Intima media thickness of carotid arteries is reduced in heterozygous carriers of the Gly972Arg variant in the insulin receptor substrate-1 gene.
BACKGROUND
The Gly972Arg mutation in the IRS-1 gene has been found to be associated with insulin resistance and type II diabetes. A recently published study described an association between the Arg allele and an increased risk for coronary artery disease. In the present study we asked whether the presence of the codon 972 mutation in the IRS-1 gene is associated with higher IMT values of the carotid arteries.


METHODS
To address this question, genotypes of the codon 972 polymorphism were determined in 1018 healthy unrelated individuals aged 40-65 years. Three homozygous carriers of the mutation were excluded for statistical analysis. In all subjects, intima media thickness (IMT) and B-scores of carotid arteries as well as a large number of metabolic parameters were determined.


RESULTS
Heterozygous carriers of the Arg972 allele exhibited significantly lower IMT and B-score values than noncarriers. Total cholesterol, LDL-cholesterol and serum levels of apolipoprotein B were significantly lower in the carriers. Furthermore, a significant interaction between Gly972Arg-carrier status and mean daytime 24-h systolic blood pressure with regard to IMT could be observed; carriers with a systolic blood pressure above the median had lower IMT values than carriers with a systolic blood pressure equal or below the median. All these effects were more pronounced in females and remained significant after adjustment for sex, age, BMI, systolic blood pressure and serum apolipoprotein B levels. No significant differences between the carriers and the noncarriers could be found for BMI, insulin sensitivity or frequency of type II diabetes.


CONCLUSIONS
The results of our study demonstrate that the presence of the Arg972 allele is associated with lower IMT values of the carotid arteries. This finding is partly explained by lower serum levels of apolipoprotein B in carriers. The protective effect of the Gly972 Arg mutation seems to be stronger in the presence of a higher systolic blood pressure. Our data contradict previous findings suggesting an increased risk for insulin resistance, type II diabetes and atherosclerotic vascular disease in carriers of the mutation.
Hölzl
B
B
1st Department Int. Medical, St. Johanns Spital, Salzburg, Austria. b.hoelzl@lks.at
Iglseder
B
B
Stadlmayr
A
A
Hedegger
M
M
Moré
E
E
Reiter
R
R
Sandhofer
F
F
Paulweber
B
B
D000328:Adult; D000368:Aged; D001055:Apolipoproteins B / Q000097:blood; D001794:Blood Pressure / Q000235:genetics; D015992:Body Mass Index; D002339:Carotid Arteries / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics*; D011446:Prospective Studies; D012307:Risk Factors; D017539:Tunica Intima / Q000473:pathology; D017540:Tunica Media / Q000473:pathology
D001055:Apolipoproteins B; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D008055:Lipids; D010750:Phosphoproteins