Fc gamma RIIA alleles are heritable risk factors for lupus nephritis in African Americans.

Abstract

Allelic variants of Fc ␥ R confer distinct phagocytic capacities providing a mechanism for heritable susceptibility to immune complex disease. Human Fc ␥ RIIa has two codominantly expressed alleles, R131 and H131, which differ substantially in their ability to ligate human IgG2. The Fc ␥ RIIa-H131 is the only human Fc ␥ R which recognizes IgG2 efficiently and optimal IgG2 handling occurs only in the homozygous state. Therefore, since immune complex clearance is essential in SLE, we hypothesized that Fc ␥ RIIA genes are important disease susceptibility factors for SLE, particularly lupus nephritis. In a two-stage cross-sectional study, we compared the distribution of Fc ␥ RIIA alleles in African Americans with SLE to that in African American non-SLE controls. A pilot study of 43 SLE patients and 39 controls demonstrated a skewed distribution of Fc ␥ RIIA alleles, with only 9% of SLE patients homozygous for Fc ␥ RIIa-H131 compared with 36% of controls (odds ratio, 0.18; 95% CI, 0.05-0.69, P ϭ 0.009). This was confirmed with a multicenter study of 214 SLE patients and 100 non-SLE controls. The altered distribution of Fc ␥ RIIA alleles was most striking in lupus nephritis. Trend analysis of the genotype distribution showed a highly significant decrease in Fc ␥ RIIA-H131 as the likelihood for lupus nephritis increased ( P ϭ 0.0004) consistent with a protective effect of the Fc ␥ RIIA-H131 gene. The skewing in the distribution of Fc ␥ RIIA alleles identifies this gene as a risk factor with pathophysiologic importance for the SLE diathesis in African Americans. ( J.

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

“…The etiology of SLE has a definite genetic component as inferred from increased familial aggregation among siblings and an increased concordance rate among monozygotic twins compared to dizygotic twins. [1][2][3] This is further supported by the identification of genetic associations of candidate gene polymorphisms 4,5 as well as the establishment of linkage to loci in genome-wide scans in SLE. [6][7][8][9][10][11][12] In man, SLE is not often a single gene disorder; the genetic effect generally appears to be conferred by polymorphisms in multiple genes.…”

Fcγriia polymorphism as a risk factor for invasive pneumococcal infections in systemic lupus erythematosus

“…FcyRIIA genotyping was performed by polymerase chain reaction amplification of genomic DNA from peripheral blood leukocytes, using allele-specific primers as previously described (10). Four of the 5 patients were determined to be homozygous for the R131 allele, while the fifth (patient 5) was an R131/H131 heterozygote.…”

“…The increased gene frequency of FcyRIIA-R131 in SLE (and particularly in lupus nephritis, in which the allelic frequency is up to 65%) defines these patients as a population with an inherently increased predilection for invasive pneumococcal infections (10). This independent risk may act synergistically with other concomitant conditions, such as splenic dysfunction, hypocomplementemia, and immunosuppression, to potentiate propensity for infections by encapsulated organisms like Spneumoniae.…”

FcγR expression on NK cells influences disease severity in rheumatoid arthritis

“…8 We have recently found that FcgRIIc is predominantly expressed on NK cells and that it is able to trigger NK cell lysis of antibody-coated target cells and cytokine production. [9][10][11] Allelic polymorphisms of FcgR genes have been described 9,[12][13][14][15] that affect the function of cells of the innate immune system including FcgRIIIA, 14,16 FcgRIIA, 17 FcgRIIC, 7,18 and FcgRIA. 19 In general, these polymorphisms have been shown to alter the ligand binding specificity of particular FcgR, such as FcgRIIa, 17 and FcgRIIIa.…”

“…19 In general, these polymorphisms have been shown to alter the ligand binding specificity of particular FcgR, such as FcgRIIa, 17 and FcgRIIIa. 14,16 These allelic polymorphisms have proved to be clinically significant in infectious 20,21 and autoimmune 12,13,[22][23][24] diseases.…”