Reference
Complete the bibliographic reference for the article according to AJE format.
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Humphries SE, Talmud PJ, Hawe E, Bolla M, Day INM, Miller GJ. Apolipoprotein E4 and coronary heart disease in middle-aged men who smoke: a prospective study. Lancet 2001;358:115-9.
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Category of HuGE information
Specify the types of information (from the list below) available in the article:
- Prevalence of gene variant
- Gene-disease association
- Gene-environment interaction
- Gene-gene interaction
- Genetic test evaluation/monitoring
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- Prevalence of gene variant
- Gene-disease association
- Gene-environment interaction
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Study hypotheses or purpose
The authors study hypotheses or main purpose for conducting the study |
Hypothesis: Smoking and APOE*ε4 are both associated with increased risk of coronary heart disease (CHD), and both have atherogenic effects on the oxidation of lipoprotein particles. The association of smoking with CHD might therefore vary by APOE genotype.
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Gene(s)
Identification of the following:
- Gene name
- Chromosome location
- Gene product/function
- Alleles
- OMIM #
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- Gene name: APOE
- Chromosome location: 19z13.2
- Gene product/function: Apolipoprotein E, a principal apoprotein of chylomicrons, binds to receptors on liver cells and peripheral cells and facilitates uptake and catabolism of chylomicron fragments; also functions in protection of lipoproteins from oxidation
- Alleles: ε2, ε3, ε4
- OMIM#: 107741
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Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)
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Smoking
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Health outcome(s)
Identification of the major health outcome(s) studied |
Incident coronary heart disease (defined as fatal CHD events and nonfatal myocardial infarction [MI], based on WHO criteria), coronary artery surgery, and silent MI on follow-up ECG
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Study design
Specification of the type of study design(s)
- Case-control
- Cohort
- Cross-sectional
- Descriptive or case series
- Clinical trial
- Population screening
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Cohort |
Cohort definition
For study designs 2, 3, and 6, the following are defined, where available:
- Cohort selection criteria
- Exclusion criteria
- Gender
- Race/ethnicity
- Age
- Time period
- Geographic location
- Number of participants
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- Cohort selection criteria: Healthy men aged 50-61 years registered in nine general medical practices in the UK
- Exclusion criteria: “...free of history of unstable angina, myocardial infarction or evidence of silent infarction, coronary surgery, aspirin or anticoagulant therapy, cardiovascular disease, malignant disease (except skin cancer other than melanoma), or any condition precluding informed consent.” Also excluded were nonwhites (not defined), subjects without DNA samples, and those with genotype ε2/ε4.
- Gender: Male
- Race/ethnicity: White
- Age: 50-61 years at entry
- Time period: Recruitment period not reported; follow-up duration not reported although reported person-years and sample size permit estimate of average duration = 8.3 years.
- Geographic location: United Kingdom (Camberly, Chesterfield, Halesworth, Harefield, North Mymms, Poole, St. Andrews)
- Number of participants: 2,258
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Assessment of environment factors
For studies that include gene-environment interactions, define the following, if available:
- Environmental factor
- Exposure assessment
- Exposure definition
- Number of participants with exposure data (% of total eligible)
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- Environmental factor: Smoking
- Exposure assessment: Self-report
- Exposure definition:
a. Smokers: Smoking at least one cigarette daily on average for a year or more
b. Ex-smokers: Smoking less than one cigarette a day
c. Never smokers: Not defined
- Number of participants with exposure data: N ( % of total eligible ) 234/236 patients ( 99% ) for cases and 634 ( 86% ) for controls.
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Genotyping
Specify the following:
- Gene
- DNA source
- Methodology
- Number of participants genotyped (% of total eligible)
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- Gene: APOE
- DNA source: Venous Blood
- Methodology: “Salting out” with 6M NaCl and ethanol as described in Miller SA et al. Nucleic Acids Res 1988;16:1215.
- Number of participants genotyped: 2303/3052 eligible (75%) but full data were available on 2258, after exclusion of 45 men with the ε2/ε3 genotype
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Results
Describe the major results under each of the following HuGE categories. Include tables when data are provided:
- Prevalence of gene variant
- Gene-disease association
- Gene-environment interaction
- Gene-gene interaction
- Genetic test evaluation/monitoring
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- Prevalence of APOE genotypes in subjects with triglyceride and smoking measures.
Genotype |
Number (%) |
ε3/ε3 |
1339 (60.5) |
ε2/ε2 and ε2/ε3 |
288 (13.0) |
ε3/ε3 and ε3/ε4 |
587 (26.5) |
- Gene-disease association: Not provided due to significant interaction with smoking
- Gene-environment interaction:
Smoking/Genotype Stratum |
Number/Events |
Hazard Ratio [95%CI] |
Adjusted Hazard Ratio [95% CI] |
Never smokers |
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|
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All genotypes |
727/32 |
1.00 |
1.00 |
Ex-smokers |
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ε3/ε3 |
554/41 |
1.74 [1.10-2.77] |
1.49 [0.93-2.37] |
ε2/ε2and ε2/ε3 |
100/2 |
0.48 [0.12-2.02] |
0.47 [0.11-1.94] |
ε3/ε3 and ε3/ε4 |
248/9 |
0.84 [0.40-1.75] |
0.74 [0.35-1.55] |
Smokers |
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|
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ε3/ε3 |
367/5 |
1.68 [1.01-2.83] |
1.47 [0.87-2.51] |
ε2/ε2and ε2/ε3 |
98/5 |
1.18 [0.46-3.03] |
0.85 [0.30-2.43] |
ε3/ε3 and ε3/ε4 |
163/21 |
3.17 [1.82-5.51] |
2.79 [1.59-4.91] |
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Conclusion
State the author's overall conclusions from the study |
Smoking is risk factor for CHD, particularly in men carrying the ε4 allele. A gradient of increasing CHD risk from never smoker to ex-smoker to current smoker was observed in all genotype groups, but this gradient was greater in the ε4 group than in all others combined.
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Comments
Provide additional insight, including methodologic issues and/or concerns about the study |
The study would have been stronger if CHD events had excluded coronary bypass surgery, though in the presumed period of follow-up surgical referrals might not have been expected to be strongly influenced by knowledge of APOE genotype.
Completeness of follow-up was not reported.
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