Variation in the Sodium-Dependent Vitamin C Transporter 2 Gene Is Associated with Risk of Acute Coronary Syndrome among Women

Background

Vitamin C is associated with a lower risk of coronary heart disease possibly due to its anti-oxidative effects, beneficial effects on endothelial function and importance in collagen synthesis. The sodium-dependent vitamin C transporter 2 is responsible for the transport of vitamin C into various cells and malfunction of this protein leads to reduced vitamin C in tissue, including the arterial wall. We tested the hypothesis that candidate variations rs6139591 and rs1776964 in the gene coding for sodium-dependent vitamin C transporter 2 are associated with development of acute coronary syndrome.

Design

In the Danish Diet, Cancer and Health cohort study, we performed a case-cohort study among 57,053 subjects aged 50–64 years.

Results

During a mean follow-up period of 6.4 years, we identified 936 cases and randomly selected a sub-cohort (n = 1,580) with full information on genotypes and covariates. Using Cox proportional hazard models, we found that women with the rs6139591 TT genotype and a lower than median dietary vitamin C intake had a higher risk of acute coronary syndrome compared with those with the CC genotype (adjusted HR 5.39, 95% confidence interval, 2.01–14.50). We also observed a not as strong but positive although inconsistent association for women at a higher than median intake of vitamin C rich food. For the rs1776964 polymorphism, we found a higher risk (adjusted HR 3.45, 95% CI, 1.16–10.28) among TT-homozygous women with higher than median vitamin C intake compared with the CC genotype and low vitamin C intake. Among men, weaker and non-significant associations were observed for both polymorphisms.

Conclusion

Genetic variation in the sodium-dependent vitamin C transporter 2 is associated with risk of incident acute coronary syndrome in women. The genotype effects may not be fully compensated by a higher intake of vitamin C rich food.     

Overweight in Childhood,Adolescence and Adulthood and Cardiovascular Risk in Later Life: Pooled Analysis of Three British Birth Cohorts

Background

Overweight and obesity in adulthood are established risk factors for adverse cardiovascular outcomes, but the contribution of overweight in childhood to later cardiovascular risk is less clear. Evidence for a direct effect of childhood overweight would highlight early life as an important target for cardiovascular disease prevention. The aim of this study was to assess whether overweight and obesity in childhood and adolescence contribute to excess cardiovascular risk in adults.

Methods and findings

Data from three British birth cohorts, born in 1946, 1958 and 1970, were pooled for analysis (n = 11,447). Individuals were categorised, based on body mass index (BMI), as being of normal weight or overweight/obese in childhood, adolescence and adulthood. Eight patterns of overweight were defined according to weight status at these three stages. Logistic regression models were fitted to assess the associations of patterns of overweight with self-reported type 2 diabetes, hypertension, and coronary heart disease (CHD) in adulthood (34–53 years). Compared to cohort members who were never overweight, those who were obese in adulthood had increased risk of all outcomes. For type 2 diabetes, the odds ratio was higher for obese adults who were also overweight or obese in childhood and adolescence (OR 12.6; 95% CI 6.6 to 24.0) than for those who were obese in adulthood only (OR 5.5; 95% CI 3.4 to 8.8). There was no such effect of child or adolescent overweight on hypertension. For CHD, there was weak evidence of increased risk among those with overweight in childhood. The main limitations of this study concern the use of self-reported outcomes and the generalisability of findings to contemporary child populations.

Conclusions

Type 2 diabetes and to a lesser extent CHD risk may be affected by overweight at all stages of life, while hypertension risk is associated more strongly with weight status in adulthood.     

New-Onset Atrial Fibrillation Is a Predictor of Subsequent Hyperthyroidism: A Nationwide Cohort Study

Aims

To examine the long-term risk of hyperthyroidism in patients admitted to hospital with new-onset AF. Hyperthyroidism is a well-known risk factor for atrial fibrillation (AF), but it is unknown whether new-onset AF predicts later-occurring hyperthyroidism.

Methods and Results

All patients admitted with new-onset AF in Denmark from 1997–2009, and their present and subsequent use of anti-thyroid medication was identified by individual-level linkage of nationwide registries. Patients with previous thyroid diagnosis or thyroid medication use were excluded. Development of hyperthyroidism was assessed as initiation of methimazole or propylthiouracil up to a 13-year period. Risk of hyperthyroidism was analysed by Poisson regression models adjusted for important confounders such as amiodarone treatment. Non-AF individuals from the general population served as reference. A total of 145,623 patients with new-onset AF were included (mean age 66.4 years [SD ±13.2] and 55.3% males) of whom 3% (4,620 events; 62.2% women) developed hyperthyroidism in the post-hospitalization period compared to 1% (48,609 events; 82% women) in the general population (n = 3,866,889). In both women and men we found a significantly increased risk of hyperthyroidism associated with new-onset AF compared to individuals in the general population. The highest risk was found in middle-aged men and was consistently increased throughout the 13-year period of observation. The results were confirmed in a substudy analysis of 527,352 patients who had thyroid screening done.

