Genome-wide Association Study Reveals Multiple Nasopharyngeal Carcinoma-Associated Loci within the HLA Region at Chromosome 6p21.3

Ka Po Tse; Wen Hui Su; Kai Ping Chang; Ngan Ming Tsang; Chia Jung Yu; Petrus Tang; Lee Chu See; Chuen Hsueh; Min Lee Yang; Sheng Po Hao; Hong Yi Li; Ming Hsi Wang; Li Ping Liao; Lih Chyang Chen; Sheue Rong Lin; Timothy J. Jorgensen; Yu Sun Chang; Yin Yao Shugart

doi:10.1016/j.ajhg.2009.07.007

Genome-wide Association Study Reveals Multiple Nasopharyngeal Carcinoma-Associated Loci within the HLA Region at Chromosome 6p21.3

Ka Po Tse, Wen Hui Su, Kai Ping Chang, Ngan Ming Tsang, Chia Jung Yu, Petrus Tang, Lee Chu See, Chuen Hsueh, Min Lee Yang, Sheng Po Hao, Hong Yi Li, Ming Hsi Wang, Li Ping Liao, Lih Chyang Chen, Sheue Rong Lin, Timothy J. Jorgensen, Yu Sun Chang, Yin Yao Shugart

Research output: Contribution to journal › Article › peer-review

125 Scopus citations

Abstract

Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy closely associated with genetic factors and Epstein-Barr virus infection. To identify the common genetic variants linked to NPC susceptibility, we conducted a genome-wide association study (GWAS) in 277 NPC patients and 285 healthy controls within the Taiwanese population, analyzing 480,365 single-nucleotide polymorphisms (SNPs). Twelve statistically significant SNPs were identified and mapped to chromosome 6p21.3. Associations were replicated in two independent sets of case-control samples. Two of the most significant SNPs (rs2517713 and rs2975042; p_combined = 3.9 × 10^-20 and 1.6 × 10^-19, respectively) were located in the HLA-A gene. Moreover, we detected significant associations between NPC and two genes: specifically, gamma aminobutyric acid b receptor 1 (GABBR1) (rs29232; p_combined = 8.97 × 10^-17) and HLA-F (rs3129055 and rs9258122; p_combined = 7.36 × 10^-11 and 3.33 × 10^-10, respectively). Notably, the association of rs29232 remained significant (residual p < 5 × 10^-4) after adjustment for age, gender, and HLA-related SNPs. Furthermore, higher GABA_B receptor 1 expression levels can be found in the tumor cells in comparison to the adjacent epithelial cells (p < 0.001) in NPC biopsies, implying a biological role of GABBR1 in NPC carcinogenesis. To our knowledge, it is the first GWAS report of NPC showing that multiple loci (HLA-A, HLA-F, and GABBR1) within chromosome 6p21.3 are associated with NPC. Although some of these relationships may be attributed to linkage disequilibrium between the loci, the findings clearly provide a fresh direction for the study of NPC development.

Original language	English (US)
Pages (from-to)	194-203
Number of pages	10
Journal	American journal of human genetics
Volume	85
Issue number	2
DOIs	https://doi.org/10.1016/j.ajhg.2009.07.007
State	Published - Aug 14 2009
Externally published	Yes

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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Tse, K. P., Su, W. H., Chang, K. P., Tsang, N. M., Yu, C. J., Tang, P., See, L. C., Hsueh, C., Yang, M. L., Hao, S. P., Li, H. Y., Wang, M. H., Liao, L. P., Chen, L. C., Lin, S. R., Jorgensen, T. J., Chang, Y. S., & Shugart, Y. Y. (2009). Genome-wide Association Study Reveals Multiple Nasopharyngeal Carcinoma-Associated Loci within the HLA Region at Chromosome 6p21.3. American journal of human genetics, 85(2), 194-203. https://doi.org/10.1016/j.ajhg.2009.07.007

Tse, KP, Su, WH, Chang, KP, Tsang, NM, Yu, CJ, Tang, P, See, LC, Hsueh, C, Yang, ML, Hao, SP, Li, HY, Wang, MH, Liao, LP, Chen, LC, Lin, SR, Jorgensen, TJ, Chang, YS & Shugart, YY 2009, 'Genome-wide Association Study Reveals Multiple Nasopharyngeal Carcinoma-Associated Loci within the HLA Region at Chromosome 6p21.3', American journal of human genetics, vol. 85, no. 2, pp. 194-203. https://doi.org/10.1016/j.ajhg.2009.07.007

