The D9N, N291S and S447X variants in the lipoprotein lipase (LPL) gene are not associated with Type III Hyperlipidemia

<p>Abstract</p> <p>Background</p> <p>Type III hyperlipidemia (Type III HLP) is associated with homozygosity for the ε2 allele of the APOE gene. However only about 10% of ε2 homozygotes develop Type III HLP and it is assumed that additional genetic and/or environmental factors are required for its development. Common variants in the LPL gene have been proposed as likely genetic co-factors.</p> <p>Methods</p> <p>The frequency of the LPL SNPs D9N, N291S and S447X in 100 patients with hyperlipidemia and APOE2/2 genotype has been determined and compared to that in healthy blood donors and patients with hyperlipidemia.</p> <p>Results</p> <p>There were no statistically significant difference in the frequencies of the variants between APOE2/2 patients and controls.</p> <p>Conclusion</p> <p>It is unlikely that the D9N, N291S or S447X variants in the LPL gene play an important role in the development of Type III HLP.</p

TP73 allelic expression in human brain and allele frequencies in Alzheimer's disease

BACKGROUND: The p73 protein, a paralogue of the p53 tumor suppressor, is essential for normal development and survival of neurons. TP73 is therefore of interest as a candidate gene for Alzheimer's disease (AD) susceptibility. TP73 mRNA is transcribed from three promoters, termed P1 – P3, and there is evidence for an additional complexity in its regulation, namely, a variable allelic expression bias in some human tissues. METHODS: We utilized RT-PCR/RFLP and direct cDNA sequencing to measure allele-specific expression of TP73 mRNA, SNP genotyping to assess genetic associations with AD, and promoter-reporter assays to assess allele-specific TP73 promoter activity. RESULTS: Using a coding-neutral BanI polymorphism in TP73 exon 5 as an allelic marker, we found a pronounced allelic expression bias in one adult brain hippocampus, while 3 other brains (two adult; one fetal) showed approximately equal expression from both alleles. In a tri-ethnic elderly population of African-Americans, Caribbean Hispanics and Caucasians, a G/A single nucleotide polymorphism (SNP) at -386 in the TP73 P3 promoter was weakly but significantly associated with AD (crude O.R. for AD given any -386G allele 1.7; C.I. 1.2–2.5; after adjusting for age and education O.R. 1.5; C.I. 1.1–2.3, N= 1191). The frequency of the -386G allele varied by ethnicity and was highest in African-Americans and lowest in Caucasians. No significant differences in basal P3 promoter activity were detected comparing -386G vs. -386A promoter-luciferase constructs in human SK-NSH-N neuroblastoma cells. CONCLUSIONS: There is a reproducible allelic expression bias in mRNA expression from the TP73 gene in some, though not all, adult human brains, and inter-individual variation in regulatory sequences of the TP73 locus may affect susceptibility to AD. However, additional studies will be necessary to exclude genetic admixture as an alternative explanation for the observed associations

Genome-Wide Association Analysis of Incident Coronary Heart Disease (CHD) in African Americans: A Short Report

African Americans have the highest rate of mortality due to coronary heart disease (CHD). Although multiple loci have been identified influencing CHD risk in European-Americans using a genome-wide association (GWAS) approach, no GWAS of incident CHD has been reported for African Americans. We performed a GWAS for incident CHD events collected during 19 years of follow-up in 2,905 African Americans from the Atherosclerosis Risk in Communities (ARIC) study. We identified a genome-wide significant SNP (rs1859023, MAF = 31%) located at 7q21 near the PFTK1 gene (HR = 0.57, 95% CI 0.46 to 0.69, p = 1.86×10−08), which replicated in an independent sample of over 8,000 African American women from the Women's Health Initiative (WHI) (HR = 0.81, 95% CI 0.70 to 0.93, p = 0.005). PFTK1 encodes a serine/threonine-protein kinase, PFTAIRE-1, that acts as a cyclin-dependent kinase regulating cell cycle progression and cell proliferation. This is the first finding of incident CHD locus identified by GWAS in African Americans

Apolipoprotein E gene polymorphism is not a strong risk factor for diabetic nephropathy and retinopathy in Type I diabetes: case-control study

