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TNFRSF1B in Genetic Predisposition to Clinical Neuropathy and Effect on HDL Cholesterol and Glycosylated Hemoglobin in Type 2 Diabetes

¹ Basic Clinical Genomics Laboratory, Department of Physiology and Institute for Biomedical Research, the University of Sydney, Sydney, Australia
² Cardiovascular Genetics Laboratory and the
³ Department of Endocrinology, Prince of Wales Hospital, Sydney, Australia
⁴ Centre for Thrombosis and Vascular Research, University of New South Wales, Sydney, Australia
⁵ Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas

OBJECTIVE—Genetic variation in the tumor necrosis factor (TNF) receptor 2 gene (TNFRSF1B) has shown association with insulin resistance in type 2 diabetes, hypercholesterolemia, coronary artery disease, and essential hypertension. Here we tested the TNFRSF1B marker used in the latter studies in type 2 diabetes patients.

RESEARCH DESIGN AND METHODS—A case-control study of a microsatellite marker with five alleles (CA13– 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 (frequency = 27% in 69 patients with the condition versus 16% in 230 subjects without the condition; 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. The 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 glycosylated 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 Bonferroni correction for multiple testing.

CONCLUSIONS—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 response.

Abbreviations: ANOVA, analysis of variance • apoA-I, apolipoprotein A-I • OR, odds ratio • sTNF-R2, soluble tumor necrosis factor receptor 2 • TNF, tumor necrosis factor • TNF-R2, tumor necrosis factor receptor 2 • UTR, untranslated region

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