Mona Seibt Palmér

Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos

The pathogenesis of spontaneous abortion is complex, presumably involving the interaction of several genetic and environmental factors. The methylenetetrahydrofolate reductase (MTHFR) gene C677T and A1298C polymorphisms are commonly associated with defects in folate dependent homocysteine metabolism and have been implicated as risk factors for recurrent embryo loss in early pregnancy. In the present study we have determined the prevalence of combined MTHFR C677T and A1298C polymorphisms in DNA samples from spontaneously aborted embryos (foetal death between sixth and twentieth week after conception) and adult controls using solid-phase minisequencing technique. There was a significant odds ratio of 14.2 (95% CI 1.78-113) in spontaneously aborted embryos comparing the prevalence of one or more 677T and 1298C alleles vs the wild type combined genotype (677CC/1298AA), indicating that the MTHFR polymorphisms may have a major impact on foetal survival. Combined 677CT/1298CC, 677TT/1298AC or 677TT/1298CC genotypes, which contain three or four mutant alleles, were not detected in any of the groups, suggesting complete linkage disequilibrium between the two polymorphisms. The present finding of high prevalence of mutated MTHFR genotypes in spontaneously aborted embryos emphasises the potential protective role of periconceptional folic acid supplementation.

Influence of the apolipoprotein E ε4 allele on human embryonic development

Human apolipoprotein E (apoE) exists in three major isoforms encoded by distinct alleles (APOE epsilon2, epsilon3 and epsilon4) and has important functions in nerve development and repair. Inheritance of the 4 allele is a major risk factor for the development of Alzheimers disease. To investigate the role of APOE polymorphisms in embryonic development, we analyzed the APOE genotypes of 81 spontaneously aborted embryos and 110 adult controls using a solid-phase minisequencing technique. The epsilon4 allele was significantly less frequent in the spontaneous abortion group than in the control group (P=0.009), while the frequency of epsilon3 was significantly increased (P=0.005), suggesting that epsilon4 may have protective effects during embryogenesis. These protective effects might counterbalance the deleterious age-related effects of the epsilon4 allele in natural selection.

The Transcobalamin (TC) Codon 259 Genetic Polymorphism Influences Holo-TC Concentration in Cerebrospinal Fluid from Patients with Alzheimer Disease

Two proteins bind vitamin B12 in plasma: haptocorrin (transcobalamin I) and transcobalamin (transcobalamin II; TC). The latter is the critical transporter that delivers vitamin B12 to peripheral tissues. TC carries one-third of the circulating B12 (holo-TC), but most TC is unsaturated (apo-TC) (1)(2). Polyacrylamide gel electrophoresis has revealed two common TC isotypes, M and X, and two rare variants, S and F (3)(4), that may influence the cellular availability of vitamin B12 (5)(6). The phenotypic variability is a multifactorial phenomenon that probably includes cell-type-specific processing of translated TC (5), but the substitution of proline (P) for arginine (R) at codon 259 of the TC gene is the major determinant of the TC variability, at least in Caucasians (5)(7), and affects TC concentrations in plasma (5)(8). Most 259PP individuals have the TC M phenotype, whereas most 259RR individuals have the X phenotype. Vitamin B12 is essential for the function of the central nervous system (CNS) (9). Little is known about vitamin B12 transport in the human brain, but early in vitro data indicate that TC plays a central role (10). Cerebrospinal fluid (CSF) contains both haptocorrin and TC, with the latter predominating (11). The CSF:plasma ratio of TC is high compared with other plasma proteins (12), which suggests an active transport mechanism or synthesis by cells in the CNS. Cultured astrocytes have been shown to produce and secrete TC in vitro (13), indicating that at least some of the TC in CSF originates from within the CNS. However, because vitamin B12 is not synthesized in human cells, it must enter the brain and CSF from the blood across the blood–brain barrier, conceivably via interaction between holo-TC and the TC receptor. In the present investigation, …

Methylenetetrahydrofolate Reductase Genetic Polymorphisms in Patients with Primary Open-Angle Glaucoma

Purpose: Hyperhomocysteinemia has been found in patients with primary open-angle glaucoma. The purpose of the present study was to determine if hyperhomocysteinemia-associated polymorphisms of the methylenetetrahydrofolate reductase gene (MTHFR) are overrepresented in primary open-angle glaucoma. Methods: Patients with primary open-angle glaucoma (n = 243) and controls (n = 187) were analyzed for the MTHFR 677 C > T and 1298 A > C polymorphisms using minisequencing technique. Results: No significant differences were observed in allele and genotype frequencies of the MTHFR 677C > T and 1298A > C polymorphisms between controls and the primary open-angle glaucoma group. Conclusions: If hyperhomocysteinemia is important in the pathogenesis of glaucoma, this study does not support a role for MTHFR polymorphisms in this context.

The apolipoprotein E polymorphism and the cholesterol-raising effect of coffee

BackgroundThe response of serum cholesterol to diet may be affected by the apolipoprotein E (APOE) ε2/ε3/ε4 polymorphism, which also is a significant predictor of variation in the risk of coronary heart disease (CHD) and CHD death. Here, we test the hypothesis that the APOE polymorphism may modulate the cholesterol-raising effect of coffee.ObjectiveWe determined the effect of a coffee abstention period and a daily intake of 600 mL coffee on serum cholesterol and triglycerides with respect to the APOE polymorphism.Design121 healthy, non-smoking men (22%) and women (78%) aged 29–65 years, took part in a study with four intervention periods: 1 and 3) a coffee free period of three weeks, 2 and 4) 600 mL coffee/day for four weeks.ResultsAPOE ε 2 positive individuals had significantly lower total cholesterol concentration at baseline (4.68 mmol/L and 5.28 mmol/L, respectively, p = 0.01), but the cholesterol-raising effect of coffee was not influenced significantly by APOE allele carrier status.ConclusionsThe APOE ε 2 allele is associated with lower serum cholesterol concentration. However, the APOE polymorphism does not seem to influence the cholesterol-raising effect of coffee.