BACKGROUND: The gene encoding apolipoprotein E (APOE) has been proposed as a candidate gene for vascular complications in Type I diabetes. This study aimed to investigate the influence of three-allelic variations in the APOE gene for the development of diabetic retinopathy and nephropathy. RESULTS: Neither APOE alleles frequencies or APOE genotypes frequencies differed between Type I diabetic groups either with or without nephropathy. Similar results were found for patients with and without diabetic retinopathy. CONCLUSIONS: APOE gene polymorphism does not determine genetic susceptibility for the development of diabetic retinopathy in Type I diabetes patients. Association between APOE gene polymorphism and diabetic nephropathy may be weak or moderate, but not strong

The importance of plasma apolipoprotein E concentration in addition to its common polymorphism on inter-individual variation in lipid levels: results from Apo Europe

The ApoEurope group, collaborating centres, and their associated investigators: Portugal: Unidade de Química Clínica, Instituto Nacional de Saúde, Lisboa: Maria do Carmo Martins, Maria Odete Rodrigues, Maria Isabel Albergaria, Maria Liseta AlpendreInterindividual variation in the concentration of plasma lipids which are associated with coronary artery disease (CAD) risk is determined by a combination of genetic and environmental factors. This study investigates the effects of apoE genotype and plasma concentration on cholesterol and triglycerides (TG) levels in subjects from five countries: Finland, France, Northern Ireland, Portugal, and Spain. Age and sex significantly influenced serum cholesterol, TG and apoE concentrations. The age effect differs in males and females. The allele frequencies of the apoE gene, one of the most widely studied CAD susceptibility genes, were determined: the epsilon2 allele frequency and the apoE concentration showed a north-south increasing gradient while the epsilon4 allele frequency showed the reverse. ApoE plays an important role in lipid metabolism. Total cholesterol and TG concentrations were significantly dependent on apoE genotype in both sexes. These differences in lipids between genotypes were more pronounced when plasma apoE concentrations were taken into account

Birth weight and blood lipid levels in Spanish adolescents: Influence of selected APOE, APOC3 and PPARgamma2 gene polymorphisms. The AVENA Study

Background There is increasing evidence indicating that genes involved in certain metabolic processes of cardiovascular diseases may be of particular influence in people with low body weight at birth. We examined whether the apolipoprotein (APO) E, APOC3 and the peroxisome proliferator-activated receptor-γ-2 (PPARγ2) polymorphisms influence the association between low birth weight and blood lipid levels in healthy adolescents aged 13–18.5 years. Methods A cross-sectional study of 502 Spanish adolescents born at term was conducted. Total (TC) and high density lipoprotein cholesterol (HDLc), triglycerides (TG), apolipoprotein (apo) A and B, and lipoprotein(a) [Lp(a)] were measured. Low density lipoprotein cholesterol (LDLc), TC-HDLc, TC/HDLc and apoB/apoA were calculated. Results Low birth weight was associated with higher levels of TC, LDLc, apoB, Lp(a), TC-HDLc, TC/HDLc and apoB/apoA in males with the APOE ε3ε4 genotype, whereas in females, it was associated with lower HDLc and higher TG levels. In males with the APOC3 S1/S2 genotype, low birth weight was associated with lower apoA and higher Lp(a), yet this association was not observed in females. There were no associations between low birth weight and blood lipids in any of the PPARγ2 genotypes. Conclusion The results indicate that low birth weight has a deleterious influence on lipid profile particularly in adolescents with the APOE ε3/ε4 genotype. These findings suggest that intrauterine environment interact with the genetic background affecting the lipid profile in later life.The AVENA study was supported by the Spanish Ministry of Health Instituto de Salud Carlos III (FIS PI021830), the Spanish Ministry of Health, FEDER-FSE funds FIS n° 00/0015, CSD grants 05/UPB32/0, 109/UPB31/03 and 13/UPB20/04, the Spanish Ministry of Education (AP-2004-2745; EX-2007-1124), scholarships from Panrico S.A., Madaus S.A. and Procter and Gamble S.A

Cerebrospinal Fluid Concentration of Brain-Derived Neurotrophic Factor and Cognitive Function in Non-Demented Subjects

