Related Experiment Videos
IL-6 haplotypes, inflammation, and risk for cardiovascular disease in a multiethnic dialysis cohort
Yongmei Liu1, Yvette Berthier-Schaad, Margaret D Fallin
1Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Insights
Genetic variations in the Interleukin-6 (IL-6) gene influence inflammation and cardiovascular disease (CVD) risk in dialysis patients. This study suggests a causal role for IL-6 in CVD development.
Area of Science:
- Genetics
- Immunology
- Cardiovascular Medicine
Background:
- Interleukin-6 (IL-6) is a key inflammatory regulator, but its direct role in atherosclerosis is unclear.
- Genetic studies can circumvent reverse causality issues inherent in observational studies of inflammation and disease.
- Dialysis patients exhibit elevated IL-6 levels, making them a relevant cohort for studying IL-6's impact on cardiovascular disease (CVD).
Purpose of the Study:
- To investigate whether genetic variations in the IL6 gene predict cardiovascular disease (CVD) risk in incident dialysis patients.
- To explore the association between specific IL6 gene polymorphisms and circulating IL-6 levels, albumin levels, and CVD events.
Main Methods:
- Construction of a phylogenetic tree for the IL6 gene based on resequencing data.
- Genotyping of two clade tag polymorphisms (-174G/C, 1888G/T) and two missense variants (Pro32Ser, Asp162Val).
- Measurement of serum IL-6 and albumin, and ascertainment of CVD events over a median follow-up of 2.5 years in 775 patients.
Main Results:
- Coding variants Pro32Ser and Asp162Val were linked to lower IL-6 and higher albumin levels.
- The -174G/C promoter variant strongly correlated with increased CVD risk.
- Clade 3 (defined by -174C and absence of 162 Val) showed significantly higher IL-6 levels and CVD risk (HR 1.44).
Conclusions:
- Functional variants within the IL6 gene significantly impact inflammation and CVD risk.
- Findings support a causal role for IL-6 in the pathogenesis of CVD among patients undergoing dialysis.
Abstract:
It is unknown whether IL-6, a central regulator of inflammation, is a cause of or just a marker of atherosclerosis. Studies of genetic susceptibility to inflammation, however, avoid the potential for reverse causality. Variation in IL6 gene was studied as a predictor of cardiovascular disease (CVD) risk in a cohort of 775 incident dialysis patients, in whom IL-6 levels are elevated. On the basis of published resequencing data on the IL6 gene, a phylogenetic tree with three main branches (clades 1 to 3) was constructed. Two "clade tag" polymorphisms, -174G/C and 1888G/T, and two missense variants, Pro32Ser and Asp162Val, were genotyped. Circulating IL-6 and albumin were measured a median of 5 mo after the start of dialysis. CVD events were ascertained from medical records. During a median follow-up of 2.5 yr, 294 CVD events occurred. The two coding variants, Pro32Ser (present only in black patients, 10% Ser allele) and Asp162Val (present only in white patients, 1% Val), were associated with lower levels of IL-6 and higher levels of albumin. The common variant in the promoter region, -174G/C, was strongly associated with higher CVD risk and weakly with IL-6 levels. Clade 3 (-174C carriers in the absence of 162 Val allele) was associated with higher IL-6 levels (P=0.03) and higher CVD risk (hazard ratio 1.44, P=0.006) after adjustment for covariates. The IL6 gene has functional variants that affect inflammation and risk for CVD among dialysis patients, supporting a causal role for IL6 in CVD.