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese |
| title_full_unstemmed | HLA-A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese |
| title_short | HLA-A SNPs and amino acid variants are associated with nasopharyngeal carcinoma in Malaysian Chinese |
| title_sort | hla a snps and amino acid variants are associated with nasopharyngeal carcinoma in malaysian chinese |
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