Abstract-Interleukin-6 (IL-6) synthesized in response to diverse stimuli may play an important role in bridging the inflammatory and atherosclerotic processes. The acute-phase response after coronary artery bypass graft surgery (CABG) is associated with the induction and release of cytokines, such as IL-6. We have examined the effect of common polymorphisms in the IL-6 gene promoter (Ϫ174GϾC, Ϫ572GϾC, and Ϫ597GϾA) on IL-6 levels after elective CABG. DNA extracted from the peripheral blood of 127 patients was amplified by polymerase chain reaction. IL-6 genotypes were resolved by gel electrophoresis after restriction enzyme digestion. Serum IL-6 was measured before surgery and in serial samples at 6, 24, 48, and 72 hours after CABG. Genotype distribution was as expected for a population in Hardy-Weinberg equilibrium for all polymorphisms. Rare allele frequencies (Ϯ95% CIs) were similar to those reported previously: Ϫ597A 0.36 (0.30 to 0.42), Ϫ572C 0.07 (0.04 to 0.10), and Ϫ174C 0.37 (0.31 to 0.43). The Ϫ174GϾC and Ϫ597GϾA genotypes were in strong allelic association (⌬ϭ0.97, PϽ0.001). Baseline IL-6 levels did not significantly differ between patients with different genotypes for any polymorphism. However, 6 hours after CABG, peak IL-6 levels were significantly higher (Pϭ0.03) in carriers of the Ϫ572C allele than in those of the Ϫ572GG genotype (355Ϯ67 versus 216Ϯ13 pg/mL, respectively) and in those with genotype Ϫ174CC compared with Ϫ174G allele carriers (287Ϯ31 versus 227Ϯ15 pg/mL, respectively; Pϭ0.04). These effects remained statistically significant after adjusting for possible confounders, including age, sex, smoking, duration of cardiopulmonary bypass, aortic cross-clamp time, and total duration of surgery. These data demonstrate that IL-6 promoter polymorphisms influence peak IL-6 production after CABG, suggesting that these polymorphisms, which are functional in vitro, are also functional in vivo, suggesting a genetic influence on IL-6 levels after acute severe injury. (Arterioscler Thromb Vasc

This study provides the first in vivo evidence of a role for UCP2 in modifying oxidative stress and CHD risk in humans.

Accumulating evidence suggests that athletic performance is strongly influenced by genetic variation. One such locus of influence is the gene for angiotensin-I converting enzyme (ACE), which exhibits a common variant [ACE insertion (I)/deletion (D)]. ACE can drive formation of vasoconstrictor ANG II but preferentially degrades vasodilator bradykinin. The ACE I allele is associated with higher kinin activity. A common gene variant in the kinin beta(2) receptor (B(2)R) exists: the -9 as opposed to +9 allele is associated with higher receptor mRNA expression. We tested whether this variant was associated with the efficiency of muscular contraction [delta efficiency (DE)] in 115 healthy men and women, or with running distance among 81 Olympic standard track athletes. We further sought evidence of biological interaction with ACE I/D genotype. DE was highly significantly associated with B(2)R genotype (23.84 +/- 2.41 vs. 24.25 +/- 2.81 vs. 26.05 +/- 2.26% for those of +9/+9 vs. +9/-9 vs. -9/-9 genotype; n = 25, 61, and 29, respectively; P = 0.0008 for ANOVA adjusted for sex). There was evidence for interaction with ACE I/D genotype, with individuals who were ACE II, with B(2)R -9/-9 having the highest DE at baseline. The ACE I/B(2)R -9 "high kinin receptor activity" haplotype was significantly associated with endurance (predominantly aerobic) event among elite athletes (P = 0.003). These data suggest that common genetic variation in the B(2)R is associated with efficiency of skeletal muscle contraction and with distance event of elite track athletes and that at least part of the associations of ACE and fitness phenotypes is through elevation of kinin activity.

