DRD4 and novelty seeking: results of meta-analyses.

Studies of the association between polymorphisms within and near the dopamine D4 receptor (DRD4) gene and novelty seeking (NS) have produced inconsistent results, raising questions about the strength of the relationship and the methodological conditions under which the relationship holds. We conducted three meta-analyses of existing studies to provide formal statistical measures of the strength of the DRD4-NS relationship. Results provided no support for a relationship between NS and the presence of the 7-repeat allele of the VNTR polymorphism. A small positive effect, however, was found for long repeats of the same polymorphism. The most promising findings were obtained for the relationship with the -521 C/T promoter polymorphism, for which the analysis showed an effect size of 0.32. The positive findings are consistent with a polygenic model of influence on fundamental personality dimensions.

APOE genotype influences acquisition and recall following traumatic brain injury.

APOE has been demonstrated to influence traumatic brain injury (TBI) outcome. The relationship between APOE genotype and memory following TBI was examined in 110 participants in the Defense and Veterans' Head Injury Program. Memory performance was worse in those who had an APOE epsilon 4 allele (n = 30) than those who did not (n = 80), whereas genotype groups did not differ on demographic or injury variables or on measures of executive functioning. These data support a specific role for the APOE protein in memory outcome following TBI, and suggest an APOE isoform-specific effect on neuronal repair processes.

A functional polymorphism within the mu-opioid receptor gene and risk for abuse of alcohol and other substances.

Genetic association studies investigating the role of the +118A allele of the human mu-opioid receptor gene in risk for alcohol dependency have produced inconsistent findings, possibly because of the failure to recognize sampling methodology difficulties inherent in association studies of polygenic disorders. We examined the frequency of the AA genotype and A allele in several groups of substance-dependent cases, unrestricted controls, and super controls screened for the use of alcohol and cigarettes. Our findings and analyses suggest that the OPRM1 +118 polymorphism is a general risk gene for substance dependence, but is not specific to a particular substance. The nature of the conferred risk is likely to be in use of multiple substances, but it is not yet determined if the risk could be expressed in severity of use of any particular substance. The contribution of the gene to risk for substance dependence is small, and is detected most easily in studies that use control samples that are screened for all forms of substance dependence.

Association between Alzheimer's disease and a functional polymorphism in the Myeloperoxidase gene.

A polymorphism in the Myeloperoxidase gene (MPO) has previously been demonstrated to be associated with gender-specific risk in an Alzheimer's Disease (AD) autopsy sample. We have investigated this polymorphism in our own samples of 226 Caucasian cases and 166 controls and 59 Hispanic cases and 75 controls. In Caucasians we find a significant association between MPO genotype and AD (P = 0.03), although we do not observe any effects of gender or any interaction with the APOE gene. Specifically, the MPO GG genotype contributes a 1.57-fold increased risk for AD. In Hispanics there was no effect of MPO genotype, or of MPO genotype in interaction with age or gender, on diagnosis of AD.

A polymorphism in the cystatin C gene is a novel risk factor for late-onset Alzheimer's disease.

OBJECTIVE: To investigate whether or not a coding polymorphism in the cystatin C gene (CST3) contributes risk for AD. DESIGN: A case-control genetic association study of a Caucasian dataset of 309 clinic- and community-based cases and 134 community-based controls. RESULTS: The authors find a signficant interaction between the GG genotype of CST3 and age/age of onset on risk for AD, such that in the over-80 age group the GG genotype contributes two-fold increased risk for the disease. The authors also see a trend toward interaction between APOE epsilon4-carrying genotype and age/age of onset in this dataset, but in the case of APOE the risk decreases with age. Analysis of only the community-based cases versus controls reveals a significant three-way interaction between APOE, CST3 and age/age of onset. CONCLUSION: The reduced or absent risk for AD conferred by APOE in older populations has been well reported in the literature, prompting the suggestion that additional genetic risk factors confer risk for later-onset AD. In the author's dataset the opposite effects of APOE and CST3 genotype on risk for AD with increasing age suggest that CST3 is one of the risk factors for later-onset AD. Although the functional significance of this coding polymorphism has not yet been reported, several hypotheses can be proposed as to how variation in an amyloidogenic cysteine protease inhibitor may have pathologic consequences for AD.

The genetic association between Cathepsin D and Alzheimer's disease.

The aspartyl protease Cathepsin D has previously been suggested to play a role in the Alzheimer's disease (AD) process because of its ability to cleave the beta-amyloid precursor protein and the possibility that it may be one of the 'secretase' enzymes. A functional C-->T polymorphism in the Cathepsin D gene (CATD) has been reported to be associated with increased risk for AD in Caucasian case-control studies; specifically, the T-carrying genotypes confer increased risk. We have examined this association in our own Caucasian dataset of 210 AD cases and 120 controls, and in an additional Hispanic dataset comprising 79 AD cases and 112 controls. In Hispanics we find a modest interaction between CATD genotype and age of onset on risk for AD, such that the non-T-carrying genotype confers increased risk. In our Caucasian dataset we find no evidence for association between the CATD polymorphism and AD, although we do observe a small tendency towards an increase in the T-carrying genotypes in the case group, consistent with previous studies. We conducted an aggregate analysis of the published Caucasian datasets and found evidence that this CATD polymorphism (or another locus in linkage disequilibrium) does contribute significant, but small (<2%) risk for AD.

