Dataset Information

Association of human leukocyte antigens with nasopharyngeal carcinoma in high-risk multiplex families in Taiwan.

ABSTRACT: An association between specific human leukocyte antigens (HLA) alleles and nasopharyngeal carcinoma (NPC) has been reported for sporadic NPC, but studies of familial NPC are lacking. We evaluated this association with familial NPC in a study of 301 NPC cases and 1010 family and community controls from Taiwan. Class I HLA alleles were characterized using a sequence-based typing protocol. Allele frequencies between case and control groups were compared by chi(2) or exact tests. For alleles associated with NPC, odds ratios (OR) and 95% confidence intervals (CI) were calculated. Similar allelic frequency distribution and HLA associations were found as those previously reported for sporadic NPC: protective effect for HLA-A*1101 and increased risk for HLA-A*0207, HLA-A*3303, HLA-B*3802, and HLA-B*5801. Overall, the magnitude of observed associations was weakest when cases were compared with sibling controls and strongest when compared with unrelated community controls. Evaluating the joint effect of HLA-A*0207 and HLA-B*4601, individuals who were carriers of HLA-A*0207 with or without the presence of HLA-B*4601 had a 1.9-fold (95% CI = 1.0-3.4) and 2.1-fold (95% CI = 0.83-5.3) risk of NPC, respectively. Conversely, carriers of HLA-B*4601 in the absence of HLA-A*0207 had a 50% reduction in NPC risk (95% CI = 0.27-0.93). Comparable findings from our family study and those from previous sporadic studies were found with the notable exception of a lack of positive association between HLA-B*4601 and familial NPC in the absence of HLA-A*0207. This finding requires replication in larger studies.

SUBMITTER: Yu KJ

PROVIDER: S-EPMC2764811 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Association of human leukocyte antigens with nasopharyngeal carcinoma in high-risk multiplex families in Taiwan.

Yu Kelly J KJ Gao Xiaojiang X Chen Chien-Jen CJ Yang Xiaohong Rose XR Diehl Scott R SR Goldstein Alisa A Hsu Wan-Lun WL Liang Xueying Sharon XS Marti Darlene D Liu Mei-Ying MY Chen Jen-Yang JY Carrington Mary M Hildesheim Allan A

Human immunology 20090813 11

An association between specific human leukocyte antigens (HLA) alleles and nasopharyngeal carcinoma (NPC) has been reported for sporadic NPC, but studies of familial NPC are lacking. We evaluated this association with familial NPC in a study of 301 NPC cases and 1010 family and community controls from Taiwan. Class I HLA alleles were characterized using a sequence-based typing protocol. Allele frequencies between case and control groups were compared by chi(2) or exact tests. For alleles associa ...[more]

PMID: 19683024

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Project description:BackgroundEpstein-Barr Virus (EBV)-associated nasopharyngeal carcinoma (NPC) exhibits unusual geographic restriction despite ubiquitous lifelong infection. Screening programs can detect most NPC cases at an early stage, but existing EBV diagnostics are limited by false positives and low positive predictive value (PPV), leading to excess screening endoscopies, MRIs, and repeated testing. Recent EBV genome-wide association studies (GWAS) suggest that EBV BALF2 variants account for more than 80% of attributable NPC risk. We therefore hypothesized that high-risk BALF2 variants could be readily detected in plasma for once-lifetime screening triage.MethodsWe designed and validated a multiplex genotyping assay to detect EBV BALF2 polymorphisms in human plasma. Targeted next-generation sequencing was used to validate this assay, conduct association studies with clinical phenotype, and longitudinally genotype plasma to assess within-host haplotype stability. We examined the association between NPC and BALF2 haplotypes in a large non-endemic population and three prior EBV GWAS. Finally, we estimated NPC mortality reduction, resource utilization, and cost-effectiveness of BALF2 variant-informed screening using a previously-validated cohort model.ResultsFollowing analytical validation, the BALF2 genotyping assay had 99.3% concordance with sequencing in a cohort of 24 NPC cases and 155 non-NPC controls. BALF2 haplotype was highly associated with NPC in this non-endemic population (I613V: odds ratio [OR] 7.9; V317M: OR 178.8). No other candidate BALF2 polymorphisms were significantly associated with NPC or hematologic disorders. Longitudinal genotyping revealed 97.8% within-host haplotype concordance, indicative of lifelong latent infection. In a meta-analysis of 755 NPC cases and 981 non-NPC controls, BALF2 I613V and V317M were significantly associated with NPC in both endemic and non-endemic populations. Modeled variant-informed screening strategies achieved a 46% relative increase in PPV with 7% decrease in effective screening sensitivity, thereby averting nearly half of screening endoscopies/MRIs among endemic populations in east/southeast Asia.ConclusionsEBV BALF2 haplotypes are temporally stable within hosts and can be readily detected in plasma via an inexpensive multiplex genotyping assay that offers near-perfect sequencing concordance. In endemic and non-endemic populations, I613V and V317M were highly associated with NPC and could be leveraged to develop variant-informed screening programs that mitigate false positives with small reductions in screening sensitivity.

Dataset Information

Association of human leukocyte antigens with nasopharyngeal carcinoma in high-risk multiplex families in Taiwan.

Publications

Association of human leukocyte antigens with nasopharyngeal carcinoma in high-risk multiplex families in Taiwan.

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