FcyRIIaArg His131 Polymorphism

The Arg/His amino acid variation at position 131 of FcyRIIa affects the ability of murine monoclonal IgGl as well as human IgG2 to activate platelets (Horsewood et al., 1991; Tomiyama et al., 1992; Parren et al., 1992; Bachelot et al., 1995). These observations prompted Burgess et al. (1995) to suggest that FcyRIIa variants could be a risk factor for developing HIT. In a small cohort of patients, they found an overrepresentation of the FcyRIIa-His131 variant. They hypothesized that IgG2 might be an important IgG subclass among HIT-IgG, as this could explain an apparent association between HIT and the FcyRIIa-His131 variant. However, subsequent reports argued against this hypothesis: IgGl rather than IgG2 was the predominant subclass among HIT-IgG (Arepally et al., 1997; Denomme et al., 1997; Suh et al., 1997). Nevertheless, in support of a biological basis for a possible increased frequency of FcyRIIa-His131, two groups found that HIT antibodies, including those that were predominantly IgGl, preferentially activated washed platelets of the His131 variant in vitro (Denomme et al., 1997; Bachelot-Loza et al., 1998). However, Brandt et al. (1995) found the opposite activation profile in platelet aggregation studies using citrated PRP (i.e., the FcyRIIa-Arg variant was preferentially activated by HIT plasma). No consensus has emerged from the six studies that investigated the frequency of FcyRIIa-Arg/His131 variants for patients with HIT: three studies show an overrepresentation of FcyRIIa-His131 (Burgess et al., 1995; Brandt et al., 1995; Denomme et al., 1997); two studies found no correlation with either variant (Arepally et al., 1997; Bachelot-Loza et al., 1998); and one study (the largest) showed the reverse correlation (Carlsson et al., 1998).

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