Germline variation in complement genes and event-free survival in follicular and diffuse large B-cell lymphoma.
The complement pathway plays a central role in innate immunity, and also functions as a regulator of the overall immune response. We evaluated whether polymorphisms in complement genes are associated with event-free survival (EFS) in follicular lymphoma (FL) and diffuse large B-cell (DLBCL) lymphoma. We genotyped 167 single nucleotide polymorphisms (SNPs) from 30 complement pathway genes in a prospective cohort study of newly diagnosed FL (N = 107) and DLBCL (N = 82) patients enrolled at the Mayo Clinic from 2002 to 2005. Cox regression was used to estimate hazard ratios (HRs) for individual SNPs with EFS, adjusting for FLIPI or IPI and treatment. For gene-level analyses, we used a principal components based gene-level test. In gene-level analyses for FL EFS, CFH (P = 0.009), CD55 (P = 0.006), CFHR5 (P = 0.01), C9 (P = 0.02), CFHR1 (P = 0.03), and CD46 (P = 0.03) were significant at P < 0.05, and these genes remained noteworthy after accounting for multiple testing (q < 0.15). SNPs in CFH, CFHR1, and CFHR5 showed stronger associations among patients receiving any rituximab, while SNPs from CD55 and CD46 showed stronger associations among patients who were observed. For DLBCL, only CLU (P = 0.001) and C7 (P = 0.03) were associated with EFS, but did not remain noteworthy after accounting for multiple testing (q>0.15). Genes from the regulators of complement activation (CFH, CD55, CFHR1, CFHR5, CD46) at 1q32-q32.1, along with C9, were associated with FL EFS after adjusting for clinical variables, and if replicated, these findings add further support for the role of host innate immunity in FL prognosis.
Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Bridget
B
Charbonneau
Matthew J
MJ
Maurer
Zachary S
ZS
Fredericksen
Clive S
CS
Zent
Brian K
BK
Link
Anne J
AJ
Novak
Stephen M
SM
Ansell
George J
GJ
Weiner
Alice H
AH
Wang
Thomas E
TE
Witzig
Ahmet
A
Dogan
Susan L
SL
Slager
Thomas M
TM
Habermann
James R
JR
Cerhan
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D015331:Cohort Studies; D003167:Complement Activation / Q000235:genetics*; D003165:Complement System Proteins / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008224:Lymphoma, Follicular / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D000069283:Rituximab
D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab; D003165:Complement System Proteins