Haines, J.L.

A pooled case-control study of the apolipoprotein E (APOE) gene in age-related maculopathy (Article)

2002-12-01T00:00:00Z

Age-related maculopathy (ARM) is a multifactorial disorder known to have a substantial genetic component. The epsilon4 allele of the apolipoprotein E gene (APOE-4) has previously been reported to have a protective effect on ARM risk, while the APOE-2 allele may increase disease risk. This study combined four independent data sets (three US and one European) of Caucasian ARM patients and controls in order to obtain better statistical power to examine the role of APOE in ARM. APOE genotype and allele frequencies were compared for 617 ARM cases and 1260 controls, adjusting for age and sex differences between the two groups via multiple logistic regression. The protective effect of the APOE-4 allele on ARM risk was confirmed (age- and sex-adjusted odds ratio (OR) for APOE-4 carriers 0.54, 95% confidence interval (CI) 0.41-0.70, p < 0.0001). The effect of APOE-4 did not differ significantly between males and females and was observed consistently for both atrophic and neovascular ARM. Evidence for an increased risk of ARM due to the APOE-2 allele was found for men, but not for women (OR for men 1.54, 95% CI 0.97-2.45; OR for women 0.74, 95% CI 0.52-1.06, p = 0.01 for interaction of sex and APOE-2 carrier status). These data confirm that the APOE-4 allele, or an allele in linkage disequilibrium with it, reduces the risk of ARM. They also suggest that the effect of the APOE-2 allele may vary by gender, and that APOE-2 may confer an increased risk only to males.

Evidence for major gene inheritance of Alzheimer disease in families of patients with and without apolipoprotein E ε 4. (Article)

1996-01-01T00:00:00Z

Apolipoprotein E (APOE) genotype is the single most important determinant to the common form of Alzheimer disease (AD) yet identified. Several studies show that family history of AD is not entirely accounted for by APOE genotype. Also, there is evidence for an interaction between APOE genotype and gender. We carried out a complex segregation analysis in 636 nuclear families of consecutively ascertained and rigorously diagnosed probands in the Multi-Institutional Research in Alzheimer Genetic Epidemiology study in order to derive models of disease transmission which account for the influences of APOE genotype of the proband and gender. In the total group of families, models postulating sporadic occurrence, no major gene effect, random environmental transmission, and Mendelian inheritance were rejected. Transmission of AD in families of probands with at least one epsilon 4 allele best fit a dominant model. Moreover, single gene inheritance best explained clustering of the disorder in families of probands lacking epsilon 4, but a more complex genetic model or multiple genetic models may ultimately account for risk in this group of families. Our results also suggest that susceptibility to AD differs between men and women regardless of the proband's APOE status. Assuming a dominant model, AD appears to be completely penetrant in women, whereas only 62%-65% of men with predisposing genotypes develop AD. However, parameter estimates from the arbitrary major gene model suggests that AD is expressed dominantly in women and additively in men. These observations, taken together with epidemiologic data, are consistent with the hypothesis of an interaction between genes and other biological factors affecting disease susceptibility.

Apolipoprotein E genotype in patients with Alzheimer's disease: implications for the risk of dementia among relatives. (Article)

1995-01-01T00:00:00Z

Numerous studies have shown that the risk of Alzheimer's disease (AD) is associated with the dose of the epsilon 4 allele of apolipoprotein E (ApoE). However, more than one third of AD patients lack epsilon 4 and many persons having epsilon 4 survive cognitively intact to old age. We evaluated the lifetime risk of disease in 3,999 first-degree relatives of 549 probands who met the criteria for probable or definite AD and whose ApoE genotypes were known. ApoE genotypes for relatives were not determined. After age 65 the risk among relatives was proportional, as much as 7 to 10% at age 85, to the number of epsilon 4 alleles present in the proband. Risks to relatives of ApoE 2/2 and 2/3 probands were nearly identical at all ages to risks for relatives of ApoE 3/3 probands. The expected proportion of relatives having at least one epsilon 4 allele was calculated for each genotype group based on the distribution of parents, sibs, and offspring in the sample. Among relatives in the ApoE 3/3 group, the lifetime risk for AD by age 90 was three times greater than the expected proportion of epsilon 4 carriers, suggesting that factors other than ApoE contribute to AD susceptibility. Furthermore, the 44% risk of AD by age 93 among relatives of ApoE 4/4 probands indicates that as many as 50% of people having at least one epsilon 4 allele do not develop AD. We also found that among male relatives, risk of AD in the ApoE 3/4 group was similar to that for the ApoE 3/3 group but significantly less than the risk for the ApoE 4/4 group. In contrast, among female relatives the risk for the ApoE 3/4 group was nearly twice that for the ApoE 3/3 group and identical to the risk for the ApoE 4/4 group. These findings are consistent with a sex-modification effect of the E4 isoform on disease susceptibility.