A comprehensive evaluation of the role of genetic variation in follicular lymphoma survival

BMC Medical Genetics

Karin E Smedby²  Christine F Skibola⁴  Keith Humphreys⁷  Jianjun Liu⁵  Lucia Conde⁴  Mads Melbye⁹  Bengt Glimelius³  Hans-Olov Adami^1,10  Richard Rosenquist¹  Henrik Hjalgrim^1,11  Robert Karlsson⁷  Hatef Darabi⁷  Paige Bracci⁸  Jia-Nee Foo⁵  Fredrik Baecklund⁶ 

[1] Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden;Department of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden;Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden;Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA;Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, Singapore;Department of Oncology, Karolinska University Hospital Solna, Stockholm, Sweden;Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden;Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA;Division of National Health Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark;Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA;Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark

关键词: Candidate gene study;    Genome-wide association study;    Single nucleotide polymorphism;    Prognosis;    Follicular lymphoma;   

Others  :  1090478
DOI  :  10.1186/s12881-014-0113-6

 received in 2014-02-04, accepted in 2014-09-29,  发布年份 2014

【 摘 要 】

Background

Survival in follicular lymphoma (FL) is highly variable, even within prognostic groups defined by tumor grade and the Follicular Lymphoma International Prognostic Index. Studies suggest that germline single nucleotide polymorphisms (SNPs) may hold prognostic information but further investigation is needed.

Methods

We explored the association between SNPs and FL outcome using two approaches: 1) Two independent genome-wide association studies (GWAS) of ~300.000 SNPs followed by a meta-analysis encompassing 586 FL patients diagnosed in Denmark/Sweden 1999–2002 and in the United States 2001–2006; and 2) Investigation of 22 candidate-gene variants previously associated with FL outcome in the Danish/Swedish cohort (N = 373). We estimated time to lymphoma-specific death (approach 1 and 2) and lymphoma progression (approach 2) with hazard ratios (HR) and 95% confidence intervals (CI) in a multivariable Cox regression model.

Results

In the GWAS meta-analysis, using a random effects model, no variants were associated with lymphoma-specific death at a genome-wide significant level (p < 5.0 ×10⁻⁸). The strongest association was observed for tightly linked SNPs on 17q24 near the ABCA10 and ABCA6 genes (rs10491178 HR_random = 3.17, 95% CI 2.09-4.79, p_random = 5.24 ×10⁻⁸). The ABCA10 and ABCA6 genes belong to a family of genes encoding for ABC transporter proteins, implicated in multidrug resistance. In line with a previous study, rs2466571 in CD46 (HR = 0.73, 95% CI 0.58-0.91, p = 0.006) showed nominal association with lymphoma progression, as did two highly linked SNPs in IL8 (rs4073 HR = 0.78, 95% CI 0.62-0.97, p = 0.02; rs2227307 HR = 0.75, 95% CI 0.60-0.94, p = 0.01) previously associated with overall survival.

Conclusions

The results suggest a possible role for multidrug resistance in FL survival and add to the evidence that genetic variation in CD46 and IL8 may have prognostic implications in FL. Our findings need further confirmation in other independent populations or in a larger multicenter GWAS.

【 授权许可】

   
2014 Baecklund et al.; licensee BioMed Central Ltd.

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