Genome-wide scan for familial nasopharyngeal carcinoma reveals evidence of linkage to chromosome 4

Abstract

Nasopharyngeal carcinoma (NPC) occurs with high frequency in Asian populations, especially among people of Cantonese ancestry. In areas with high incidence, NPC clusters in families, which suggests that both geography and genetics may influence disease risk1,2,3,4,5,6. Although the HLA-Bw46 locus is associated with increased risk of NPC7,8, no predisposing genes have been identified so far. Here we report the results of a genome-wide search carried out in families at high risk of NPC from Guangdong Province, China. Parametric analyses provide evidence of linkage to the D4S405 marker on chromosome 4 with a logarithm of odds for linkage (lod) score of 3.06 and a heterogeneity-adjusted lod (hlod) score of 3.21. Fine mapping with additional markers flanking D4S405 resulted in a lod score of 3.54 and hlod score of 3.67 for the region 4p15.1–q12. Multipoint nonparametric linkage analysis gives lod scores of 3.54 at D4S405 (P = 5.4 × 10−5) and 4.2 at D4S3002 (P = 1.1 × 10−5), which is positioned 4.5 cM away from D4S405. When Epstein–Barr virus antibody titer was included as a covariate, the lod scores reached 4.70 (P = 2.0 × 10−5) and 5.36 (P = 4.36 × 10−6) for D4S405 and D4S3002, respectively. Our findings provide evidence of a major susceptibility locus for NPC on chromosome 4 in a subset of families.

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Figure 1: The multipoint lod, hlod and NPL scores in genome-wide linkage analyses.
Figure 2: Scale map of markers on chromosome 4 for fine mapping of the NPC susceptibility locus.
Figure 3: The lod scores of multipoint and two-point analyses from fine mapping on chromosome 4.
Figure 4: Pedigree structure and haplotypes of family 34 and family 31.

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Acknowledgements

We thank colleagues in the Cancer Center, Sun Yat-sen University, for providing information about families with NPC; and K. Jacobs and B. Doan for help with preparing data and test-running the β10 version of SAGE. This work was supported by the China Medical Board, the National Key Basic Research Projects of China, the National Outstanding Youth Grant of China, the Key Projects of National Natural Science Foundation, the National High Technology Project, the Foundation of Guangdong Science and Technology Committee and the Shanghai Municipal Foundation for Sciences and Technologies.

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Correspondence to Yi-Xin Zeng.

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