Genetic linkage of Fc gamma RIIa and Fc gamma RIIIa and implications for their use in predicting clinical responses to CD20-directed monoclonal antibody therapy.
BACKGROUND
Polymorphisms in FcgammaRIIa and FcgammaRIIIa receptors are associated with responses to the CD20-directed immunoglobulin G1 (IgG1) monoclonal antibody rituximab among patients with indolent lymphoma. At odds with the aforementioned clinical observations has been the finding that IgG1 binding is impacted by polymorphisms in FcgammaRIIIa but not FcgammaRIIa. One possibility for this discrepancy might involve linkage of polymorphisms between FcgammaRIIa and FcgammaRIIIa.


METHODS
As such, we performed allelespecific polymerase chain reaction and directed sequencing of the genomic DNA coding region of FcgammaRIIA and FcgammaRIIIA for 52 healthy individuals.


RESULTS
Two common polymorphisms were observed for FcgammaRIIA (at positions 27 and 131) and FcgammaRIIIA (at positions 48 and 158). Importantly, we observed linkage among polymorphisms within and between FcgammaRIIa and FcgammaRIIIa, including the expression of histidine at FcgammaRIIa-131 and valine at FcgammaRIIIa, both of which are associated with enhanced responses to rituximab. The results of these studies demonstrate that there is wide linkage within and between polymorphisms in FcgammaRIIa and FcgammaRIIIa and might provide an explanation for why polymorphisms at FcgammaRIIa are associated with rituximab responses despite a lack of impact on IgG1 binding.


CONCLUSIONS
Knowledge of such linkages could facilitate the development of diagnostic tests aimed at identifying patients who might be more suitable for treatment with rituximab and possibly other therapeutic antibodies.
Hatjiharissi
Evdoxia
E
Bing Center for Waldenstrom's Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Hansen
Mark
M
Santos
Daniel Ditzel
DD
Xu
Lian
L
Leleu
Xavier
X
Dimmock
Elizabeth W
EW
Ho
Allen W
AW
Hunter
Zachary R
ZR
Branagan
Andrew R
AR
Patterson
Christopher J
CJ
Kortsaris
Alexandros
A
Verselis
Sigitas
S
Fox
Edward
E
Treon
Steven P
SP
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD / Q000235:genetics*; D018951:Antigens, CD20 / Q000235:genetics / Q000276:immunology*; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D017452:Receptors, IgG / Q000235:genetics*; D000069283:Rituximab; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D015703:Antigens, CD; D018951:Antigens, CD20; C496124:FCGR3A protein, human; C080568:Fc gamma receptor IIA; D007074:Immunoglobulin G; D017452:Receptors, IgG; D000069283:Rituximab