title: A comprehensive evaluation of the role of genetic variation in follicular lymphoma survival.
abstract: 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 HRrandom = 3.17, 95% CI 2.09-4.79, prandom = 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.
authors.affiliation: Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden. fredrik.baecklund@ki.se.|Department of Oncology, Karolinska University Hospital Solna, Stockholm, Sweden. fredrik.baecklund@ki.se.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Baecklund
authors.affiliation: Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, Singapore. foojn@gis.a-star.edu.sg.
authors.forename: Jia-Nee
authors.initials: JN
authors.lastname: Foo
authors.affiliation: Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA. paige.bracci@ucsf.edu.
authors.forename: Paige
authors.initials: P
authors.lastname: Bracci
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. hatef.darabi@ki.se.
authors.forename: Hatef
authors.initials: H
authors.lastname: Darabi
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. robert.karlsson@ki.se.
authors.forename: Robert
authors.initials: R
authors.lastname: Karlsson
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. hhj@ssi.dk.
authors.forename: Henrik
authors.initials: H
authors.lastname: Hjalgrim
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. richard.rosenquist@igp.uu.se.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. hadami@hsph.harvard.edu.|Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA. hadami@hsph.harvard.edu.
authors.forename: Hans-Olov
authors.initials: HO
authors.lastname: Adami
authors.affiliation: Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden. bengt.glimelius@onkologi.uu.se.|Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden. bengt.glimelius@onkologi.uu.se.
authors.forename: Bengt
authors.initials: B
authors.lastname: Glimelius
authors.affiliation: Division of National Health Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark. mme@ssi.dk.
authors.forename: Mads
authors.initials: M
authors.lastname: Melbye
authors.affiliation: Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA. lconde@uab.edu.
authors.forename: Lucia
authors.initials: L
authors.lastname: Conde
authors.affiliation: Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, Singapore. liuj3@gis.a-star.edu.sg.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. keith.humphreys@ki.se.
authors.forename: Keith
authors.initials: K
authors.lastname: Humphreys
authors.affiliation: Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA. cskibola@uab.edu.
authors.forename: Christine F
authors.initials: CF
authors.lastname: Skibola
authors.affiliation: Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden. karin.ekstrom.smedby@ki.se.|Department of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden. karin.ekstrom.smedby@ki.se.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Smedby
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000401:mortality*; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics*; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016019:Survival Analysis; D055815:Young Adult
chemical_list: C476234:ABCA10 protein, human; C434046:ABCA6 protein, human; D018528:ATP-Binding Cassette Transporters; C497857:CD46 protein, human; C508606:CXCL8 protein, human; D016209:Interleukin-8; D051916:Membrane Cofactor Protein