Genetic Variation in Cell Death Genes and Risk of Non-Hodgkin Lymphoma

Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.
PLoS ONE (Impact Factor: 3.23). 02/2012; 7(2):e31560. DOI: 10.1371/journal.pone.0031560
Source: PubMed


Non-Hodgkin lymphomas are a heterogeneous group of solid tumours that constitute the 5(th) highest cause of cancer mortality in the United States and Canada. Poor control of cell death in lymphocytes can lead to autoimmune disease or cancer, making genes involved in programmed cell death of lymphocytes logical candidate genes for lymphoma susceptibility.
We tested for genetic association with NHL and NHL subtypes, of SNPs in lymphocyte cell death genes using an established population-based study. 17 candidate genes were chosen based on biological function, with 123 SNPs tested. These included tagSNPs from HapMap and novel SNPs discovered by re-sequencing 47 cases in genes for which SNP representation was judged to be low. The main analysis, which estimated odds ratios by fitting data to an additive logistic regression model, used European ancestry samples that passed quality control measures (569 cases and 547 controls). A two-tiered approach for multiple testing correction was used: correction for number of tests within each gene by permutation-based methodology, followed by correction for the number of genes tested using the false discovery rate.
Variant rs928883, near miR-155, showed an association (OR per A-allele: 2.80 [95% CI: 1.63-4.82]; p(F) = 0.027) with marginal zone lymphoma that is significant after correction for multiple testing.
This is the first reported association between a germline polymorphism at a miRNA locus and lymphoma.

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    • "Since the association of H2AFX variants with glioma is reportedly stronger in males [12], we hypothesized that effect of H2AFX genotype on NHL risk may also be influenced by sex. To assess interaction with sex, the SNP with the most significant p value within each NHL subtype was chosen to represent the gene for that subtype [17] and was analyzed by logistic regression comparing a full model including sex*SNP as an interaction term, to a reduced model with sex, age group, region of residence and SNP. For subtypes in which this analysis was significant, the data was stratified by sex and logistic regression separately in the female and male strata (correcting for age group and region of residence) for all 13 SNPs. "
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    ABSTRACT: H2AFX encodes a histone variant involved in signaling sites of DNA damage and recruiting repair factors. Genetic variants in H2AFX may influence risk of non-Hodgkin lymphoma (NHL), a heterogeneous group of lymphoid tumors that are characterized by chromosomal translocations. We previously reported that rs2509049, a common variant in the promoter of H2AFX, was associated with risk for NHL in the British Columbia population. Here we report results for 13 single nucleotide polymorphisms (SNPs) in 100 Kb surrounding H2AFX in an expanded collection of 568 NHL cases and 547 controls. After correction for multiple testing, significant associations were present for mantle cell lymphoma (p=0.007 for rs604714) and all B-cell lymphomas (p=0.046 for rs2509049). Strong linkage disequilibrium in the 5 Kb upstream of H2AFX limited the ability to determine which specific SNP (rs2509049, rs7759, rs8551, rs643788, rs604714, or rs603826), if any, was responsible. There was a significant interaction between sex and rs2509049 in the all B-cell lymphomas group (p=0.002); a sex-stratified analysis revealed that the association was confined to females (p=0.001). Neither the overall nor the female-specific association with rs2509049 was replicated in any of four independent NHL sample sets. Meta-analysis of all five study populations (3,882 B-cell NHL cases and 3,718 controls) supported a weak association with B-cell lymphoma (OR=0.92, 95% CI=0.86-0.99, p=0.034), although this association was not significant after exclusion of the British Columbia data. Further research into the potential sex-specificity of the H2AFX-NHL association may identify a subset of NHL cases that are influenced by genotype at this locus.
    PLoS ONE 09/2013; 8(9):e74619. DOI:10.1371/journal.pone.0074619 · 3.23 Impact Factor
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    • "We illustrate the features of the CrypticIBDcheck package using the genetic data Nhlsim that comes with the package. These data were simulated to mimic the characteristics of SNP genotypes in subjects of European ancestry from a candidate-gene, case-control study of non-Hodgkin Lymphoma [21]. The data set is a list comprised of (i) a snp.matrix object called with genotypes for 108 controls and 100 cases; (ii) a vector chromosome of chromosome numbers for each SNP; (iii) a vector physmap of physical map positions of each SNP, from build 36 of the human genome; and (iv) a binary vector csct with value one for cases and zero for population controls. "
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    ABSTRACT: In population association studies, standard methods of statistical inference assume that study subjects are independent samples. In genetic association studies, it is therefore of interest to diagnose undocumented close relationships in nominally unrelated study samples. We describe the R package CrypticIBDcheck to identify pairs of closely-related subjects based on genetic marker data from single-nucleotide polymorphisms (SNPs). The package is able to accommodate SNPs in linkage disequibrium (LD), without the need to thin the markers so that they are approximately independent in the population. Sample pairs are identified by superposing their estimated identity-by-descent (IBD) coefficients on plots of IBD coefficients for pairs of simulated subjects from one of several common close relationships. The methods implemented in CrypticIBDcheck are particularly relevant to candidate-gene association studies, in which dependent SNPs cluster in a relatively small number of genes spread throughout the genome. The accommodation of LD allows the use of all available genetic data, a desirable property when working with a modest number of dependent SNPs within candidate genes. CrypticIBDcheck is available from the Comprehensive R Archive Network (CRAN).
    Source Code for Biology and Medicine 02/2013; 8(1):5. DOI:10.1186/1751-0473-8-5
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    ABSTRACT: MicroRNAs (miRNAs) are small RNA molecules that regulate the expression of corresponding messenger RNAs (mRNAs). Variations in the level of expression of distinct miRNAs have been observed in the genesis, progression and prognosis of multiple human malignancies. The present study was aimed to investigate the association between four highly studied miRNA polymorphisms (mir-146a rs2910164, mir-196a2 rs11614913, mir-149 rs2292832 and mir-499 rs3746444) and cancer risk by using a two-sided meta-analytic approach. An updated meta-analysis based on 53 independent case-control studies consisting of 27573 cancer cases and 34791 controls was performed. Odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association. Overall, the pooled analysis showed that mir-196a2 rs11614913 was associated with a decreased cancer risk (OR = 0.846, P = 0.004, TT vs. CC) while other miRNA SNPs showed no association with overall cancer risk. Subgroup analyses based on type of cancer and ethnicity were also performed, and results indicated that there was a strong association between miR-146a rs2910164 and overall cancer risk in Caucasian population under recessive model (OR = 1.274, 95%CI = 1.096-1.481, P = 0.002). Stratified analysis by cancer type also associated mir-196a2 rs11614913 with lung and colorectal cancer at allelic and genotypic level. The present meta-analysis suggests an important role of mir-196a2 rs11614913 polymorphism with overall cancer risk especially in Asian population. Further studies with large sample size are needed to evaluate and confirm this association.
    PLoS ONE 11/2012; 7(11):e50966. DOI:10.1371/journal.pone.0050966 · 3.23 Impact Factor
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