Genetic variation in B-cell-activating factor is associated with an increased risk of developing B-cell non-Hodgkin lymphoma - PubMed (original) (raw)

. 2009 May 15;69(10):4217-24.

doi: 10.1158/0008-5472.CAN-08-4915. Epub 2009 Apr 21.

Susan L Slager, Zachary S Fredericksen, Alice H Wang, Michelle M Manske, Steven Ziesmer, Mark Liebow, William R Macon, Stacey R Dillon, Thomas E Witzig, James R Cerhan, Stephen M Ansell

Affiliations

Genetic variation in B-cell-activating factor is associated with an increased risk of developing B-cell non-Hodgkin lymphoma

Anne J Novak et al. Cancer Res. 2009.

Abstract

Elevated B-cell-activating factor (BAFF; TNFSF13B) levels have been found in patients with B-cell malignancies and autoimmune diseases, suggesting that it may play a pathogenic role. We previously found that a single nucleotide polymorphism (SNP) in the TNFSF13B promoter resulted in increased transcription, suggesting that genetic variation in TNFSF13B may influence its expression. We therefore wanted to determine if genetic variation in TNFSF13B is associated with high BAFF levels and non-Hogkin lymphoma (NHL) risk. We genotyped 9 tagSNPs within TNFSF13B in a clinic-based study of 441 NHL cases and 475 matched controls and evaluated the association of individual SNPs with risk of NHL; 3 tagSNPs were significant (P < 0.05). When categorized into low-, moderate-, and high-risk groups based on risk alleles, we found the permutation-corrected odds ratio for the trend to be 1.43 (P = 0.0019) for risk of B-cell NHL, 1.69 (P = 0.0093) for diffuse large B-cell lymphoma, 1.43 (P = 0.029) for follicular lymphoma, and 1.06 (P = 0.21) for chronic lymphocytic leukemia/small lymphocytic lymphoma. The mean serum BAFF level in those who carried the low-risk alleles was 2 ng/mL compared with 4.3 ng/mL in those with the high-risk alleles (P = 0.02). Taken together, our data suggest that genetic variation in the TNFSF13B gene is significantly associated with NHL risk and elevated serum BAFF levels.

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Figures

Figure 1

Figure 1. TNFSF13B gene structure and tagSNP mapping

A. Three SNPs, rs1224141, rs12583006, and rs12428930 in TNFSF13B are significantly associated with NHL risk and are located in the non-coding region of TNFSF13B flanking exon 3. B. Linkage disequilibrium (LD) chart showing strong LD among rs1224141, rs12583006, and rs12428930. Numbers represent |D’| values and darker shading represents higher r^2 values of correlation between SNPs.

Figure 2

Figure 2. Association of elevated serum BAFF levels with the high risk TNFSF13B gene alleles and NHL

Serum BAFF levels were tested by ELISA as described in Materials and Methods. A. Serum from untreated cases who had been genotyped and carried either the TNFSF13B low risk alleles (n=8) or high risk alleles (n=42) and untreated controls that carried either the TNFSF13B low risk alleles (n=18) or high risk alleles (n=32) B. Serum BAFF levels in controls (n=50) versus cases (n=50). C. Serum BAFF levels by histologic subtype (DLBCL n=11, FL n=21). D Serum BAFF levels in DLBCL patients (n=57). E. Serum BAFF levels in FL patients (n=32). *p<0.05

Figure 3

Figure 3. Expression of ΔBAFF is not associated with the high risk TNFSF13B gene alleles

A. Expression of BAFF, ΔBAFF, and BAFFφ mRNA was determined by RT-PCR. Two DNA specimens and a no DNA template control are shown. B. ΔBAFF mRNA levels in individuals (untreated cases and controls) who carry the high risk alleles (n=42) versus low risk alleles (n=18) were determined by PCR. Primers were designed to amplify full-length BAFF as well as ΔBAFF and data were quantified and normalized to full-length BAFF as described in Materials and Methods. Values represent the ratio of the densitometric value of ΔBAFF/BAFF.

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