EPHA2 polymorphisms in Estonian patients with age-related cataract

Abstract Background: Ephrin receptors (Ephs) are tyrosine kinases that together with their ligands, ephrins, are considered important in cell–cell communication, especially during embryogenesis but also for epithelium homeostasis. Studies have demonstrated the involvement of mutations or common variants of the gene encoding Eph receptor A2 (EPHA2), in congenital cataract and in age-related cataract. This study investigated a number of disease-associated single nucleotide polymorphisms (SNPs) in EPHA2 in patients with age-related cataract. Materials and methods: The study included 491 Estonian patients who had surgery for age-related cataract, classified as nuclear, cortical, posterior subcapsular and mixed lens opacities, and 185 controls of the same ethnical origin. Seven SNPs in EPHA2 (rs7543472, rs11260867, rs7548209, rs3768293, rs6603867, rs6678616, rs477558) were genotyped using TaqMan Allelic Discrimination. Statistical analyses for single factor associations used χ2-test and logistic regression was performed including relevant covariates (age, sex and smoking). Results: In single-SNP allele analysis, only the rs7543472 showed a borderline significant association with risk of cataract (p = 0.048). Regression analysis with known risk factors for cataract showed no significant associations of the studied SNPs with cataract. Stratification by cataract subtype did not alter the results. Adjusted odds ratios were between 0.82 and 1.16 (95% confidence interval 0.61–1.60). Conclusions: The present study does not support a major role of EphA2 in cataractogenesis in an Estonian population.

Apolipoprotein E polymorphism in patients with cataract

Based on similarities in epidemiology and biochemistry, it has been suggested that cataract and Alzheimer’s disease (AD) share the same aetiological mechanisms. Comorbidity of cataract and AD in trisomy 21 (Down’s syndrome) is well known1,2 and both diseases are characterised by aggregated proteins exhibiting excessive glycation and racemisation of aspartyl residues.3 Several AD related proteins—amyloid precursor protein (APP), β amyloid (Aβ), and presenilin (PS)—are expressed in the lens4,5 and Aβ is accumulated in the cytosol of lens fibres in cataractous lenses of people with AD.6 Human apolipoprotein E (apoE) exists in three major isoforms encoded by distinct alleles (APOE e2, e3, and e4). The different APOE alleles have been studied in relation to several human age related diseases: inheritance of the e4 allele is a strong risk factor for AD and influences Aβ metabolism.7,8 The purpose of this study was to investigate the APOE e2/e3/e4 polymorphism in patients with cataract. After informed consent, patients with senile cataract …

Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y polymorphism in Alzheimer's disease

Alzheimers disease (AD) is characterized by protein aggregates, i.e. senile plaques and neurofibrillary tangles. The ubiquitin-proteasome system has been proposed a role in proteolytic removal of these protein aggregates. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme with important functions in recycling of ubiquitin. The S18Y polymorphism of the UCHL1 gene confers protection against Parkinsons disease. In this study, the genotype and allele frequencies of the UCHL1 S18Y polymorphism were investigated in 452 AD patients and 234 control subjects, recruited from four memory clinics in Sweden. Using a binary logistic regression model including UCHL1 allele A and APOE ε4 allele positivity, age and sex as covariates with AD diagnosis as dependent variable, an adjusted OR of 0.82 ([95% CI 0.55-1.24], P = 0.35) was obtained for a positive UCHL1 allele A carrier status. The present study thus do not support a protective effect of the UCHL1 S18Y polymorphism against AD.

Ubiquitin Carboxyl-Terminal Esterase L1 (UCHL1) S18Y Polymorphism In Patients With Cataracts

Background: Cataract is characterized by light-scattering protein aggregates. The ubiquitin-proteasome system has been proposed a role in proteolytic removal of these protein aggregates. Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is a de-ubiquitinating enzyme with important functions in recycling of ubiquitin. A protective role of the p.S18Y polymorphism of the UCHL1 gene has been shown in Parkinson`s disease. The current study aimed to examine possible effects on cataract formation. Methods: Patients with cataract (n = 493) and controls (n = 142) were analyzed for the UCHL1 p.S18Y polymorphism using dynamic allele-specific hybridization. Results: Significant differences were observed in allele and genotype frequencies of the p.S18Y polymorphism between controls and cataract patients, where a positive UCHL1 allele A carrier status was associated with the cataract diagnosis (adjusted OR 1.7 [95% CI = 1.1–2.6] p = 0.02). No significant differences were seen in genotype distribution when stratifying for type of cataract. Nor did the mean age at cataract surgery differ between genotypes. Conclusion: The current study does not support a protective role for the UCHL1 S18Y polymorphism in cataract development, but may instead suggest a disease-promoting effect.

Estrogen-related Polymorphisms in Estonian Patients with Age-related Cataract

Department of Clinical Neuroscience and Rehabilitation/Ophthalmology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden, Department of Mathematical Statistics, Institute of Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden, Department of Human Biology and Genetics, Institute of General and Molecular Pathology, University of Tartu, Tartu, Estonia, Department of Clinical Sciences/Ophthalmology, Umeå University, Umeå, Sweden, Department of Medical Chemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden, and UCL Institute of Neurology, Queen Square, London, UK