Germline variation in apoptosis pathway genes and risk of non-Hodgkin's lymphoma.
BACKGROUND
The t(14;18)(q32;q21) translocation is the most commonly observed chromosomal translocation in non-Hodgkin's lymphoma (NHL), resulting in constitutive Bcl-2 expression and apoptosis inhibition. In addition, germline variation in both BCL2L11 (BIM) and CASP9, known regulators of apoptosis, has recently been linked to NHL risk. We conducted a comprehensive evaluation of 36 apoptosis pathway genes with risk of NHL.


METHODS
We genotyped 226 single-nucleotide polymorphisms (SNP) from 36 candidate genes in a clinic-based study of 441 newly diagnosed NHL cases and 475 frequency-matched controls. We used principal components analysis to assess gene-level associations, and logistic regression to assess SNP-level associations. MACH was used for imputation of SNPs in BCL2L11 and CASP9.


RESULTS
In gene-level analyses, BCL2L11 (P = 0.0019), BCLAF1 (P = 0.0097), BAG5 (P = 0.026), and CASP9 (P = 0.0022) were associated with NHL risk after accounting for multiple testing (tail strength, 0.38; 95% confidence interval, 0.05-0.70). Two of the five BCL2L11 tagSNPs (rs6746608 and rs12613243), both genotyped BCLAF1 tagSNPs (rs797558 and rs703193), the single genotyped BAG5 tagSNP (rs7693), and three of the seven genotyped CASP9 tagSNPs (rs6685648, rs2020902, and rs2042370) were significant at P < 0.05. We successfully imputed BCL2L11 and CASP9 SNPs previously linked to NHL, and replicated all four BCL2L11 and two of three CASP9 SNPs.


CONCLUSIONS
We replicated the association of BCL2L11 and CASP9 with NHL risk at the gene and SNP level, and identified novel associations with BCLAF1 and BAG5.


CONCLUSIONS
Closer evaluation of germline variation of genes in the apoptosis pathway with risk of NHL and its subtypes is warranted.
Kelly
Jennifer L
JL
School of Medicine and Dentistry, University of Rochester, Rochester, New York, USA.
Novak
Anne J
AJ
Fredericksen
Zachary S
ZS
Liebow
Mark
M
Ansell
Stephen M
SM
Dogan
Ahmet
A
Wang
Alice H
AH
Witzig
Thomas E
TE
Call
Timothy G
TG
Kay
Neil E
NE
Habermann
Thomas M
TM
Slager
Susan L
SL
Cerhan
James R
JR
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D053453:Caspase 9 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C496515:BAG5 protein, human; C000606775:BCL2L11 protein, human; C119386:BCLAF1 protein, human; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; C506433:CASP9 protein, human; D053453:Caspase 9