Late-onset Coronary Artery Disease Research Articles

Improved prediction of early-onset coronary artery disease using APOE ε4, BChE-K, PPARγ2 Pro12 and ENOS T-786C in a polygenic model

Objectives: Coronary artery disease (CAD) is often polygenic due to multiple mutations that contribute small effects to susceptibility. Since most prior studies only evaluated the contribution of single candidate genes, we therefore looked at a combination of genes in predicting early-onset CAD [apolipoprotein E ( APOE) ε4, butyrylcholinesterase ( BChE) K, peroxisome proliferator-activated receptor γ2 (PPARγ2) Pro12Ala and endothelial nitric oxide synthase ( ENOS) T-786C]. Design and methods: We examined the frequencies, individually and in combination, of all four alleles among patients with early-onset CAD ( n = 150; <50 years), late-onset CAD ( n = 150; >65 years) and healthy controls ( n = 150, age range 47–93 years). Differences in the proportion of subjects in each group with the given gene combination were assessed and likelihood ratios (LR) were calculated using logistic regression to combine the results of multiple genes. Results: Early-onset CAD patients had increased, but non-significant, frequencies of PPARγ2 Pro12/Pro12 ( P = 0.39) and ENOS T-786C ( P = 0.72), while BChE-K was only significantly higher in early-onset CAD patients compared to controls ( P = 0.03). There were significantly more APOE ε4 alleles alone ( P = 0.02) or in combination with BChE-K ( P = 0.02) among early-onset CAD patients compared to late-onset CAD ones or controls. When combined, there was a higher prevalence of all four alleles in early-onset CAD (early-onset CAD patients: 10.7%, late-onset CAD patients: 3.3% and controls: 2.7%, P = 0.01). LR for early-onset CAD for a single allele was relatively small (1.08 for PPARγ2 to 1.70 for APOE ε4). This increased to 2.78 (1.44–5.37) when combining all four alleles, therefore increasing the pre-test probability of CAD from 5% to a post-test probability of 12.7%. Conclusions: While any single mutation causes only a mildly increased LR (none > 1.7), in combination, the likelihood of early-onset CAD increased to 2.78 with four mutations. The genetics of early-onset CAD appear to be multifactorial, requiring polygenic models to elucidate risk.

Relation between butyrylcholinesterase K variant, paraoxonase 1 (PON1) Q and R and apolipoprotein E ϵ4 genes in early-onset coronary artery disease

Objectives: The common K variant of butyrylcholinesterase (BChE-K), an enzyme which metabolizes acetylcholine and organophosphates, has been associated with Alzheimer’s disease, especially in the presence of the apolipoprotein E ϵ4 allele (APOE-ϵ4). Although APOE-ϵ4 has been associated with the development of coronary artery disease (CAD), an association between the BChE-K variant and CAD has not been explored. Paraoxonase 1 (PON1), located within HDL, is an enzyme which also metabolizes organophosphates and may be antiatherogenic. The R192 variant of PON1 (PON1-R) has been associated with CAD. Design and methods: To determine whether BChE-K is also associated with premature CAD, we examined the frequency of BChE-K among patients with early-onset CAD ( n = 150; < 50 yr) vs. late-onset CAD ( n = 150; > 65 yr) by molecular analysis. We also examined the frequency of the PON1-R allele in both groups, and explored whether there was synergism between BChE-K and APOE-ϵ4, BChE-K and PON1-R or PON1-R and APOE-ϵ4. Results: The frequency of the BChE-K allele tended to be greater among early-onset CAD patients compared to late-onset CAD patients (41.3% vs. 31.3%; p = 0.07), but without any significant difference between males and females. There was no difference in the prevalence of the PON1-R allele between those with early- or late-onset CAD (46.0% vs. 52.7%; p = 0.25). Twenty-two patients with early-onset CAD had both the BChE-K plus APOE-ϵ4 alleles (14.7%) compared to 11 late-onset CAD patients (7.3%) ( p = 0.04). There was no such association between BChE-K and PON1-R, nor PON1-R and APOE-ϵ4. Conclusions: Our study suggests that there is a minor association between BChE-K and early-onset CAD, especially in the presence of the APOE-ϵ4 allele.

Plasma homocysteine level and development of coronary artery disease.

The plasma level of homocysteine is an independent risk factor for atherosclerotic vascular disease. The relationship between plasma homocysteine level and the onset of coronary artery disease (CAD) has not been established. To investigate the relationship between plasma homocysteine level and the age at which CAD was diagnosed. Fifty-seven male patients aged < or = 65 years (mean age 53 years) with angiographically proven symptomatic CAD seen consecutively and 138 age-matched male control subjects (mean age 52 years) free from atherosclerotic vascular disease were studied. They were divided into two subgroups, a group of younger subjects (aged < or = 55 years) and a group of older subjects (aged 56-65 years). Plasma homocysteine levels in CAD patients significantly exceeded those of control subjects (means 13.4 versus 10.6 nmol/ml, P = 0.0002). Plasma homocysteine level of subjects in younger CAD group was significantly higher than that of subjects in older CAD group (15.0 versus 11.3 nmol/ml, P = 0.03), and age and logarithmically transformed plasma homocysteine level exhibited a significant negative correlation (r = -0.28, P = 0.03) for subjects in CAD group. Among control subjects, members of our two age subgroups had similar plasma homocysteine levels. Younger CAD patients had significantly higher plasma homocysteine levels than did younger controls (15.0 versus 10.4 nmol/ml, P < 0.0001). However, for older groups there was no significant difference between plasma homocysteine levels in CAD patients and controls (11.3 versus 10.9 nmol/ml). Multiple regression analysis showed that only logarithmically transformed plasma homocysteine level was a significant predictor for age of onset of CAD. An elevated level of plasma homocysteine is more important in the development of premature CAD than it is in that of late-onset CAD among men.