IL-6 haplotypes, inflammation, and risk for cardiovascular disease in a multiethnic dialysis cohort.
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.
Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Yongmei
Y
Liu
Yvette
Y
Berthier-Schaad
Margaret D
MD
Fallin
Nancy E
NE
Fink
Russell P
RP
Tracy
Michael J
MJ
Klag
Michael W
MW
Smith
Josef
J
Coresh
D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000208:ethnology / Q000235:genetics*; D015331:Cohort Studies; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015994:Incidence; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D018836:Inflammation Mediators / Q000032:analysis; D015850:Interleukin-6 / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000208:ethnology / Q000235:genetics / Q000628:therapy; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D011446:Prospective Studies; D006435:Renal Dialysis / Q000009:adverse effects / Q000379:methods*; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D015996:Survival Rate
D018836:Inflammation Mediators; D015850:Interleukin-6