Improved prediction of early-onset coronary artery disease using APOE epsilon4, BChE-K, PPARgamma2 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) epsilon4, butyrylcholinesterase (BChE) K, peroxisome proliferator-activated receptor gamma2 (PPARgamma2) 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 PPARgamma2 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 epsilon4 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 PPARgamma2 to 1.70 for APOE epsilon4). 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.

Trends in five-year survival of patients discharged after acute myocardial infarction.

BACKGROUND: It has previously been shown that the increased use of therapeutic intervention may not reduce patient fatality if there is a simultaneous increase in case severity. The present study was designed to extend the relationship between case severity and therapeutic interventions to long-term survival in the same study population. OBJECTIVE: To compare five-year survival of patients discharged after acute myocardial infarction from 1984 to 1988 and from 1989 to 1993, and to evaluate possible reasons for survival differences. METHODS: The present study was population-based. Survival time was determined by record linkage into the Canadian Mortality Database. Association of five-year survival with patient characteristics, in-hospital treatment and discharge medications was assessed by logistical regression analysis. Case severity was calculated as the probability of death within five years, given the patient profile and excluding any interventions. RESULTS: Between the two study periods, most patient characteristics and treatment intensity changed, but case severity for the study population remained constant. Five-year survival improved from 74.8% to 79.2% (P(chi2)=0.001). The improvement was adequately described by the combination of changes in patient profile and treatment without residual period effect (P(goodness-of-fit)=0.752). The treatments significantly associated with five-year survival were coronary artery bypass graft surgery (OR 2.74; 95% CI 1.86 to 4.05), percutaneous coronary intervention (OR 2.63; 95% CI 1.67 to 4.14) and thrombolysis (OR 1.98; 95% CI 1.50 to 2.62) during admission, as well as acetylsalicylic acid (OR 1.39; 95% CI 1.15 to 1.68) or beta-blocker (OR 1.60; 95% CI 1.34 to 1.92) prescription at discharge. CONCLUSIONS: Changes in patient profile did not affect long-term prognosis; instead, treatment modalities accounted for the observed improvement in five-year survival.

Relation between butyrylcholinesterase K variant, paraoxonase 1 (PON1) Q and R and apolipoprotein E epsilon 4 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 epsilon 4 allele (APOE-epsilon 4). Although APOE-epsilon 4 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-epsilon 4, BChE-K and PON1-R or PON1-R and APOE-epsilon 4. 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-epsilon 4 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-epsilon 4. CONCLUSIONS: Our study suggests that there is a minor association between BChE-K and early-onset CAD, especially in the presence of the APOE-epsilon 4 allele.

Trends in event rate and case fatality of patients hospitalized with myocardial infarction between 1984 and 2001.

Between 1984 and 1993, prevalence and case fatality of hospitalized acute myocardial infarction (AMI) had declined in the population of Halifax County. We aimed to determine whether these trends continued into the 21st century by investigating patient characteristics, treatment methods, and fatality for hospital admissions of residents of Halifax County, aged 25-74, during 1984-1989 (period 1), 1990-1993 (period 2), and 1998-2001 (period 3) and diagnosed as AMI that were extracted from databases for the Halifax County MONICA and ICONS (Improving Cardiovascular Outcomes in Nova Scotia) Studies. Trends in patient characteristics and treatment methods were assessed by chi2 statistics. Their association with 28-day fatality was determined by logistic regression. Event rate declined during 1984-1993 but not into 1998-2001 (p = 0.206). Compared with 1990-1993, fewer AMI patients during 1998-2001 were > or = 55 years (73.3% vs. 69.9%), cigarette smokers (49.8% vs. 42.9%), had a history of myocardial infarction (28.9% vs. 24.9%), and had an admission heart rate >100 (34.8% vs. 17.4%). Additionally, more patients had a history of diabetes (22.5% vs. 28.1%). Case fatality declined progressively over the 3 study time periods (16.6%, 13.1%, and 9.4%, respectively). Changes also occurred in prevalence of Killip class 4 status during admission (20.2%, 10.3%, and 13.3%, respectively), use of thrombolysis (9.0%, 30.9, and 32.6%, respectively), and percutaneous coronary intervention (PCI) (4.3%, 11.2%, and 22.4%, respectively) in the different periods. Significant associations were found between case fatality and patient history of diabetes, history of MI, age, elevated admission heart rate, Killip class 4 impairment, thrombolysis, and PCI. The ICONS registry of hospitalized acute myocardial infarctions was used to compare case fatality during 1998-2001 with that reported by the Halifax County MONICA Project for 1984-1993. Whereas the population rate of myocardial infarctions had declined between 1984-1993 but not subsequently, case fatality declined significantly throughout the study period. The continued decline in case fatality is likely explained by changes in patient profile on presentation and medical therapies, including the increased use of thrombolysis and PCI.