Conclusion

New-onset AF seems to be a predictor of hyperthyroidism. Increased focus on subsequent risk of hyperthyroidism in patients with new-onset AF is warranted.     

Assessment of Health Benefits and Cost-Effectiveness of 10-Valent and 13-Valent Pneumococcal Conjugate Vaccination in Kenyan Children

Background

The GAVI Alliance supported10-valent pneumococcal conjugate vaccine (PCV10) introduction in Kenya. We estimated the cost-effectiveness of introducing either PCV10 or the13-valent vaccine (PCV13) from a societal perspective and explored the incremental impact of including indirect vaccine effects.

Methods

The costs and effects of pneumococcal vaccination among infants born in Kenya in 2010 were assessed using a decision analytic model comparing PCV10 or PCV13, in turn, with no vaccination. Direct vaccine effects were estimated as a reduction in the incidence of pneumococcal meningitis, sepsis, bacteraemic pneumonia and non-bacteraemic pneumonia. Pneumococcal disease incidence was extrapolated from a population-based hospital surveillance system in Kilifi and adjustments were made for variable access to care across Kenya. We used vaccine efficacy estimates from a trial in The Gambia and accounted for serotype distribution in Kilifi. We estimated indirect vaccine protection and serotype replacement by extrapolating from the USA. Multivariable sensitivity analysis was conducted using Monte Carlo simulation. We assumed a vaccine price of US$ 3.50 per dose.

Findings

The annual cost of delivering PCV10 was approximately US$14 million. We projected a 42.7% reduction in pneumococcal disease episodes leading to a US$1.97 million reduction in treatment costs and a 6.1% reduction in childhood mortality annually. In the base case analysis, costs per discounted DALY and per death averted by PCV10, amounted to US$ 59 (95% CI 26–103) and US$ 1,958 (95% CI 866–3,425), respectively. PCV13 introduction improved the cost-effectiveness ratios by approximately 20% and inclusion of indirect effects improved cost-effectiveness ratios by 43–56%. The break-even prices for introduction of PCV10 and PCV13 are US$ 0.41 and 0.51, respectively.

Conclusions

Introducing either PCV10 or PCV13 in Kenya is highly cost-effective from a societal perspective. Indirect effects, if they occur, would significantly improve the cost-effectiveness.     

Is R2* a New MRI Biomarker for the Progression of Parkinson’s Disease? A Longitudinal Follow-Up

Purpose

To study changes of iron content in basal ganglia in Parkinson’s disease (PD) through a three-year longitudinal follow-up of the effective transverse relaxation rate R₂*, a validated MRI marker of brain iron content which can be rapidly measured under clinical conditions.

Methods

Twenty-seven PD patients and 26 controls were investigated by a first MRI (t₀). Longitudinal analysis was conducted among the 18 controls and 14 PD patients who underwent a second MRI (t₁) 3 years after. The imaging protocol consisted in 6 gradient echo images obtained at different echo-times for mapping R₂*. Quantitative exploration of basal ganglia was performed by measuring the variation of R₂* [R₂*(t₁) – R₂*(t₀)] in several regions of interest.

Results

During the three-year evolution of PD, R₂* increased in Substantia nigra (SN) (by 10.2% in pars compacta, p = 0.001, and 8.1% in pars reticulata, p = 0.013) and in the caudal putamen (11.4%, p = 0.011), without significant change in controls. Furthermore, we showed a positive correlation between the variation of R₂* and the worsening of motor symptoms of PD (p = 0.028).

Conclusion

Significant variation of R₂* was longitudinally observed in the SN and caudal putamen of patients with PD evolving over a three-year period, emphasizing its interest as a biomarker of disease progression. Our results suggest that R₂* MRI follow-up could be an interesting tool for individual assessment of neurodegeneration due to PD, and also be useful for testing the efficiency of disease-modifying treatments.     

Genotoxicity, inflammation and physico-chemical properties of fine particle samples from an incineration energy plant and urban air