@article{a89a27b080964f12b63238ffe7b9a800,

title = "Genome-wide Association Study Reveals Multiple Nasopharyngeal Carcinoma-Associated Loci within the HLA Region at Chromosome 6p21.3",

abstract = "Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy closely associated with genetic factors and Epstein-Barr virus infection. To identify the common genetic variants linked to NPC susceptibility, we conducted a genome-wide association study (GWAS) in 277 NPC patients and 285 healthy controls within the Taiwanese population, analyzing 480,365 single-nucleotide polymorphisms (SNPs). Twelve statistically significant SNPs were identified and mapped to chromosome 6p21.3. Associations were replicated in two independent sets of case-control samples. Two of the most significant SNPs (rs2517713 and rs2975042; pcombined = 3.9 × 10-20 and 1.6 × 10-19, respectively) were located in the HLA-A gene. Moreover, we detected significant associations between NPC and two genes: specifically, gamma aminobutyric acid b receptor 1 (GABBR1) (rs29232; pcombined = 8.97 × 10-17) and HLA-F (rs3129055 and rs9258122; pcombined = 7.36 × 10-11 and 3.33 × 10-10, respectively). Notably, the association of rs29232 remained significant (residual p < 5 × 10-4) after adjustment for age, gender, and HLA-related SNPs. Furthermore, higher GABAB receptor 1 expression levels can be found in the tumor cells in comparison to the adjacent epithelial cells (p < 0.001) in NPC biopsies, implying a biological role of GABBR1 in NPC carcinogenesis. To our knowledge, it is the first GWAS report of NPC showing that multiple loci (HLA-A, HLA-F, and GABBR1) within chromosome 6p21.3 are associated with NPC. Although some of these relationships may be attributed to linkage disequilibrium between the loci, the findings clearly provide a fresh direction for the study of NPC development.",

author = "Tse, {Ka Po} and Su, {Wen Hui} and Chang, {Kai Ping} and Tsang, {Ngan Ming} and Yu, {Chia Jung} and Petrus Tang and See, {Lee Chu} and Chuen Hsueh and Yang, {Min Lee} and Hao, {Sheng Po} and Li, {Hong Yi} and Wang, {Ming Hsi} and Liao, {Li Ping} and Chen, {Lih Chyang} and Lin, {Sheue Rong} and Jorgensen, {Timothy J.} and Chang, {Yu Sun} and Shugart, {Yin Yao}",

note = "Funding Information: We thank all of the individuals who participated in the study, as well as our colleagues in the Molecular Epidemiology Core and Biostatistics Core of Chang Gung Molecular Medicine Research Center. We are additionally grateful to Bruno Paquin (Genizon Biosciences, Quebec, Canada) for suggestions on data analysis and to P.C. Huang (Department of Biochemistry and Molecular Biology, Johns Hopkins University, Baltimore, MD, USA), Kung-Yee Liang (Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA), and Cathy S.J. Fann (Institute of Biomedical Sciences, Academic Sinica, Taipei, Taiwan) for critical reading of the manuscript. The study is supported by grants from the Ministry of Education (to Chang Gung University), the National Science Council (NSC 94-2314-B-182A-188, 94-3112-B-182-005, 95-2320-B-182-001, and 97-3112-B-182-008) and Chang Gung Memorial Hospital (CMRPD150961 and CMRPG360221), Taiwan. Y.Y.S. was previously supported by an RO3 (CA123620) grant from National Cancer Institute and the Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, USA. This work was performed before Y.Y.S. moved to the Institute of Mental Health of the National Institutes of Health, USA. ",

year = "2009",

month = aug,

day = "14",

doi = "10.1016/j.ajhg.2009.07.007",

language = "English (US)",

volume = "85",

pages = "194--203",

journal = "American journal of human genetics",

issn = "0002-9297",

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TY - JOUR

T1 - Genome-wide Association Study Reveals Multiple Nasopharyngeal Carcinoma-Associated Loci within the HLA Region at Chromosome 6p21.3

AU - Tse, Ka Po

AU - Su, Wen Hui

AU - Chang, Kai Ping

AU - Tsang, Ngan Ming

AU - Yu, Chia Jung

AU - Tang, Petrus

AU - See, Lee Chu

AU - Hsueh, Chuen

AU - Yang, Min Lee

AU - Hao, Sheng Po

AU - Li, Hong Yi

AU - Wang, Ming Hsi

AU - Liao, Li Ping

AU - Chen, Lih Chyang

AU - Lin, Sheue Rong

AU - Jorgensen, Timothy J.

