Genomes and Genes
A Genome-Wide Association Study of Non-Hodgkin Lymphoma
Principal Investigator: Christine F Skibola
Abstract: Incidence rates of non-Hodgkin lymphoma (NHL) have increased dramatically in the U.S. and other industrialized countries over the past 40 years, though reasons for this rise in rates are largely unexplained. In 2005, it has been estimated that NHL will account for 56,390 newly diagnosed cases and 19,200 associated deaths. Family and population-based studies provide evidence that genetic susceptibility plays a role in lymphomagenesis. However, the contribution of common genetic alleles and gene-environment interactions needs further investigation. Using Perlegen high-density oligonucleotide arrays, genome-wide genotyping on pooled DNA will be conducted to screen for NHL susceptibility markers. 267,000 haplotype tagging single nucleotide polymorphisms (SNPs) will be evaluated that span the genome on DNA pools from 1,000 NHL cases and 1,000 controls in a large population-based case-control study in the San Francisco Bay Area (recruitment of 2,000 cases and 2,000 controls to be completed in Spring 2006). Over 1,400 cases and 1,400 controls already have been ascertained with extensive epidemiological information collected from all study participants. Once target genes are identified by pooled genotyping, the association of these loci with NHL risk will be verified and further investigated by individual genotyping. An additional 7,000 SNPs will be individually genotyped in the human leukocyte antigen (HLA) region to investigate the involvement of HLA loci in the pathogenesis of NHL. Positive findings will be replicated in a second set of 1,000 NHL cases and 1,000 controls. Fine mapping genotyping will be performed on confirmed genes of interest. To add an additional replication step, another approximately 400 NHL cases and 800 controls from a previous NHL study (based in the San Francisco Bay Area) will be genotyped. This study, which constitutes one of the largest case-control NHL genetic epidemiology studies conducted to date, will broaden our current understanding of important mechanistic pathways involved in lymphomagenesis. Furthermore, these results may be translated to NHL screening, prevention or treatment regimens. The data generated from this study will provide a framework for further investigation within the NHL consortium, InterLymph. Results will later be combined with that from other InterLymph case-control studies in pooled analyses.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT
- A functional TNFRSF5 gene variant is associated with risk of lymphomaChristine F Skibola
Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720 7360, USA
Blood 111:4348-54. 2008..These results suggest that the TNFRSF5 -1C>T polymorphism may increase FL susceptibility through mechanisms that hinder cellular immune responses. Further studies are needed to explore these findings...
- Non-Hodgkin lymphoma risk and variants in genes controlling lymphocyte developmentJohanna M Schuetz
Canada s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada
PLoS ONE 8:e75170. 2013..It is likely that moderate sample size, inter-subtype and other genetic heterogeneity, and small true effect sizes account for the lack of replicable findings. ..
- Coding variants at hexa-allelic amino acid 13 of HLA-DRB1 explain independent SNP associations with follicular lymphoma riskJia Nee Foo
Human Genetics, Genome Institute of Singapore, Agency for Science, Technology, and Research, Singapore 138672, Singapore
Am J Hum Genet 93:167-72. 2013..01 × 10⁻¹⁴). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis...
- Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemiaSonja I Berndt
Division of Cancer Epidemiology and Genetics, National Cancer Institute NCI, Bethesda, Maryland, USA
Nat Genet 45:868-76. 2013..3 (ODF1, P=5.40×10(-8)) and 5p15.33 (TERT, P=1.92×10(-7)). Although further studies are required, the proximity of several of these loci to genes involved in apoptosis suggests a plausible underlying biological mechanism...
- Integrating GWAS and expression data for functional characterization of disease-associated SNPs: an application to follicular lymphomaLucia Conde
Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA 94720 7360, USA
Am J Hum Genet 92:126-30. 2013..The application of integrative methods, such as those presented here, to other post-GWAS investigations will help identify causal disease variants and enhance our understanding of biological disease mechanisms...
- PRRC2A and BCL2L11 gene variants influence risk of non-Hodgkin lymphoma: results from the InterLymph consortiumAlexandra Nieters
Centre of Chronic Immunodeficiency, University Medical Center Freiburg, Engesser Strasse4, Freiburg, Germany
Blood 120:4645-8. 2012..These results are consistent with the known biology of NHL and provide insights into shared pathogenic components, including apoptosis and immune regulation, for the major B-cell lymphoma subtypes...
- A meta-analysis of genome-wide association studies of follicular lymphomaChristine F Skibola
School of Public Health, Division of Environmental Health Sciences, University of California, Berkeley, 94720, USA
BMC Genomics 13:516. 2012....
- Common variants within 6p21.31 locus are associated with chronic lymphocytic leukaemia and, potentially, other non-Hodgkin lymphoma subtypesSusan L Slager
Mayo Clinic College of Medicine, Rochester, MN, USA
Br J Haematol 159:572-6. 2012..These variants also showed a trend towards association with some of the other NHL subtypes. Our results validate the prior work and support specific genetic pathways for risk among NHL subtypes...
