Letter by Schroecksnadel et al Regarding Article, “β2-Microglobulin as a Biomarker in Peripheral Arterial Disease: Proteomic Profiling and Clinical Studies”
To the Editor:
We read with great interest the article by Wilson and coworkers,1 in which levels of β2-microglobulin (B2M) were demonstrated to correlate closely with the severity of peripheral arterial disease (PAD). Interestingly, the corresponding editorial2 mentioned several factors that could potentially limit the routine administration of B2M to measure peripheral artery disease (PAD) in patients and also stated that no one would have chosen B2M as a candidate marker before this proteomic approach. We think the opposite is the case; many researchers have tested the potential use of B2M as a marker, but because B2M is strongly influenced by renal function, it was disregarded as an independent marker.3 In fact, monitoring of blood B2M concentrations has been approved for the detection of early renal dysfunction, and one can assume that a significant part of the marker quality may be lost when B2M levels are corrected for renal function.
Furthermore, as mentioned also in the editorial,2 B2M is linked to immune activation and inflammation. Therefore, the diagnostic potential of B2M greatly overlaps with that of other macrophage activation markers, such as neopterin. It has been established that inflammation and macrophage activation are involved in the pathogenesis of atherogenesis, and earlier data showing a positive association between neopterin concentrations and the extent of carotid atherosclerosis4 strongly support this thesis.
In vitro B2M production by cells and cell lines is greatly enhanced on stimulation with Th1-type cytokine interferon-γ,5 which is also the primary inducer of neopterin release by human monocyte-derived macrophages. Significant associations between neopterin and B2M concentrations have been described in HIV-infected patients, as well as in other patients.5,6 Thus, one would expect that B2M and neopterin might also be strongly correlated in patients at risk for PAD. In fact, higher neopterin concentrations have been described in patients with PAD several years ago.
Another important point that should be kept in mind is the fact that the proteomics approach used for identifying B2M in the study by Wilson et al1 ignores all nonprotein markers, including the well-recognized cardiovascular risk markers homocysteine and neopterin.
Thus, we have the impression that some of the conclusions drawn in the 2 articles1,2 are by far too optimistic. The proteomic profiling approach may represent a good alternative, but it is certainly not the ultimate strategy for defining risk markers.
Dr Weiss has received research grants from the European Union and other research support from the AMGEN research project. The other authors report no conflicts.
Wilson AM, Kimura E, Harada RK, Nair N, Narasimhan B, Meng X-Y, Zhang F, Beck KR, Olin JW, Fung ET, Cooke JP. β2-microglobulin as a biomarker in peripheral arterial disease: proteomic profiling and clinical studies. Circulation. 2007; 116: 1396–1403.
Annex BH. Is a simple biomarker for peripheral arterial disease on the horizon? Circulation. 2007; 116: 1346–1348.
Fuchs D, Hausen A, Reibnegger G, Werner ER, Felmayer GW, Wachter H. Beta 2-microglobulin and immune activation. Clin Chem. 1989; 35: 2158–2159.