Background: Proteomics is expected to provide novel insights in the underlying pathophysiology of type 2 diabetes mellitus. In the present study, we aimed to identify and biochemically characterize proteins associated with diabetes mellitus in a Qatari population.
Methods: In a diabetes case-control study (175 cases, 164 controls; Arab, South Asian and Philippine ethnicities), we conducted a discovery study to screen 1141 blood protein levels for associations with diabetes mellitus. Additional analyses were done in controls in relation to Hb1Ac, and biochemical characterization of the main findings was performed with metabolomics (501 metabolites). We performed two-sample Mendelian Randomization to provide evidence of potential causality using data from European descent of the DIAGRAM consortium (74,124 cases of diabetes mellitus and 824,006 controls) for the identified proteins for T2D and Hb1Ac.
Results: After accounting for multiple testing, 30 protein levels were different (p-values<8.6e-5) between cases and controls. Of these, a higher Hb1Ac in controls was associated with a lower IGFBP-2 level (p-value = 4.1e-6). IGFBP-2 protein level was found lower among cases compared with controls across all ethnicities. In controls, IGFBP-2 was associated with 21 metabolite levels, but specifically connected to the metabolite citrulline in network analyses. We observed no evidence, however, that the association between IGFBP-2 and diabetes mellitus was causal.
Conclusions: We specifically identified IGFBP-2 to be associated with diabetes mellitus, although with no evidence for causality, which was specifically connected to citrulline metabolism.
Keywords: Case-control study; Diabetes mellitus; Mendelian randomization; Metabolomics; Proteomics.
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