Is APOE--epsilon4 a risk factor for cognitive impairment in normal aging?

OBJECTIVES: To examine the relationship between APOE genotype and cognitive functioning in normal aging, and to determine whether this relationship was moderated by age or the presence of a number of disease conditions, including cardiovascular disease and diabetes. METHODS: The sample was drawn from the Charlotte County Healthy Aging Study, a community-based, cross-sectional study of randomly selected older adults in Charlotte County, FL. A total of 413 older adults (mean age = 72.90 years) were examined in the current study. Participants completed tasks that indexed a variety of dimensions of cognitive functioning, including episodic memory, implicit memory, psychomotor speed, and attention. In addition, participants provided self-reported and objective indices of health status and were genotyped for APOE. RESULTS: Mean-level results indicated that groups with and without the APOE-epsilon4 allele performed similarly on all domains of cognitive functioning. Significant age group differences were observed in episodic memory, psychomotor speed, and attention but not implicit memory. Significant gender differences were present for episodic memory and the Stroop test. Analyses also indicated that participants' age did not exert an impact on the relationship between APOE-epsilon4 and cognitive functioning. Further, the presence of cardiovascular disease or diabetes did little to moderate the relationship between APOE-epsilon4 and cognition. CONCLUSIONS: The authors found no evidence for a relationship between presence of the APOE-epsilon4 allele and cognitive functioning. Further, age or the presence of a number of chronic conditions did not significantly moderate the effect of APOE genotype on cognitive performance. These results indicate that the presence of the epsilon4 allele is not a risk factor for cognitive impairment in normal aging.

Intravascular beta-amyloid infusion increases blood pressure: implications for a vasoactive role of beta-amyloid in the pathogenesis of Alzheimer's disease.

Hypertension has been recognized as a risk factor for Alzheimer's disease (AD). Moreover, serum beta-amyloid (A beta) levels are elevated in several mutations linked to familial AD, as well as in some sporadic AD individuals. To determine the in vivo effects of A beta on blood pressure, A beta(1-40) was infused intra-arterially into anesthetized rats. For all animals, strong correlations exist between pre-infusion mean arterial blood pressure (MA beta) and post-arterial infusion increases in blood pressure. In spontaneously hypotensive animals, A beta infusion resulted in substantial increases in MA beta compared to vehicle distilled water infusion. A beta(1-40) was also able to accelerate MA beta return from induced hypotension, but infusion of A beta(1-42), or rat amylin had no such effect. These results provide evidence that circulating A beta(1-40) can exert vasopressor actions in vivo. Moreover, they suggest a pathophysiologic role for vascular A beta in AD that precedes A beta deposition and dementia onset.

Preoperative prediction of postoperative pulmonary arteriolar resistance after surgical repair of complete atrioventricular canal defect.

The natural history of patients with complete atrioventricular canal defect is one of unrelenting development of pulmonary vascular obstructive disease. Corrective surgery, which can be performed with low mortality during infancy, reduces the time that the pulmonary vascular bed is exposed to excessively high pressure and blood flow. In some patients, however, advanced vascular disease may already be established at operation. Surgical intervention in these patients may not prevent the progression of obliterative pulmonary vascular disease and may in time even result in right ventricular failure, since after the corrective operation there is no ventricular septal defect to shunt away the right ventricular pressure overload. This article outlines a numeric method for predicting pulmonary vascular resistance after surgical correction; the method is based on age and hemodynamic data available from preoperative cardiac catheterization. Retrospective analysis of preoperative and postoperative data from 20 patients produced a regression equation in which a linear combination of inverse pulmonary/systemic blood flow ratio and age at operation predicted pulmonary vascular resistance after operation, with a multiple correlation coefficient of 0.85. This newly discovered relationship may provide valuable insight into the probable outcome of surgical intervention in cases in which pulmonary vascular obstructive disease is suspected as significant.

Cleft lip with or without cleft palate: identification of sporadic cases with a high level of genetic predisposition.

Previous studies have suggested that asymmetry for certain bilaterally represented features may be an indicator of genetic predisposition to cleft lip with or without cleft palate and may therefore be of value in the individual assessment of recurrence risk, particularly for sporadic cases. An asymmetry score has been devised that may be of use in identifying those with a high level of genetic predisposition. Stepwise logistic regression selected nine variables that together correctly classified 85% of familial cleft patients and unrelated non-cleft controls. Applying the same regression equation to sporadic cases, 26% fell into the range occupied by the majority of familial patients, suggesting that these had a high level of genetic predisposition.

Difficulties in obtaining a sample of young adult cleft lip and palate subjects and their relatives.

Families of individuals aged 15-24 yr born with cleft lip, with or without cleft palate, and suitable control families were required for a study of inherited predisposition to the malformation. Cleft patients were identified through hospital discharge listings, but the overall yield of participating patients was only 8% of the cases listed. An attempt to recruit control subjects by the same method, using patients who had been hospitalized for dissection tonsillectomy, yielded only 4% of those identified as suitable in the discharge listings. The results highlight the value of specialized, regularly updated disease registers in the recruitment of subjects for research purposes.