As shown in , 4652, 4778, 4876, and 4835 ARIC female study participants at baseline in 1987-1989 met the study inclusion criteria for the apoE, CETP, LIPC, and LPL analyses, respectively. All women included in our analyses had repeated cholesterol measurements at either 3 or all 4 ARIC visits. describes baseline characteristics of the study sample by menopausal status. Postmenopausal women were older, had a higher frequency of obesity and overweight, were more likely to be taking cholesterol-lowering medication and hormone replacement therapy, more commonly had diabetes, and were more frequently current smokers than pre-/perimenopausal women at baseline. Approximately three-fourths of the women in this dataset were Caucasian, but there was a higher percentage of African-Americans among the postmenopausal women than in the pre-/perimenopausal group.
Study Sample (n) and Exclusions [n excluded at each step], ARIC
Baseline ARIC characteristics by menopausal status, 1987-1989*
All four genes were in Hardy-Weinberg equilibrium within race groups (). For the CETP gene, Caucasians had much higher proportions of genotypes AA and AG, whereas over half of the African-Americans were genotype GG. The majority of Caucasians carried at least one C allele for LIPC, whereas the majority of African-Americans were carriers of the T allele. Less than 5% of Caucasians were TT for the LIPC gene, yet almost 28% of African-Americans were genotype TT.
Genotype frequencies by race group, ARIC
Before formal genotype-lipid and genotype-menopause interaction analyses, we tested an interaction between genotype and race. The interactions were not statistically significant for the apoE, CETP, or LPL genes (all interactions p>0.05). However, the effect of LIPC genotypes on HDL-c levels was modified by race (p=0.02). Although the genotype-race interaction was significant for LIPC, the mean HDL-c concentrations by menopausal status were similar to the means reported in for all women except pre-/perimenopausal African Americans. Therefore, we report only pooled results. Additionally, we tested for a gene*visit interaction and found no significant interaction by visit for any of the genes (all interactions p>0.10). Since the effect of genotype on mean cholesterol level did not vary by visit, we report estimates pooled over all four ARIC visits.
Adjusted Mean LDL-c and HDL-c Levels by Menopausal Status, ARIC
The individual associations of genotypes with mean LDL-c and HDL-c, after accounting for time trend and the effect of aging, were consistent with findings from previous literature (). For example, compared to the ε33 genotype of apoE, the ε2 allele was associated with 16.5 mg/dL lower LDL-c and the ε4 allele was associated with 6.4 mg/dL higher LDL-c. Postmenopausal status was associated with an 8.2 mg/dL greater LDL-c compared to pre-/perimenopausal women (p<0.0001). There was no significant difference in HDL-c between the pre-/perimenopausal women and the postmenopausal women (p>0.10).
Mean Difference in LDL-c and HDL-c by Genotype, ARIC
The models testing the interaction between genotype and menopause are found in . Menopausal status did not modify the association of apoE genotype on LDL-c levels (interaction p=0.47). HDL-c levels among genotypes for the LIPC and LPL genes were comparable between the pre-/perimenopausal group and the postmenopausal group (both interactions p>0.10). The only statistically significant gene by menopause interaction was with the CETP gene on HDL-c concentrations (p=0.04). Postmenopausal women who were carriers of the A allele of the CETP gene had approximately 0.7 mg/dL lower mean HDL-c levels than pre-/perimenopausal counterparts, whereas the opposite pattern of HDL-c (0.4 mg/dL higher HDL-c postmenopausally) was observed for the GG genotype.