TNFRSF1B in genetic predisposition to clinical neuropathy and effect on HDL cholesterol and glycosylated hemoglobin in type 2 diabetes

OBJECTIVE - Genetic variation in the tumor necrosis factor (TNF) receptor 2 gene (TNFRSF1B) has shown association with insulin resistance in type 2 di abetes, hypercholesterolemia, coronary artery disease, and essential hypert ension. Here we tested the TNFSF1B marker used in the latter studies in typ e 2 diabetes patients. RESEARCH DESIGN AND METHODS - A case-control study of a microsatellite mark er with five alleles (CA1.3- CA17) in intron 4 of TNFRSF1B was performed in 357 well-characterized white patients and 183 healthy control subjects. RESULTS - The CA16 allele was associated with clinical neuropathy (frequenc y = 27% in 69 patients with the condition versus 16% in 230 subjects withou t the condition: chi (2) = 9.0. P = 0.011; odds ratio = 2.1 [95% CI 1.2-3.8 ]). No association was seen with other complications or diabetes itself. Th e CA16 allele tracked with elevation plasma HDL cholesterol (1.3 +/- 0.2, 1 .2 +/- 0.4. and 1.1 +/- 0.2 for CA16/CA16, Ca16/-, and -/-, respectively; n = 9, 110, and 218, respectively; P = 0.009) and reduction in plasma glycos ylated hemoglobin (6.6 +/- 0.3. 8.3 +/- 0.2, and 8.1 +/- 0.1 for CA16/CA16, CA16/-, and -/-, respectively; n = 9, 102, 205, respectively; P = 0.007). Significance remained after Bonferront correction for multiple testing. CONCLUSION - Genetic variation in or near TNFRSF1B may predispose clinical neuropathy, reduced glycosylated hemoglobin, and increased HDL cholesterol in type 2 diabetes patients. The latter could be part of a protective respo nse.