Apolipoprotein E genotype in Spanish schizophrenic patients

Apolipoprotein E (ApoE) is a lipoprotein that, in the central nervous system, is thought to play a role in neuronal growth and repair. ApoE has three isoforms (ApoE2, ApoE3 and ApoE4) coded by three different alleles (epsilon2, epsilon3 and epsilon4). Evidence from family, twin and adoption studies suggest that there is an important genetic contribution to the etiology of schizophrenia. Schizophrenia is in some cases associated with cognitive impairment similar to that of Alzheimer patients; therefore, one may postulate that the ApoE gene, whose role in the dementia of Alzheimer's type has been clearly demonstrated, may also be involved in schizophrenia. In the present study, we have genotyped 114 schizophrenic Spanish patients and 94 healthy matched controls, and found no association between the ApoE genotype and schizophrenia. Subdivision of patients in clinical subgroups showed a slight increase of ApoE4 in early-age onset of the disease and a slight decrease in positive family history for psychiatric diseases; the group with a poor response to neuroleptic drugs had a lower ApoE2 allele frequency. However, as the differences did not reach statistical significance, we cannot draw evidence of an association. Our negative data do not support an involvement of ApoE in schizophrenia, and suggest that the underlying mechanism for the cognitive impairment found in schizophrenic patients is not related to that of Alzheimer's patients nor to a higher prevalence of the ApoE allele 4.     

Apolipoprotein E genotype influences spatial distribution of cerebral microbleeds

In cerebral amyloid angiopathy patients, microbleeds often cluster, mostly occipital, and are associated with apolipoprotein E (APOE) genotype. Microbleeds also frequently occur in the asymptomatic, general population. In this population, we investigated spatial distribution of microbleeds and whether this is influenced by APOE genotype. In 292 persons with microbleeds, we labeled microbleeds on baseline and follow-up magnetic resonance images. We calculated distance between incident and prevalent microbleeds within and between persons and performed lobar segmentation on the magnetic resonance images. Subsequently, we investigated proximity and lobar distribution in strata of APOE genotype. Microbleeds occurred closer within persons than between persons (−42.2 mm, 95% confidence interval, −44.6 to −39.9; p < 0.001). Microbleeds within APOE ε2 and ε4 carriers occurred closer than those in persons with ε3ε3 genotype (−11.9 mm, 95% confidence interval, −24.4 to 0.6; p = 0.06). Persons with ε2 and ε4 alleles had a larger proportion of microbleeds in the occipital lobe than persons with ε3ε3 genotype. Similar to cerebral amyloid angiopathy patients, microbleeds in the general population cluster and the distribution is affected by APOE genotype.     

Apolipoprotein E gene polymorphisms in patients with migraine.

To investigate the role of apolipoprotein E (APOE) polymorphisms in migraine, we analyzed the APOE genotypes of 241 migraine patients and 587 controls. The results of a Chi-square analysis indicated that APOE alleles were similarly distributed (chi(2)=2.89, P=0.24) between cases and controls. However, we found a significant (P<0.001) increase of the varepsilon2-varepsilon4 genotype in the group of migraine patients. Patients were divided into three subgroups: migraine with aura; migraine without aura; and mixed headaches (migraine associated with tension-type headache). Subgroup analysis showed that the varepsilon2-varepsilon4 genotype was significantly increased only in patients with mixed headaches. The stratification of patients by APOE status did not reveal significant associations with the clinical features of the disease. In conclusion, we observed no significant association between APOE polymorphisms and migraine. The association between the APOE varepsilon2-varepsilon4 genotype and the tension-type headache deserves further evaluation.     

Obsessive-compulsive alcohol craving is not associated with Apolipoprotein E genotype

This study examined a possible association with obsessive and compulsive alcohol craving in 192 alcohol-dependent patients undergoing detoxification treatment. Statistical analysis revealed no significant association between Apolipoprotein E polymorphism and obsessive-compulsive alcohol craving (analysis of variance: F=1.11, P=0.358).     

Apolipoprotein E genotype and its pathological correlation in Chinese Alzheimer's disease with late onset.