Human physical performance is influenced by genetic factors. A variation in the human angiotensin I-converting enzyme (ACE) gene has been identified, in which the insertion (I) variant may be associated with elite endurance performance, and the deletion (D) variant seems overrepresented amongst elite sprinters and short-distance swimmer status. We might thus anticipate I-allele frequency to be elevated amongst swimmers competing over very much greater distances, and have examined this hypothesis. Thirty-five truly elite very-long-distance swimmers were classified as better at 1- to 10-km distances (n=19, SLD group) or those best at 25-km races (n=16, LLD group). Genotype frequencies (II versus ID versus DD) differed between the two groups: 6% versus 47% versus 47% for SLD, and 18.8% versus 75% versus 6.2% for LLD (P=0.01). I-allele frequency was 0.29 for the shorter distance swimmers, and 0.59 for the 25 km group. These data are consistent with an association of ACE I allele with longer distance swimming, and the ACE D allele with swimming shorter distances.

Variation in the IL-6 gene seems to influence the defense against bacterial pathogens in the very preterm infant.

Abstract-Renin-angiotensin systems may mediate cardiovascular disease pathogenesis through a balance of actions of angiotensin II on (potentially proatherogenic) constitutive type 1 (AT 1 R) and (potentially antiatherogenic) inducible type 2 (AT 2 R) receptors. We explored such potential roles in a prospective candidate gene association study. Cardiovascular end points (fatal, nonfatal, and silent myocardial infarction and coronary artery bypass surgery/angioplasty) were documented among 2579 healthy UK men (mean age, 56.1Ϯ3.5 years; median follow-up, 10.1 years) genotyped for the AT 1 R1166AϾC and the X chromosome located AT 2 R1675AϾG and 3123CϾA polymorphisms. Baseline characteristics, including blood pressure, were independent of genotype. The AT 1 R1166CC genotype was associated with relative cardiovascular risk (hazard ratio, 1.65 [1.05 to 2.59]; Pϭ0.03) independent of blood pressure. Systolic blood pressure was associated with risk (Pϭ0.0005), but this association was restricted to AT 2 R1675A allele carriers (PϽ0.00001), with G allele carriers protected from the risk associated with blood pressure (Pϭ0.18). Hypertensive carriers with the AT 2 R1675A/3123A haplotype were at most risk, with 37.5% having an event. This is the first study to demonstrate an association of AT 2 R genotype with coronary risk, an effect that was confined to hypertensive subjects and supports the concept that the inducible AT 2 R is protective. Conversely, the AT 1 R1166CC genotype was associated with cardiovascular risk irrespective of blood pressure. These data are important to our understanding of the divergent role of angiotensin II acting at its receptor subtypes and coronary disease pathogenesis and for the development of future cardiovascular therapies. Coronary vascular ACE drives Ang II synthesis, whose action on local AT 1 and inducible AT 2 receptors (AT 2 R) 2,3 may contribute to coronary heart disease (CHD) pathogenesis: AT 1 R activation causes vascular smooth muscle cell hypertrophy, extracellular matrix production, and local inflammation, driving atherogenesis and plaque rupture, 4 whereas AT 2 R agonism inhibits vascular cell proliferation 5 and may be antiatherogenic. 6 The balance between AT 1 R and AT 2 R activation may therefore influence CHD risk. However, this remains difficult to explore, and supportive data are sparse. Studies involving selective AT 1 R antagonism are perhaps less informative than they might at first appear: although lowering CHD risk more than equihypotensive ␤-blockade, 7 this may be partly mediated through AT 2 R agonism-loss of negative feedback raising Ang II levels and hence binding to the vacant AT 2 R. 8Could there be a role for both the AT 1 R and AT 2 R in the development of CHD? Genetic studies may provide insight. A polymorphism of the AT 1 R gene exists at position 1166, where the C (rather than A) allele is associated with increased Ang II responsiveness. 9 Meanwhile, the A (rather than G) allele at position 1675 of the X-chromosomal AT 2 R gene is associated with a greater ...

No abstract

In a population of surviving children who were born at < or =32 weeks' gestational age, variation of the gene that may increase IL-6 synthesis is associated with disabling brain injury but not cognitive development despite association with worse early critical care indices.