Coronary Artery Disease–Associated Locus on Chromosome 9p21 and Early Markers of Atherosclerosis

Background— Genome-wide association studies have recently identified a locus on chromosome 9p21 that influences risk of coronary artery disease (CAD). The effect of the locus on early markers of atherosclerosis is unknown. We examined its association with carotid intima-media thickness (CIMT) and brachial flow-mediated dilatation (FMD). Methods and Results— We genotyped 2277 individuals, age 24 to 39 years, from the Cardiovascular Risk in Young Finns Study with CIMT and FMD measurements and 1295 individuals, age 46 to 76 years, from the Health 2000 Survey with CIMT for rs1333049, the chromosome 9p21 variant showing the strongest association with CAD. Both mean and maximum CIMT were significantly higher (P<0.001) in the older subjects of the Health 2000 Survey compared with the Young Finns Study. However, there was no association of the rs1333049 genotype with either mean or maximum CIMT at either age (P=0.959 and 0.977 for the 2 phenotypes in the Young Finns Study and P=0.714 and 0.725 in the Health 2000 Survey). Similarly, there was no association of the locus with variation in FMD in the Young Finns cohort (P=0.521). Conclusions— The chromosome 9p21 locus does not influence CAD risk through a mechanism that also affects CIMT or induces early changes in FMD. We examined the association with carotid intima-media thickness and brachial flow mediated dilatation of the recently identified susceptibility locus for coronary artery disease on chromosome 9p21. We found no evidence that the risk variant affects either of these early markers of atherosclerosis, suggesting an alternate mechanism for its effect on risk of CAD

The association between sub-clinical atherosclerosis measured from the carotid artery and the genetic risk score formed from 24 risk variants previously associated with coronary artery disease.

<p>Adjustments: Model 1 – unadjusted; Model 2 – age, sex and Body Mass Index; Model 3a – age, sex, body mass index, apoliprotein A, apolipoprotein B, systolic blood pressure and waist circumference; Model 3b – age, sex, body mass index, blood glucose, waist circumference and diastolic blood pressure.</p><p>*Beta for a change of one standard deviation in the risk score.</p><p>**For an increase of one risk allele in the GRS_24SNP/CAD.</p><p>***The 6-year incidence of carotid atherosclerosis is defined as the occurrence of substantial CIMT (age-, sex- and BMI- adjusted CIMT- value over 90% percentile) or plaque in 2007 in subjects who did not have substantial CIMT or plaque in 2001.</p><p>Abbreviations: S.E., Standard Error; OR, Odds Ratio; CI, Confidence interval.</p

The association between carotid intima media thickness and genetic risk score (GRS) among two different study populations of the Bogalusa Heart Study.

<p>The GRS was calculated as a weighted sum of coronary artery disease risk alleles from 24 known variants.</p><p>Adjustments: Model 1 –unadjusted; Model 2 – age, sex and Body Mass Index; Model 3a (European ancestry) – age, sex, body mass index, total cholesterol, low density lipoprotein -cholesterol, triglycerides and systolic blood pressure; Model 3b (African ancestry) – age, sex, body mass index, and systolic blood pressure. Abbreviations: GRS, Genetic Risk Score, S.E., Standard Error.</p><p>*Change of CIMT in millimetres corresponding to a change of one standard deviation in the risk score.</p

General characteristics of the three study populations with available ultrasound and genotype data.

<p>All units are expressed as mean (SD) except for dichotomous variables.</p><p>Abbreviations: CIMT, Carotid artery Intima Media Thickness; CAE Carotid Artery Elasticity; HDL, High Density Lipoprotein; LDL, Low Density Lipoprotein; BP, Blood Pressure; BMI, body mass index.</p