Tumor necrosis factor receptor 2 gene (TNFRSF1B) in genetic basis of coronary artery disease

Tumor necrosis factor (TNF)-alpha has been implicated in pathophysiological processes in coronary artery disease (CAD). TNF receptor 2 is of particular interest in mediating such effects. The gene for this receptor (TNF-RSFIB) has, moreover, been implicated in hypertension, elevated cholesterol and insulin resistance. TNFRSFIB is thus a worthy candidate in studies of the genetic basis of CAD. We therefore conducted a case-control study of a microsatellite marker with five alleles (CA13-CA17) in intron 4 of TNFRSFIB in 1006 well-characterized white patients with angiographically confirmed CAD and a control group of 183 healthy subjects. We found a strong association of the TNFRSFIB marker with CAD (chi (2)=40, P=0.00000069). The frequency of the CA16 allele was 33% in CAD vs. 21% in control (odds ratio, OR, to have CAD for presence vs, absence of CA16 allele in CA16 homozygotes was 4.5, 95% CI 2.1-9.4, P <0.0001; in CA16 heterozygotes OR was 1.3, 95% CI 0.94-1.89, P=0.10). The frequency of the major allele (CA15) was 43% in CAD vs, 56% in controls (in CA15 homozygotes OR 0.33, 95% CI 0.20-0.52, P <0.0001; in heterozygotes OR 0.41, 95% CI 0.26-0.63, P <0.0001). In a stepwise logistic regression model the CA16 allele was significantly associated with overweight (OR 1.44, 95% CI 1.0-1.9, P=0.027). Apolipoprotein A-I was elevated (P <0.0001), as was high-density lipoprotein (P=0.098), and severity of angina was decreased (P=0.024) as a function of genotype. Plasma soluble (s) TNF-R2 was 5.1 +/-0.1 ng/ml in CAD vs. 3.2 +/-0.1 in control (P<0.0001), 5.2<plus/minus>0.1 in the presence vs. 4.6 +/-0.2 in the absence of vessel disease (P=0.009), and rose with increasing severity of angina: 4.2 +/-0.2 (no angina), 5.0 +/-0.1 (stable angina), 5.4 +/-0.2 (unstable angina; P=0.003), sTNF-R2 was correlated with age, cholesterol, creatinine, fibrinogen, transforming growth factor P and homocysteine and was influenced by TNFRSFIB genotype. Thus genetic variation in or near the TNFRSFIB locus may predispose to CAD.