Carcinogenesis Advance Access published online on November 24, 2008
Carcinogenesis, doi:10.1093/carcin/bgn262
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A POOLED INVESTIGATION OF TOLL-LIKE RECEPTOR GENE VARIANTS AND RISK OF NON-HODGKIN LYMPHOMA
1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, MD
2 School of Public Health, The University of Sydney, Sydney, Australia
3 Department of Epidemiology and Public Health, Yale School of Medicine, New Haven, CT
4 National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
5 University of New South Wales Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Sydney, Australia
6 Department of Family Medicine and Karmanos Cancer Institute, Wayne State University, Detroit, MI
7 Mayo Clinic, College of Medicine, Rochester, MN
8 Core Genotyping Facility, Advanced Technology Center, National Cancer Institute, NIH, DHHS, Gaithersburg, MD
9 Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA
10 Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA
11 School of Public Health, The University of Sydney, Sydney, Australia
Toll-like receptors (TLRs) may influence the development of non-Hodgkin lymphoma (NHL) given their important roles in recognizing microbial pathogens and stimulating multiple immune pathways. We conducted an investigation of TLR gene variants in a pooled analysis including three population-based case-control studies of NHL (1,946 cases, 1,808 controls). Thirty-six tag single-nucleotide polymorphisms (SNPs) in TLR2, TLR4 and the TLR10-TLR1-TLR6 gene cluster were genotyped. Two TLR10-TLR1-TLR6 variants in moderate linkage disequilibrium were significantly associated with NHL: rs10008492 (odds ratio for CT genotype (ORCT) 1.12, 95% confidence interval (CI) 0.97-1.30; ORTT 1.40, 95% CI 1.15-1.71; Ptrend=0.001) and rs4833103 (ORAC 0.75, 95% CI 0.64-0.88; ORAA 0.74, 95% CI 0.62-0.90; Ptrend=0.002; Pdominant=0.0002). Associations with these SNPs were consistent across all three studies and did not appreciably differ by histologic subtype. We found little evidence of association between TLR2 variation and all NHL, although the rare variant rs3804100 was significantly associated with marginal zone lymphoma (MZL), both overall (ORCT/CC 1.89, 95% CI 1.27-2.81; Pdominant=0.002) and in two of the three studies. No associations with TLR4 variants were observed. This pooled analysis provides strong evidence that variation in the TLR10-TLR1-TLR6 region is associated with NHL risk, and suggests that TLR2 variants may influence susceptibility to MZL.
Received August 13, 2008; revised October 16, 2008; accepted November 18, 2008.