Tumour necrosis factor receptors (TNFRs) in Type 2 diabetes. Analysis of soluble plasma fractions and genetic variations of TNFR2 gene in a case‐control study

Abstract

We have studied the relationships between soluble fractions of tumour necrosis factor receptors (sTNFR1 and sTNFR2) in Type 2 diabetes (DM2) and its chronic microvascular complications. Likewise, we have analysed the genetic susceptibility of 196T > G exon6/CA-repeat intron 4 mutations in the TNFR2 gene in this population. A case-control study was conducted to examine the role of sTNFRs in 345 DM2 patients and 173 healthy subjects. The mutations were studied in all healthy subjects and in a subset of 232 patients. sTNFRs levels were similar in healthy and DM2 patients. A positive correlation between age and both sTNFRs was observed in healthy subjects. In DM2 patients, sTNFR1 showed a positive correlation with age, systolic blood pressure and leptin levels (r = 0.53, P < 0.0001; r = 0.28, P = 0.005; r = 0.46, P < 0.0001, respectively) and sTNFR2 was positively correlated with age, triglycerides and leptin levels (r = 0.34, P < 0.0001; r = 0.21, P < 0.0001; r = 0.28, P = 0.002, respectively). Patients with micro- or macroalbuminuria showed higher plasma levels of sTNFR1 and sTNFR2 than normoalbuminuric patients, after adjusting for confounding variables (B = 0.85, P = 0.022, 95% CI: 0.12-1.58 for sTNFR1 and B = 1.50, P < 0.001, 95% CI: 0.67-2.33 for sTNFR2). In DM2 patients, TT-exon 6 homozygous showed lower levels of sTNFR1 [2,4 (1.1) vs. 3.4 (1.2) ng/ml], and the CA273-allele tracked with elevated plasma HDL-cholesterol [1.8 (0.7), 1.4 (0.3) and 1.3 (0.3) mm, for CA273/273, CA273/- and CA-/-, respectively]. No association was seen with other analysed variables. Our findings suggest that chronic TNF activation may have some pathogenic role in diabetic nephropathy in DM2 patients. Genetic variations in exon 6/intron 4 of the TNFR2 gene do not predispose to a major risk for DM2 or its microvascular complications.