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

Tumor necrosis factor (TNF) receptor 2 (TNF-R2) has been implicated in insu lin resistance and metabolic syndrome disorders, one of which is hypertensi on (HT). We therefore decided to test markers in and near the TNF-R2 gene ( TNFRSF1B) for linkage and association with HT, as well as hypercholesterole mia, and plasma levels of the shed soluble receptor (sTNF-R2), The linkage study, which involved 200 HT Anglo-Celtic Caucasian sibpairs, indicated a s harp, 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, res pectively; 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 norm otensives (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 dia stolic blood pressure (BP) (P < 0.0002). A genotypic effect of TNFRSF1B on plasma sTNF-R2, as well as total, low and high density lipoprotein choleste rol, and diastolic BP was observed, These observations are consistent with a scheme leading to raised BP and hypercholesterolemia. In conclusion, TNFR SF1B may be a candidate gene for HT and other metabolic syndrome abnormalit ies.