TY - JOUR
T1 - A two-stage evaluation of genetic variation in immune and inflammation genes with risk of non-hodgkin lymphoma identifies new susceptibility locus in 6p21.3 region
AU - Cerhan, James R.
AU - Fredericksen, Zachary S.
AU - Novak, Anne J.
AU - Ansell, Stephen M.
AU - Kay, Neil E.
AU - Liebow, Mark
AU - Dogan, Ahmet
AU - Cunningham, Julie M.
AU - Wang, Alice H.
AU - Witzig, Thomas E.
AU - Habermann, Thomas M.
AU - Asmann, Yan W.
AU - Slager, Susan L.
PY - 2012/10
Y1 - 2012/10
N2 - Background: Non-Hodgkin lymphoma (NHL) is a malignancy of lymphocytes, and there is growing evidence for a role of germline genetic variation in immune genes in NHL etiology. Methods: To identify susceptibility immune genes, we conducted a 2-stage analysis of single-nucleotide polymorphisms (SNP) from 1,253 genes using the Immune and Inflammation Panel. In Stage 1, we genotyped 7,670 SNPs in 425 NHL cases and 465 controls, and in Stage 2 we genotyped the top 768 SNPs on an additional 584 cases and 768 controls. The association of individual SNPs with NHL risk from a log-additive model was assessed using the OR and 95% confidence intervals (CI). Results: In the pooled analysis, only the TAP2 coding SNP rs241447 (minor allele frequency = 0.26; Thr655Ala) at 6p21.3 (OR = 1.34, 95% CI 1.17-1.53) achieved statistical significance after accounting for multiple testing (P = 3.1 × 10-5). The TAP2 SNP was strongly associated with follicular lymphoma (FL, OR = 1.82, 95%CI 1.46-2.26; p = 6.9 × 10-8), and was independent of other known loci (rs10484561 and rs2647012) from this region. The TAP2 SNP was also associated with diffuse large B-cell lymphoma (DLBCL, OR = 1.38, 95% CI 1.08-1.77; P = 0.011), but not chronic lymphocytic leukemia (OR = 1.08; 95% CI 0.88-1.32). Higher TAP2 expression was associated with the risk allele in both FL and DLBCL tumors. Conclusion: Genetic variation in TAP2 was associated with NHL risk overall, and FL risk in particular, and this was independent of other established loci from 6p21.3. Impact: Genetic variation in antigen presentation of HLA class I molecules may play a role in lymphomagenesis.
AB - Background: Non-Hodgkin lymphoma (NHL) is a malignancy of lymphocytes, and there is growing evidence for a role of germline genetic variation in immune genes in NHL etiology. Methods: To identify susceptibility immune genes, we conducted a 2-stage analysis of single-nucleotide polymorphisms (SNP) from 1,253 genes using the Immune and Inflammation Panel. In Stage 1, we genotyped 7,670 SNPs in 425 NHL cases and 465 controls, and in Stage 2 we genotyped the top 768 SNPs on an additional 584 cases and 768 controls. The association of individual SNPs with NHL risk from a log-additive model was assessed using the OR and 95% confidence intervals (CI). Results: In the pooled analysis, only the TAP2 coding SNP rs241447 (minor allele frequency = 0.26; Thr655Ala) at 6p21.3 (OR = 1.34, 95% CI 1.17-1.53) achieved statistical significance after accounting for multiple testing (P = 3.1 × 10-5). The TAP2 SNP was strongly associated with follicular lymphoma (FL, OR = 1.82, 95%CI 1.46-2.26; p = 6.9 × 10-8), and was independent of other known loci (rs10484561 and rs2647012) from this region. The TAP2 SNP was also associated with diffuse large B-cell lymphoma (DLBCL, OR = 1.38, 95% CI 1.08-1.77; P = 0.011), but not chronic lymphocytic leukemia (OR = 1.08; 95% CI 0.88-1.32). Higher TAP2 expression was associated with the risk allele in both FL and DLBCL tumors. Conclusion: Genetic variation in TAP2 was associated with NHL risk overall, and FL risk in particular, and this was independent of other established loci from 6p21.3. Impact: Genetic variation in antigen presentation of HLA class I molecules may play a role in lymphomagenesis.
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U2 - 10.1158/1055-9965.EPI-12-0696
DO - 10.1158/1055-9965.EPI-12-0696
M3 - Article
C2 - 22911334
AN - SCOPUS:84867297787
SN - 1055-9965
VL - 21
SP - 1799
EP - 1806
JO - Cancer Epidemiology Biomarkers and Prevention
JF - Cancer Epidemiology Biomarkers and Prevention
IS - 10
ER -