Genome-wide association study reveals multiple nasopharyngeal carcinoma-associated loci within the HLA region at chromosome 6p21.3.
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 x 10(-20) and 1.6 x 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 x 10(-17)) and HLA-F (rs3129055 and rs9258122; p(combined) = 7.36 x 10(-11) and 3.33 x 10(-10), respectively). Notably, the association of rs29232 remained significant (residual p < 5 x 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.
Tse
Ka-Po
KP
Genomic Medicine Core, Chang Gung Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan.
Su
Wen-Hui
WH
Chang
Kai-Ping
KP
Tsang
Ngan-Ming
NM
Yu
Chia-Jung
CJ
Tang
Petrus
P
See
Lee-Chu
LC
Hsueh
Chuen
C
Yang
Min-Lee
ML
Hao
Sheng-Po
SP
Li
Hong-Yi
HY
Wang
Ming-Hsi
MH
Liao
Li-Ping
LP
Chen
Lih-Chyang
LC
Lin
Sheue-Rong
SR
Jorgensen
Timothy J
TJ
Chang
Yu-Sun
YS
Shugart
Yin Yao
YY
D000483:Alleles; D044466:Asian People / Q000235:genetics / Q000706:statistics & numerical data; D002277:Carcinoma / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D015810:Linkage Disequilibrium; D008297:Male; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism; D013624:Taiwan
D006680:HLA Antigens; C062341:HLA-F antigens; D015395:Histocompatibility Antigens Class I; D018080:Receptors, GABA-B