A non-conservative polymorphism in the IL-6 signal transducer (IL6ST)/gp130 is associated with myocardial infarction in a hypertensive population.
Inflammation is a key component in the development of atherosclerosis, and myocardial infarction (MI); therefore we investigated the association between an interleukin-6 signal transducer (IL6ST)/gp130 polymorphism, gp130 function and risk of MI. Structural modeling suggested that a non-conservative single nucleotide polymorphism in the gp130, Gly148Arg, can change the stability and functional properties of the molecule. In vitro studies were done with BAF/3 cells lacking endogenous gp130. Cells stably transfected with the gp130 148Arg variant proliferated less and showed slightly lower STAT-3 phosphorylation in response to gp130 stimulation as compared to cells transfected with gp130 148Gly. In a prospectively followed hypertensive cohort we identified 167 patients who suffered a MI during the study and compared them to matched controls (mean age 57 years, 73% males, n=482). Carriers of the 148Arg variant (f(Arg)=0.12) of the gp130 receptor had decreased odds ratio for MI in univariate analysis (0.56, 95% CI 0.34-0.91, p=0.02). In conclusion, a genetically determined structural variant of the IL-6 receptor subunit gp130 is, independently of other known risk factors, associated with decreased risk of MI. The variant is also associated with decreased IL-6 responsiveness and could lead to a configuration change in the gp130 receptor.
Benrick
Anna
A
Department of Neuroscience and Physiology, Göteborg University, Sweden.
Jirholt
Pernilla
P
Wernstedt
Ingrid
I
Gustafsson
Maria
M
Scheller
Juergen
J
Eriksson
Anna-Lena
AL
Borén
Jan
J
Hedner
Thomas
T
Ohlsson
Claes
C
Härd
Torleif
T
Rose-John
Stefan
S
Jansson
John-Olov
JO
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D015897:Comorbidity; D050822:Cytokine Receptor gp130 / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology / Q000235:genetics*; D011110:Polymorphism, Genetic
D015850:Interleukin-6; D050822:Cytokine Receptor gp130