Reference
Complete the bibliographic reference for the article according to AJE format.

Peila R, White LR, Petrovich H, et al. Joint effect of the APOE gene and midlife systolic blood pressure on late-life cognitive impairment. Stroke. 2001; 32(12):2882-9

Category of HuGE information
Specify the types of information (from the list below) available in the article:

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

3.  Gene-environment interaction

Study hypotheses or purpose
The authors study hypotheses or main purpose for conducting the study.

Gene(s)
Identification of the following:

1. Gene name
2. Chromosome location
3. Gene product/function
4. Alleles
5. OMIM #

1. Gene name: APOE
2. Chromosome location: 19q13.2
3. Gene product/function: Apolipoprotein E. Removes excess cholesterol from blood;  Repairs neuronal damage by helping to recycle cholesterol from dead and dying neurons to neurons undergoing terminal sprouting and synaptic remodeling.
4. Alleles: 2, 3. 4
5. OMIM #: 107741

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

1. High midlife SBP
2. Antihypertensive medications use

Health outcome(s)
Identification of the major health outcome(s) studied

Late-life cognitive function as measured at the fourth follow-up examination (1991-1994).  Cognitive function was measured by the Cognitive Abilities Screening Instrument (CASI), which has a score range of 0 to 100.  Good, intermediate, and poor cognitive function were defined as CASI scores of  ≥ 82, 74-82, and <74, respectively.

1. Case-control
2. Cohort 
3. Cross-sectional
4. Descriptive or case series
5. Clinical trial
6. Population screening

2. Cohort

Cohort definition
For study designs 2, 3, and 6, the following are defined, where available:

1. Cohort selection criteria
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants

1. Cohort selection criteria: Japanese-American men born from 1900 to 1919 who were living on Oahu , Hawaii , at baseline (1965-1968)
2. Exclusion criteria:  Men who did not participate in the fourth follow-up examination during 1991-1993 (either because of death or nonresponse) and men who did not provide blood samples for genotyping were excluded.
3. Gender: Male
4. Race/ethnicity: Japanese-American
5. Age: At baseline, ages ranged from 46 to 68 years
6. Time period: Baseline was 1965-1968.  Outcome was assessed during 1991-1993
7. Geographic location: Oahu , Hawaii
8. Number of participants: 3,605

1. Environmental factor
2. Exposure assessment
3. Exposure definition
4. Number of participants with exposure data (%
   of total eligible)

1. Environmental factor 1:  Mid-life SBP
2. Exposure assessment:   Measured at baseline (1965-1968) and two subsequent time points (1968-1970 and 1971-1974).  Standard sphygmomanometer and cuff were used to measure blood pressure.    
3. Exposure definition: A high SBP was defined as an SBP of ≥160 mmHg in at least 2 of 3 measurement occasions.
4. Number of participants with exposure data: N (% of total eligible) 3,605 (100%)

1. Environmental factor 2:  Antihypertensive medication use
2. Exposure assessment:   During the 3 midlife interviews, was assessed by self-report.  During the fourth (late-life) interview, was assessed by  interviewer examination of medication vials.   
3. Exposure definition: Use of medications at any of the four interviews versus no use
4. Number of participants with exposure data: N (% of total eligible) 3,605 (100%)

1. Gene
2. DNA source
3. Methodology
4. Number of participants genotyped (% of total eligible) 

1. Gene: APOE
2. DNA source: Blood samples drawn at fourth interview
3. Methodology: Standard DNA amplification and restriction genotyping
4. Number of participants genotyped: N (% of total eligible) 3,605 (96.5%)

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

Table 2: Relative Risk (95% CI) for Poor Cognitive Function by APOE 4 Status and Midlife High SBP in the Total Sample

Cognitive Function   Intermediate Poor SBP and APOE 4 status (n=586) (n=539) Normal SBP/No 4 1.0* 1.0* Normal SBP/ 4 1.3 (0.9-1.6) 1.3 (0.9-1.7) High SBP/No 4 1.3 (0.8-2.0) 1.8 (1.2-2.9) High SBP/ 4 1.2 (0.5-2.8) 2.9 (1.4-6.3)

*Adjusted for age, education, antihypertensive treatment, and duration of treatment.

Table 3 (partially reproduced):   Relative Risk (95% CI) of Cognitive Impairment in HAAS Participants Associated with APOE 4 Status and Midlife High SBP, Stratified by Antihypertensive Treatment

* Adjusted for age, education, smoking alcohol, body  mass index (BMI), diabetes, prevalent stroke and coronary artery disease, and ABI.

Among men not treated for hypertension in midlife, those with the APOE 4 allele and a high midlife SBP are 10 times more likely to have poor cognitive function in late life than were those with no APOE 4 allele and a normal midlife SBP.  Among men treated for hypertension, those with the APOE 4 allele and a high midlife SBP are not significantly more likely to have poor late life cognitive function than were those with no APOE 4 allele and a normal midlife SBP.

The study’s strengths included:

1. a prospective design
2. use of a validated measure of cognitive function
3. adjustment for a number of potential confounding factors
4. a biologically plausible explanation for the study findings.

However, the study also had some weaknesses:

• Although the point estimates from Table 2 suggest an APOE 4/high SBP interaction in the entire group, the APOE 4/high SBP interaction term failed to achieve statistical significance (p=.62); similarly, although the point estimates from Table 3 suggest a three way interaction may exist between APOE 4, high SBP, and antihypertensive treatment, the three-way APOE 4/high SBP/treatment interaction term was only marginally significant (p = .09). Given these p values, one must consider the possibility that the apparent interactions presented in the paper may have resulted from chance.  The lack of statistical significance may have resulted from the small number of persons in the study falling into the high SBP/ 4 group.
• The study population was limited to Japanese-American men, so the applicability of results in the paper to other groups is not clear.
• SBP was treated as a categorical variable, but SBP is continuous; it might have been more interesting to examine an interaction between APOE 4 and continuous SBP.
• The limited number of 4 homozygotes precluded examination of a gene-dose effect.
• Why the investigators chose the CASI cut-points used in the study is not clear.  Were these simply arbitrary cut-points?