Reduced risk of AIDS lymphoma in individuals heterozygous for the CCR5-delta32 mutation.
Non-Hodgkin's lymphoma (NHL) has been increasing in frequency in the industrialized world, but the environmental and genetic factors that contribute to susceptibility are not known. B-cell lymphomas represent a major cause of morbidity and mortality in HIV-infected individuals. The identification of a deletion in the CCR5 chemokine receptor gene that alters the risk for infection and progression to AIDS led us to examine a potential role of this gene in AIDS lymphoma. A matched case-control analysis was performed using all eligible NHL cases in the Multicenter AIDS Cohort Study. Patients were matched for age, study center, time AIDS-free, and slope of the CD4+ T-cell decline. The CCR5-delta32 allele was found to be associated with a 3-fold lower risk of NHL among individuals after controlling for time of infection and progression toward AIDS. The CCR5 gene was not associated with a difference in risk for Kaposi's sarcoma, another common malignancy in AIDS patients, or opportunistic infections. Costimulation of normal phorbol 12-myristate 13-acetate-treated B cells with the CCR5 ligand RANTES induced a proliferative response, indicating that RANTES is a mitogen for B cells. Taken together, these findings suggest that the CCR5 gene plays a role in the risk of NHL in HIV-infected patients, perhaps through a mechanism involving a decreased response of B cells to the mitogenic activity of RANTES.
Dean
M
M
Laboratories of Genomic Diversity, National Cancer Institute, Frederick, Maryland 21702-1201, USA.
Jacobson
L P
LP
McFarlane
G
G
Margolick
J B
JB
Jenkins
F J
FJ
Howard
O M
OM
Dong
H F
HF
Goedert
J J
JJ
Buchbinder
S
S
Gomperts
E
E
Vlahov
D
D
Oppenheim
J J
JJ
O'Brien
S J
SJ
Carrington
M
M
D017088:AIDS-Related Opportunistic Infections / Q000453:epidemiology / Q000235:genetics; D000328:Adult; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D016022:Case-Control Studies; D018946:Chemokine CCL5 / Q000502:physiology; D015331:Cohort Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D015497:HIV-1; D006801:Humans; D016483:Lymphoma, AIDS-Related / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D017354:Point Mutation; D019713:Receptors, CCR5 / Q000235:genetics*; D012306:Risk; D012514:Sarcoma, Kaposi / Q000453:epidemiology / Q000235:genetics; D017384:Sequence Deletion; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D044465:White People / Q000235:genetics
D018946:Chemokine CCL5; D019713:Receptors, CCR5; D013755:Tetradecanoylphorbol Acetate