Inflammatory Gene Load Is Associated With Enhanced Inflammation and Early Carotid Atherosclerosis in Smokers

Abstract

Background and Purpose— Smoking acts as a pro-inflammatory stimulus. Inflammation may provide a key mechanism by which smoking causes atherosclerosis. If so, then the degree to which an individual mounts an inflammatory response is likely to influence atherosclerosis severity. This study examined the impact of inflammatory gene polymorphisms and gene–smoking interactions on common carotid artery intima-media thickness (IMT), a measure of early atherosclerosis. Methods— In a community population (n=1000), mean IMT was determined using ultrasound. This population was genotyped for 6 polymorphisms in 4 inflammatory genes: IL-6-174 , IL-6-572 , and IL-6-597 ; IL-1-β-31 ; IL-1 receptor antagonist VNTR and CD14-159. Serum IL-6 levels were measured in the first 500 subjects. Genotypes/haplotypes associated with higher IL-6 levels were designated “inflammatory haplotypes.” A gene load score was calculated, in which 2 represented individuals homozygous for ≥2 inflammatory genotypes/haplotypes and 0 was homozygous for none. Results— Increasing gene load of inflammatory genotypes was associated with a linear increase in serum IL-6 levels ( P =0.018) and increased carotid artery IMT ( P =0.003). There was a significant interaction between gene load and smoking status on carotid IMT ( P for interaction=0.002). Specifically, in smokers, carriers of inflammatory haplotypes had significantly increased age- and sex-adjusted IMT ( IL-6-174C/IL-6-572G/IL-6-597A , P =0.005; IL-1-β-31T/IL-1RN*2 , P =0.04; CD14-159CC , P =0.028). Conclusions— These findings support the hypothesis that inflammation and cytokine responses provide a key mechanism by which smoking causes atherogenesis. Secondly, they highlight the importance of gene–environment, and gene–gene–environment interactions in the pathogenesis of atherosclerosis.

Association of IL-6 and a Functional Polymorphism in the IL-6 Gene with Cardiovascular Events in Patients with CKD

“…Because transmission of genes is a random phenomenon, gene polymorphisms modulating IL-6 synthesis may represent an unbiased means for testing whether the link between IL-6 and CV outcomes in patients with CKD is causal (Mendelian randomization). The 2174 G/C single-nucleotide polymorphism is a functional variant located in the promoter region of the IL-6 gene that regulates the rate of IL-6 gene transcription (22)(23)(24)(25)(26)(27)(28) and therefore represents a reliable research tool for testing the nature (causal versus noncausal) of the link between IL-6 and CV outcomes in CKD. With this background in mind, we set out to confirm findings by Barreto et al (21) in a large observational study with a carefully characterized cohort of 755 patients with stages 2-5 CKD and to test whether this relationship may underlie a causal link by applying the Mendelian randomization approach (i.e., by stratifying the study population according to the functional 2174 G/C polymorphism in the IL-6 gene).…”

Additive Effect of ANRIL and BRAP Polymorphisms on Ankle-Brachial Index in a Taiwanese Population

“…23 Evidence shows that genes involved in the inflammatory pathway might have a synergistic effect on disease susceptibility. 24 Therefore, the present study tested the individual effect of BRAP and ANRIL on the ABI value, as well as the combined effects of these 2 genes. To test the effect of these 2 genes, we included our previous BRAP data and genotyped an additional 210 samples in the analyses.…”

Markers of Carotid Atherosclerosis in Patients with Type 2 Diabetes Mellitus

“…A genetic variability of the candidate genes implicated in atherosclerosis (i.e. candidate genes of inflammation, oxidative stress, growth factors, renin-angiotensin aldosterone system, and so-forth) has so far been demonstrated in several reports to affect the development of atherosclerosis [2]. Genetic variability in the candidate genes implicated in atherosclerosis may alter their transcriptional activity and contribute to susceptibility to cardiovascular disease [3][4][5][6][7][8][9][10][11].…”