Brain-derived neurotrophic factor (BDNF) is an activity-dependent secreted protein that is critical to organization of neuronal networks and synaptic plasticity, especially in the hippocampus. We tested hypothesis that reduced CSF BDNF is associated with age-related cognitive decline.CSF concentration of BDNF, Abeta(42) and total tau were measured in 128 cognitively normal adults (Normals), 21 patients with Alzheimer's disease (AD), and nine patients with Mild Cognitive Impairment. Apolipoprotein E and BDNF SNP rs6265 genotype were determined. Neuropsychological tests were performed at baseline for all subjects and at follow-up visits in 50 Normals. CSF BDNF level was lower in AD patients compared to age-matched Normals (p = 0.02). CSF BDNF concentration decreased with age among Normals and was higher in women than men (both p<0.001). After adjusting for age, gender, education, CSF Abeta(42) and total tau, and APOE and BDNF genotypes, lower CSF BDNF concentration was associated poorer immediate and delayed recall at baseline (both p<0.05) and in follow up of approximately 3 years duration (both p<0.01).Reduced CSF BDNF was associated with age-related cognitive decline, suggesting a potential mechanism that may contribute in part to cognitive decline in older individuals

Chapter 11: Challenges in and Principles for Conducting Systematic Reviews of Genetic Tests used as Predictive Indicators

In this paper, we discuss common challenges in and principles for conducting systematic reviews of genetic tests. The types of genetic tests discussed are those used to 1). determine risk or susceptibility in asymptomatic individuals; 2). reveal prognostic information to guide clinical management in those with a condition; or 3). predict response to treatments or environmental factors. This paper is not intended to provide comprehensive guidance on evaluating all genetic tests. Rather, it focuses on issues that have been of particular concern to analysts and stakeholders and on areas that are of particular relevance for the evaluation of studies of genetic tests. The key points include:The general principles that apply in evaluating genetic tests are similar to those for other prognostic or predictive tests, but there are differences in how the principles need to be applied or the degree to which certain issues are relevant.A clear definition of the clinical scenario and an analytic framework is important when evaluating any test, including genetic tests.Organizing frameworks and analytic frameworks are useful constructs for approaching the evaluation of genetic tests.In constructing an analytic framework for evaluating a genetic test, analysts should consider preanalytic, analytic, and postanalytic factors; such factors are useful when assessing analytic validity.Predictive genetic tests are generally characterized by a delayed time between testing and clinically important events.Finding published information on the analytic validity of some genetic tests may be difficult. Web sites (FDA or diagnostic companies) and gray literature may be important sources.In situations where clinical factors associated with risk are well characterized, comparative effectiveness reviews should assess the added value of using genetic testing along with known factors compared with using the known factors alone.For genome-wide association studies, reviewers should determine whether the association has been validated in multiple studies to minimize both potential confounding and publication bias. In addition, reviewers should note whether appropriate adjustments for multiple comparisons were used

The association of APOE genotype and cognitive decline in interaction with risk factors in a 65–69 year old community sample

<p>Abstract</p> <p>Background</p> <p>While the evidence of an association between the apolipoprotein E (<it>APOE</it>) <it>*E4 </it>allele and Alzheimer's disease is very strong, the effect of the <it>*E4 </it>allele on cognitive decline in the general population is more equivocal. A cross-sectional study on the lifespan effects of the <it>*E4 </it>allele <abbrgrp><abbr bid="B1">1</abbr></abbrgrp> failed to find any effect of the <it>*E4 </it>allele on cognitive performance at ages 20–24, 40–44 or 60–64 years.</p> <p>Methods</p> <p>In this four year follow-up study, we reexamine the effect of <it>*E4 </it>in the sample of 2,021 individuals, now aged 65–69 years.</p> <p>Results</p> <p>Performance on the Mini-Mental State Examination (MMSE) was significantly poorer for <it>*E4 </it>homozygotes than heterozygotes or non-carriers. The effects of the <it>*E4 </it>genotype on cognitive decline over four years were found on the MMSE and Symbol-Digit Modalities test but only when controlling for risk factors such as head injury and education. Analyses were repeated with the exclusion of participants diagnosed with a mild cognitive disorder, with little change.</p> <p>Conclusion</p> <p>It is possible that <it>*E4 </it>carriers become vulnerable to greater cognitive decline in the presence of other risk factors at 65–69 years of age.</p