Overview of Susceptibility

Beryllium sensitization (BeS) is found in a wide range of exposed workers (1%–16%) in beryllium-related industry (Saltini et al. 2001). Individual susceptibility to sensitization and exposure circumstances are both important in developing chronic beryllium disease (CBD) (Kreiss et al. 1993). In CBD, a susceptible person develops a cell-mediated, delayed hypersensitivity reaction after beryllium exposure (Tinkle et al. 1999). This hypersensitivity leads to a spectrum of immune abnormalities and the eventual pathological changes of CBD (Dotti et al. 2004).

The Genetics of Beryllium Sensitization and Disease

Specific genes have been identified as candidates that convey increased risk of BeS and/or CBD in persons exposed to beryllium (Richeldi et al. 1993; Richeldi et al. 1997; Wang et al. 1999; Wang et al. 2001; Saltini et al. 2001; Rossman et al. 2002; Maier et al. 2003; McCanlies et al. 2004; McCanlies et al. 2003; Weston et al. 2005; McCanlies et al. 2007; Dotti et al. 2004; Sato et al. 2007). The strongest association has been found with a human leukocyte antigen gene (HLA-DPβ1), but this is complicated because this gene has more than 120 variants. The easiest concept is that variants coding for a glutamate (glutamic acid, also known as a supratypic marker) in the 69th position (Glu69) are at high risk, between 2 and 20 fold (McCanlies et al. 2003; Weston et al. 2005). However, the exact genetic risk level is not known because too few cases have been studied and other factors, exposure levels (gene environment interactions) and genes not yet studied in CBD (e.g., cytokines), may be involved. Thus, further efforts are needed to explore these factors (Richeldi et al. 1997; Weston et al. 2005). Current wisdom is that HLA-DPβ1 variants that are Glu69 positive each present a different degree of risk for BeS and CBD in persons exposed to beryllium.

In the case of the Tumor Necrosis Factor-alpha gene (TNF-α) a number of studies have been performed, but no clear result has emerged. TNF-α is a pro-inflammatory cytokine that when stimulated, results in inflammation. It has been implicated in arthritis and other immunological dysfunctional conditions. Since CBD has an inflammatory component, TNF-α is a logical candidate CBD susceptibility gene. Again, based on current knowledge a more rigorous study design needs to be developed and implemented before this gene can be implicated in or eliminated from the list of genetic risk factors for BeS and CBD in persons exposed to beryllium (Saltini et al. 2001; McCanlies et al. 2007; Dotti et al. 2004; Sato et al. 2007).

Progress Check