Linkage and association of tumor necrosis factor receptor 2 locus with hypertension, hypercholesterolemia and plasma shed receptor

• Published in: Human molecular genetics 2000-08, Vol.9 (13), p.1943-1949
• Main Authors: GLENN, C. L, WANG, W. Y. S, BENJAFIELD, A. V, MORRIS, B. J
• Format: Article
• Language: English
• Subjects: Antigens, CD - genetics; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Proteins - genetics; Blood Proteins - metabolism; Cardiology. Vascular system; Cholesterol - genetics; Cholesterol - metabolism; Classical genetics, quantitative genetics, hybrids; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Errors of metabolism; European Continental Ancestry Group - genetics; Female; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Genotype; Haplotypes; Human; Humans; Hypercholesterolemia - genetics; Hypertension - genetics; Linkage Disequilibrium; Lipids (lysosomal enzyme disorders, storage diseases); Lod Score; Male; Medical sciences; Metabolic diseases; Middle Aged; Nuclear Family; Polymerase Chain Reaction; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor, Type II; shed soluble receptor; Solubility; TNFRSF1B gene
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/9.13.1943

Tumor necrosis factor (TNF) receptor 2 (TNF-R2) has been implicated in insulin resistance and metabolic syndrome disorders, one of which is hypertension (HT). We therefore decided to test markers in and near the TNF-R2 gene (TNFRSF1B) for linkage and association with HT, as well as hypercholesterolemia, and plasma levels of the shed soluble receptor (sTNF-R2). The linkage study, which involved 200 HT Anglo-Celtic Caucasian sibpairs, indicated a sharp, significant linkage peak centered at TNFRSF1B (multipoint maximum LOD score = 2. 6 and 3.1 by weighted and unweighted MAPMAKER/SIBS, respectively; two-point LOD scores = 2.9 and 3.9 by weighted and unweighted SPLINK, respectively; P = 10(-4) by identical-by-state chi(2)). The case-control study in 134 unrelated HTs who were the offspring of two HT parents and 197 normotensives (NTs) whose parents were both NTs, indicated possible association of TNFRSF1B with HT by haplotype analysis (P = 0.008). Plasma sTNF-R2 was elevated in HTs (P < 0. 0001) and showed a correlation with systolic and diastolic blood pressure (BP) (P < 0.0002). A genotypic effect of TNFRSF1B on plasma sTNF-R2, as well as total, low and high density lipoprotein cholesterol, and diastolic BP was observed. These observations are consistent with a scheme leading to raised BP and hypercholesterolemia. In conclusion, TNFRSF1B may be a candidate gene for HT and other metabolic syndrome abnormalities.