AU - Chang, Yu Sun

AU - Shugart, Yin Yao

N1 - Funding Information: We thank all of the individuals who participated in the study, as well as our colleagues in the Molecular Epidemiology Core and Biostatistics Core of Chang Gung Molecular Medicine Research Center. We are additionally grateful to Bruno Paquin (Genizon Biosciences, Quebec, Canada) for suggestions on data analysis and to P.C. Huang (Department of Biochemistry and Molecular Biology, Johns Hopkins University, Baltimore, MD, USA), Kung-Yee Liang (Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA), and Cathy S.J. Fann (Institute of Biomedical Sciences, Academic Sinica, Taipei, Taiwan) for critical reading of the manuscript. The study is supported by grants from the Ministry of Education (to Chang Gung University), the National Science Council (NSC 94-2314-B-182A-188, 94-3112-B-182-005, 95-2320-B-182-001, and 97-3112-B-182-008) and Chang Gung Memorial Hospital (CMRPD150961 and CMRPG360221), Taiwan. Y.Y.S. was previously supported by an RO3 (CA123620) grant from National Cancer Institute and the Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, USA. This work was performed before Y.Y.S. moved to the Institute of Mental Health of the National Institutes of Health, USA.

PY - 2009/8/14

Y1 - 2009/8/14

N2 - Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy closely associated with genetic factors and Epstein-Barr virus infection. To identify the common genetic variants linked to NPC susceptibility, we conducted a genome-wide association study (GWAS) in 277 NPC patients and 285 healthy controls within the Taiwanese population, analyzing 480,365 single-nucleotide polymorphisms (SNPs). Twelve statistically significant SNPs were identified and mapped to chromosome 6p21.3. Associations were replicated in two independent sets of case-control samples. Two of the most significant SNPs (rs2517713 and rs2975042; pcombined = 3.9 × 10-20 and 1.6 × 10-19, respectively) were located in the HLA-A gene. Moreover, we detected significant associations between NPC and two genes: specifically, gamma aminobutyric acid b receptor 1 (GABBR1) (rs29232; pcombined = 8.97 × 10-17) and HLA-F (rs3129055 and rs9258122; pcombined = 7.36 × 10-11 and 3.33 × 10-10, respectively). Notably, the association of rs29232 remained significant (residual p < 5 × 10-4) after adjustment for age, gender, and HLA-related SNPs. Furthermore, higher GABAB receptor 1 expression levels can be found in the tumor cells in comparison to the adjacent epithelial cells (p < 0.001) in NPC biopsies, implying a biological role of GABBR1 in NPC carcinogenesis. To our knowledge, it is the first GWAS report of NPC showing that multiple loci (HLA-A, HLA-F, and GABBR1) within chromosome 6p21.3 are associated with NPC. Although some of these relationships may be attributed to linkage disequilibrium between the loci, the findings clearly provide a fresh direction for the study of NPC development.

AB - Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy closely associated with genetic factors and Epstein-Barr virus infection. To identify the common genetic variants linked to NPC susceptibility, we conducted a genome-wide association study (GWAS) in 277 NPC patients and 285 healthy controls within the Taiwanese population, analyzing 480,365 single-nucleotide polymorphisms (SNPs). Twelve statistically significant SNPs were identified and mapped to chromosome 6p21.3. Associations were replicated in two independent sets of case-control samples. Two of the most significant SNPs (rs2517713 and rs2975042; pcombined = 3.9 × 10-20 and 1.6 × 10-19, respectively) were located in the HLA-A gene. Moreover, we detected significant associations between NPC and two genes: specifically, gamma aminobutyric acid b receptor 1 (GABBR1) (rs29232; pcombined = 8.97 × 10-17) and HLA-F (rs3129055 and rs9258122; pcombined = 7.36 × 10-11 and 3.33 × 10-10, respectively). Notably, the association of rs29232 remained significant (residual p < 5 × 10-4) after adjustment for age, gender, and HLA-related SNPs. Furthermore, higher GABAB receptor 1 expression levels can be found in the tumor cells in comparison to the adjacent epithelial cells (p < 0.001) in NPC biopsies, implying a biological role of GABBR1 in NPC carcinogenesis. To our knowledge, it is the first GWAS report of NPC showing that multiple loci (HLA-A, HLA-F, and GABBR1) within chromosome 6p21.3 are associated with NPC. Although some of these relationships may be attributed to linkage disequilibrium between the loci, the findings clearly provide a fresh direction for the study of NPC development.

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Genome-wide Association Study Reveals Multiple Nasopharyngeal Carcinoma-Associated Loci within the HLA Region at Chromosome 6p21.3

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