FCGR3A Gene Polymorphism

Fc^RIIIa is expressed on macrophages, natural killer cells, and some dendritic cells as a transmembrane receptor. The major polymorphism of Fc^RIIIa gene is a single nucleotide substitution at position 559 resulting in the presence of either valine (V158) or phenylalanine (F158) at position 158 in the extracellular domain (41,42).

It is known that valine (V) allele of the Fc^ Rllla gene has a higher affinity to human IgG1 and IgG3 than the phenylalanine (F) allele. Cells bearing the Fc^ RIIIa V allele mediate ADCC more effectively (42,43). Dall'Ozzo et al. (44) found thatNK cells from subjects with the VV genotype for FCGR3A-158 showed a higher affinity for Fc^R and mediated ADCC at a lower concentration of monoclonal antibody than did NK cells with the FF genotype.

Hatjiharissi et al. (45) presented an important in vitro data regarding the functional assay results according to the FCGR3A genotype. They isolated peripheral blood NK cells from 52 healthy donors who were genotyped for FCGR3A-158. Higher transcript levels were noted in the VV group (23.2ng/mL) compared to the VF (6.7ng/mL) or FF group (6.2ng/mL;p < 0.0001) using allele-specific quantitative RT-PCR.

The number of CD16 receptors per NK cell was higher in a group carrying the V allele compared with the FF group (105,947 in VV; 94,863 in VF; and 69,130 in FF group; p = 0.033) by quantitative flow cytometry. Moreover, after incubation of NK cells with rituximab at a concentration of 10-200 mcg/mL, binding of rituximab to NK cells was higher among donors expressing at least one valine (72% in VV; 53% in VF; and 37% in FF group; p = 0.017). Finally, in an assay of rituximab-dependent NK cell-mediated cytotoxicity, a higher level of ADCC killing was observed in the VV (82%) or VF (80%) groups versus the FF group (23%). This study consistently showed that individuals who express at least one valine at FCGR3A-158 have increased Fc^RIIIA receptor expression on NK cells, rituximab binding to NK cells, and ADCC-mediated killing of lymphoma cells. This may explain better clinical outcomes to rituximab therapy in patients with V-allele at FCGR3A 158 loci (45).

The FCGR3A gene contains a second polymorphic site (6). A non-functional tri-allelic polymorphism in FCGR3A at amino acid position 48 within the extracellular domain has been linked to the FCGR3A-158. Further study will be needed to reach definite conclusion on the role of this polymorphism in rituximab therapy.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook

Post a comment