In this study, we attempted to find a relationship between apoliprotein E (ApoE) genotypes and Alzheimer's disease (AD) pathology in different areas of the brain in Chinese. We also studied the borderline group of possible AD (Poss). There were 34 definite or probable AD (Ad), 18 Poss, and 123 brains from age-matched normal subjects (N). ApoE genotype was determined by nested polymerase chain reaction on genomic DNA extracted from archival paraffin-embedded materials. Hippocampus (including entorhinal cortex), amygdala, superior temporal lobe, middle frontal gyrus, and inferior parietal lobule of the brains of Ad and Poss were examined with beta amyloid (A beta) immunostaining, and the same regions plus medial occipital lobe were examined with tau immunostaining. The percentage of plaque area stained for A beta in each brain region was obtained by an image analyzer, and the average number of neurofibrillary tangles stained for tau was counted with an eyepiece graticule. ApoE epsilon4 frequency was increased in both Ad (22.1%, chi2, df = 1, P = .00005), and Poss (33.3%, P = .000005) compared with N (5.3%). A beta load was significantly increased in the neocortex in Ad examined with at least 1 copy of epsilon4 compared with subjects without epsilon4 (Mann-Whitney, P = .014). The same trend, though not statistically significant, occurred in Poss (P = .15). Tau expression was associated with ApoE epsilon4 in neither Ad nor Poss. Poss is genetically and histologically similar to Ad, although the overall A beta load is significantly increased in the latter. These findings support the recent Consensus Report's findings that all Alzheimer-type pathology may be significant.     

Apolipoprotein E genotype in matched men and women with coronary heart disease

Apolipoprotein E (apo E) plays an important role in lipid metabolism and its polymorphism may be a risk determinant of coronary heart disease (CHD). Since evidence suggested a gender-specific effect of apo E polymorphism, we studied the influence of gender-specific interaction of the polymorphism on CHD. From a total of 463 Greek Caucasians (314 men and 149 postmenopausal women) with angiographically documented CHD, we selected 79 women (68+/- 9 yr old) and 79 men (66+/- 9 yr old) who were matched for clinical characteristics. Apo E genotyping was performed by PCR and RFLP analysis. Biochemical parameters were also measured. The results were as follows: the E3/3 genotype occurred in 78.5% of the patients, followed by E3/4, E2/3, E2/4, and E4/4 genotypes, which occurred in 9.5%, 9.5%, 1.9%, and 0.6% of the patients, respectively. No significant differences were observed in the apo E allele or apo E genotype distributions between the matched Greek men and women with CHD. The E3/3 men patients were more frequently part of a family with a history of CHD, compared to women (p=0.035).     

Apolipoprotein E genotype and oxidative stress response to traumatic brain injury

Traumatic Brain Injury (TBI) is known to result in oxidative stress, and as variation at the Apolipoprotein E (APOE) gene has been shown to influence outcome following TBI, but through as yet unclear mechanisms, we used transgenic APOE mouse models to examine the relationship between APOE genotype and oxidative stress following TBI. We administered a controlled cortical impact (CCI) injury or sham injury to transgenic mice expressing either human APOE3 or APOE4 on a murine APOE-deficient background. RNA was prepared from the ipsilateral hippocampi and cortices retrieved at 24 h and 1 month post-TBI. Microarray analysis was performed on unpooled samples from three mice per group to determine the genomic response to TBI and to specifically investigate the response of genes involved in oxidative stress mechanisms. Our data demonstrated TBI-induced expression of many more anti-oxidant related genes in the APOE3 mice, suggesting a potential anti-oxidative role for ApoE3 compared to ApoE4. However, in an additional cohort of mice we isolated the ipsilateral hippocampi, cortices, and cerebella at 1 month after TBI or sham injury for immunohistochemical analysis of markers of oxidative stress: the formation and presence of carbonyls (indication of general oxidative modification), 3-nitrotyrosine (3NT; specific to protein modification), or 4-hydroxyl-2-nonenal (HNE; specific to lipid peroxidation). Although we observed significant increases in all three markers of oxidative stress in response to injury, and genotype was a significant factor for carbonyl and 3NT, we found no significant interaction between genotype and injury. This may be due to the overwhelming effect of injury compared to genotype in our ANOVA, but nonetheless suggests that an influence on oxidative stress response is not the primary mechanism behind the APOE-genotype dependent effects on outcome following TBI.     

Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage

BACKGROUND: Recurrent lobar intracerebral hemorrhage is the hallmark of cerebral amyloid angiopathy. The factors that predispose patients to early recurrence of lobar hemorrhage are unknown. One candidate is the apolipoprotein E gene, since both the epsilon2 and the epsilon4 alleles of apolipoprotein E appear to be associated with the severity of amyloid angiopathy. METHODS: We performed a prospective, longitudinal study of consecutive elderly patients who survived a lobar intracerebral hemorrhage. The patients were followed for recurrent hemorrhagic stroke by interviews at six-month intervals and reviews of medical records and computed tomographic scans. RESULTS: Nineteen of 71 enrolled patients had recurrent hemorrhages during a mean follow-up period of 23.9+/-14.8 months, yielding a 2-year cumulative rate of recurrence of 21 percent. The apolipoprotein E genotype was significantly associated with the risk of recurrence. Carriers of the epsilon2 or epsilon4 allele had a two-year rate of recurrence of 28 percent, as compared with only 10 percent for patients with the common apolipoprotein E epsilon3/epsilon3 genotype (risk ratio, 3.8; 95 percent confidence interval, 1.2 to 11.6; P=0.01). Early recurrence occurred in eight patients, four of whom had the uncommon epsilon2/epsilon4 genotype. Also at increased risk for recurrence were patients with a history of hemorrhagic stroke before entry into the study (two-year recurrence, 61 percent; risk ratio, 6.4; 95 percent confidence interval, 2.2 to 18.5; P<0.001). CONCLUSIONS: The apolipoprotein E genotype can identify patients with lobar intracerebral hemorrhage who are at highest risk for early recurrence. This finding makes possible both the provision of prognostic information to patients with lobar hemorrhage and a method of targeting and assessing potential strategies for prevention.     

Apolipoprotein E polymorphism in non-diabetic patients with acute coronary syndrome.

Since a decade ago, apolipoprotein (apo) E polymorphism has been focussed as a risk factor for cardiovascular disease. ApoE plays a central role as a receptor ligand for the uptake of lipoproteins from the circulation. There was an agreement on apoE polymorphism being one of the major risk factors for coronary artery disease (CAD) by its effects on lipid profiles. However, the effects of apoE have not been noted in all populations and conflicting results in the risk of CAD have been noted. Recently, in situ expression of apoE on the atherosclerotic plaque has been studied. We, therefore, investigated the effects of apoE genotype on patients with acute coronary syndrome, including unstable angina and acute myocardial infarction, in non-diabetic patients. While we could not find significant risk effects of apoE on coronary artery disease and lipid profiles on simple comparison with the normal control group, we could find significantly decreased frequencies of apo epsilon 3 allele in patients with acute coronary syndrome compared with stable angina patients (77.8% vs 88.8%). We suggest that the apoE genotype could be associated with acute coronary events in CAD and further study with in situ biochemical methods will be needed on the effects of apoE polymorphism on plaque stability.     

Apolipoprotein E genotype and major depression in a community of older adults. The Cache County Study

BACKGROUND: The role of allelic variation in APOE, the genetic locus for apolipoprotein E, in geriatric depression is poorly understood. There are conflicting reports as to an association between the epsilon4 allele and depression in late life. METHOD: Using a community based study of non-demented elders in Cache County, Utah, that included many very old individuals, we examined the relationship between APOE and late-onset (age > 60) depression, with particular attention to possible age effects. RESULTS: There was no overall association between APOE and depression. However, there was a significant interaction effect of APOE and age such that the relationship of late-onset depression with respect to presence of the epsilon4 allele was larger among those 80 and older compared with those below age 80. Consistent with previous studies, women were more likely to experience late-onset depression than men. CONCLUSIONS: Because we excluded prevalent cases of dementia, this pattern of relative risk with age may reflect the appearance of depressive symptoms as a prodrome of Alzheimer's disease or vascular dementia. Longitudinal studies should help to confirm or refute this explanation of the data.     