- Common variation at 6p21.31 (BAK1) influences the risk of chronic lymphocytic leukemiaSusan L Slager
Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
Blood 120:843-6. 2012..This finding provides additional support for polygenic inheritance to CLL and provides further insight into the biologic basis of disease development...
- Polymorphisms in the estrogen receptor 1 and vitamin C and matrix metalloproteinase gene families are associated with susceptibility to lymphomaChristine F Skibola
School of Public Health, Division of Environmental Health Sciences, University of California Berkeley, Berkeley, California, USA
PLoS ONE 3:e2816. 2008..Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in the U.S. and few causes have been identified. Genetic association studies may help identify environmental risk factors and enhance our understanding of disease mechanisms...
- Obesity, diet and risk of non-Hodgkin lymphomaChristine F Skibola
Division of Environmental Health Sciences, School of Public Health, 140 Earl Warren Hall, University of California, Berkeley, CA 94720 7360, USA
Cancer Epidemiol Biomarkers Prev 16:392-5. 2007..The accumulated scientific evidence concerning the associations between obesity, diet, and NHL suggests several identified modifiable risk factors that might be recommended to decrease lymphoma risk...
- A search for overlapping genetic susceptibility loci between non-Hodgkin lymphoma and autoimmune diseasesLucia Conde
Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, USA
Genomics 98:9-14. 2011..These results support continued investigation to further elucidate the relationship between lymphoma and autoimmune diseases...
- Multiplexed, ligation-dependent probe amplification for rapid and inexpensive HLA-DQB1 allelotypingN K Akers
Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA
Tissue Antigens 78:275-80. 2011..This assay provides more specific allele data than genome-wide analysis and is more affordable than sequencing, making it a useful intermediate for researchers seeking to accurately allelotype human DNA samples...
- The rs5743836 polymorphism in TLR9 confers a population-based increased risk of non-Hodgkin lymphomaA Carvalho
Life and Health Sciences Research Institute, School of Health Sciences, University of Minho, Braga, Portugal
Genes Immun 13:197-201. 2012..Moreover, the increased transcriptional activity of TLR9 in mononuclear cells from patients harboring rs5743836 further supports a functional effect of this polymorphism on NHL susceptibility in a population-dependent manner...
- Post-GWAS functional characterization of susceptibility variants for chronic lymphocytic leukemiaFenna C M Sillé
Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, California, United States of America
PLoS ONE 7:e29632. 2012....
- Multi-locus HLA class I and II allele and haplotype associations with follicular lymphomaC F Skibola
Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720 7356, USA
Tissue Antigens 79:279-86. 2012..These results provide further insight into the critical roles of HLA alleles and SNPs in FL pathogenesis that involve multi-locus effects across the HLA region...
- SNP rs6457327 in the HLA region on chromosome 6p is predictive of the transformation of follicular lymphomaDavid Wrench
Centre for Haemato Oncology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Blood 117:3147-50. 2011..008) with risk of FL and demonstrate that rs6457327 predicts both time to (P = .02) and risk of (P < .01) FL transformation independently of clinical variables, including the Follicular Lymphoma International Prognostic Index...
- Association of HLA-DQB1 alleles with risk of follicular lymphomaNicholas K Akers
School of Public Health, University of California, Berkeley, CA, USA
Leuk Lymphoma 52:53-8. 2011..51, 95% CI 0.38-0.69; adjusted p-value = 4.46 × 10(-5)). Although these findings require verification, the role of HLA class II proteins in B-cell survival and proliferation makes this a biologically plausible association...
- Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32Lucia Conde
School of Public Health, University of California, Berkeley, Berkeley, California, USA
Nat Genet 42:661-4. 2010..We also found confirmatory evidence of a previously reported association between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined P = 4.24 x 10(-9))...
- Tumor necrosis factor (TNF) and lymphotoxin-alpha (LTA) polymorphisms and risk of non-Hodgkin lymphoma in the InterLymph ConsortiumChristine F Skibola
237A Hildebrand Hall, School of Public Health, University of California, Berkeley, Berkeley, CA 94720 7360, USA
Am J Epidemiol 171:267-76. 2010..04). These findings strengthen previous results for DLBCL and the LTA 252A>G/TNF -308A locus and provide robust evidence that these TNF/LTA gene variants, or others in linkage disequilibrium, are involved in NHL etiology...
- Chemokine polymorphisms and lymphoma: a pooled analysisPaige M Bracci
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94118 1944, USA
Leuk Lymphoma 51:497-506. 2010..The CCL5 -403A allele conferred reduced risks of FL and chronic lymphocytic leukemia/small lymphocytic lymphoma. Results should be interpreted conservatively. Continued investigation is warranted to confirm these findings...
- Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphomaChristine F Skibola
Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, California, USA
Nat Genet 41:873-5. 2009..7 x 10(-11)). The region of strongest association overlapped C6orf15 (STG), located near psoriasis susceptibility region 1 (PSORS1)...