Apolipoprotein E genotype has no effect on the free intracellular Ca2+ concentration of platelets from Alzheimer's disease patients

The free intracellular Ca2+ concentration [Ca2+]i of platelets was investigated in Alzheimer's disease (AD) patients and age-matched control subjects with distinct Apo E genotypes. No significant differences were found between the Apo E genotype and the [Ca2+]i levels of platelets (basal and alpha-thrombin stimulated) from AD patients and age-matched control subjects, suggesting that [Ca2+]i homeostasis of platelets from AD patients is independent of the Apo E genotype. The results are discussed in terms of involvement of Apo E and [Ca2+]i changes in the etiopathogenesis of AD.     

Apolipoprotein E alleles in women with severe pre-eclampsia.

This study investigated the frequency of apolipoprotein E (apoE) alleles among women with severe pre-eclampsia. The presence of the three most common apoE alleles (epsilon 2, epsilon 3, epsilon 4) was determined by polymerase chain reaction-restriction fragment length polymorphism in three groups of white women: non-pregnant healthy (n = 101), pregnant healthy (n = 52), and pregnant with a diagnosis of severe pre-eclampsia (n = 54). The frequency of apo epsilon 2 was highest among women with severe pre-eclampsia (16.6%) followed by non-pregnant women (12.9%), and those experiencing a healthy pregnancy (10.6%). The higher frequency of the apo epsilon 2 allele detected among women with severe pre-eclampsia suggests that apoE may play a role in the development of pre-eclampsia.     

Apolipoprotein E polymorphisms and spontaneous pregnancy loss in patients with endometriosis

Endometriosis affects >10% of women during their reproductive years, many of whom report high rates of spontaneous pregnancy loss (SPL). We examined whether gene polymorphisms in apolipoprotein E (APOE), which is involved in lipoprotein metabolism, are associated with endometriosis and/or endometriosis-associated infertility. We conducted a cross-sectional genetic association study of women surgically confirmed to have endometriosis (n = 345) and no surgical evidence of the disease (n = 266). Genotyping of APOE polymorphism (ε2, ε3, ε4) was conducted by polymerase chain reaction-restriction fragment length polymorphism followed by visualization of specific patterns by gel electrophoresis. Statistical significance of differences in genotype and allelic frequencies was assessed using Pearson's χ(2) test and Risk analysis. Overall, we found no association between APOE genotype and diagnosis of endometriosis. However, patients with endometriosis who reported at least one SPL were three times more likely to be ε2 carriers and 2-fold less likely to be ε4 carriers. Compared with ε3 carriers, patients with endometriosis who were ε2 carriers and had at least one live birth reported four times the rate of SPL, while ε4 carriers were <0.4-fold less likely to report an SPL. Our data suggest that there may be an association between APOE allelic frequency and SPL in patients with endometriosis, which appears to be independent of mechanisms associated with infertility, an intriguing observation that deserves further investigation.     

Effect of COMT genotype on aggressive behaviour in a community cohort of schizophrenic patients

This study examined the inter-ocular (alternating monocular samples) and intra-ocular (monocular or binocular samples) integration during a prehensile task with a range of occlusion intervals (0-75 ms). In the first experiment, participants were uncertain regarding the impending visual condition, as well as target size and location. In the second experiment, a pre-cue on target location was provided. Data from both experiments indicated that participants modified their movement kinematics when provided with alternating monocular samples, irrespective of whether or not there was an occlusion interval. Similar adaptations were found in conditions requiring intra-ocular integration but only following the introduction of an occlusion interval. These findings are consistent with participants having a general intolerance for alternating monocular samples and as a consequence using a more cautious reach and grasp strategy.     

Apolipoprotein E genotype does not affect the age of onset of dementia in families with defined tau mutations

We have assessed whether apolipoprotein E (ApoE) genotype influences the age of onset of dementia in a series of families with frontal temporal dementia with defined mutations in the tau gene. In contrast to the situation in Alzheimer's disease (AD), we could find no evidence that the age of onset of disease was influenced by the ApoE genotype.