Airborne particulate matter (PM) was sampled by use of an electrostatic sampler in an oven hall and a receiving hall in a waste-incineration energy plant, and from urban air in a heavy-traffic street and from background air in Copenhagen. PM was sampled for 1-2 weeks, four samples at each site. The samples were extracted and examined for mutagenicity in Salmonella typhimurium strains TA98, YG1041 and YG5161, for content of inorganic elements and for the presence of eight polycyclic aromatic hydrocarbons. The induction of IL-6 and IL-8 mRNA expression and the presence of DNA damage - tested by the comet assay - were determined after 24-h incubations with human A549 lung epithelial cells. The PM(2.5) concentration was about twofold greater in the oven hall than in the receiving hall. The particle size distribution in the receiving hall was similar to that in street air (maximum mode at about 25nm), but the distribution was completely different in the oven hall (maximum mode at about 150nm). Also chemically, the samples from the oven hall were highly different from the other samples. PM extracts from the receiving hall, street and background air were more mutagenic than the PM extracts from the oven hall. PM from all four sites caused similar levels of DNA damage in A549 cells; only the oven hall samples gave results that were statistically significantly different from those obtained with street-air samples. The receiving hall and the urban air samples were similarly inflammatory (relative IL-8 mRNA expression), whereas the oven hall did not cause a statistically significant increase in IL-8 mRNA expression. A principal component analysis separated the oven hall and the receiving hall by the first principal component. These two sites were separated from street and background air with the second principal component. Several clusters of constituents were identified. One cluster consisted of all the polycyclic aromatic hydrocarbons (PAH), several groups of metals and one group of the biological endpoints (DNA damage, IL-6 and IL-8 mRNA expression). The PAH and the inorganic content of the air in the receiving hall may be due to vehicle emissions and suspended waste particles. The inorganic content in the street and background air may have been influenced by break wear, road emissions and long-range transport. The results from a partial least-square regression analysis predicted that both PAHs and a group of metals including Fe and Mn contributed to IL-6 and IL-8 induction. Only Mn and Sr were predicted to influence DNA damage statistically significantly. Among the PAHs only chrysene had influence on DNA damage. The PM from the oven hall was markedly different from the PM at other locations in particle size distribution, chemical composition and the resulting biological effects when A549 cells were incubated with the PM. These characteristics and observations in the oven hall indicated that the PM source was oven exhaust, which was well combusted.     

XPA A23G, XPC Lys939Gln, XPD Lys751Gln and XPD Asp312Asn polymorphisms, interactions with smoking, alcohol and dietary factors, and risk of colorectal cancer

Polymorphisms in the XPD and the XPC gene have been associated with a lower DNA repair capacity. We determined the risk of colorectal cancer in association with the four polymorphisms XPA A23G, XPC Lys939Gln, XPD Lys751Gln and XPD Asp312Asn, and interactions between the polymorphisms and the environmental factors: smoking intensity, intake of alcohol, red meat, processed meat, fish and poultry, fruits and vegetables and dietary fibres, in relation to development of colorectal cancer in a study population of 405 colorectal cancer cases and a comparison group of 810 persons, nested within the Danish prospective cohort, Diet, Cancer and Health, of 57053 cohort members. No association was found between the XPC Lys939Gln, XPA A23G, XPD Lys751Gln, and XPD Asp312Asn polymorphisms and risk of colorectal cancer. The association of the XPD Lys751Gln polymorphism was statistically significantly different between genders, with a lower risk of colorectal cancer among women carrying the variant allele. We observed a statistically significant interaction between the XPC Lys939Gln polymorphism and consumption of red meat, with a 3.7-fold increase in colorectal cancer risk per 100g red meat intake per day among carriers of the homozygous variant, but virtually no effect of red meat intake among carriers of the wild type allele. In the light of the multiple comparisons being made, this result may be a chance finding. The results showed no interaction between the XPD Lys751Gln, XPA A23G, and XPD Asp312Asn polymorphisms and the environmental factors for the development of colorectal cancer. Overall, the results of the present study indicate that the four polymorphisms are not of major importance in colorectal cancer carcinogenesis.     

Novel route for elimination of brain oxysterols across the blood-brain barrier: conversion into 7alpha-hydroxy-3-oxo-4-cholestenoic acid

Recently, we demonstrated a net blood-to-brain passage of the oxysterol 27-hydroxycholesterol corresponding to 4-5 mg/day. As the steady-state levels of this sterol are only 1-2 mug/g brain tissue, we hypothesized that it is metabolized and subsequently eliminated from the brain. To explore this concept, we first measured the capacity of in vitro systems representing the major cell populations found in the brain to metabolize 27-hydroxycholesterol. We show here that 27-hydroxycholesterol is metabolized into the known C(27) steroidal acid 7alpha-hydroxy-3-oxo-4-cholestenoic acid by neuronal cell models only. Using an in vitro model of the blood-brain barrier, we demonstrate that 7alpha-hydroxy-3-oxo-4-cholestenoic acid is efficiently transferred across monolayers of primary brain microvascular endothelial cells. Finally, we measured the concentration of 7alpha-hydroxy-3-oxo-4-cholestenoic acid in plasma from the internal jugular vein and brachial artery of healthy volunteers. Calculation of the arteriovenous concentration difference revealed a significant in vivo flux of this steroid from the brain into the circulation in human. Together, these studies identify a novel metabolic route for the elimination of 27-hydroxylated sterols from the brain. Given the emerging connections between cholesterol and neurodegeneration, this pathway may be of importance for the development of these conditions.     

The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter

The late-infantile-onset forms are the most genetically heterogeneous group among the autosomal recessively inherited neurodegenerative disorders, the neuronal ceroid lipofuscinoses (NCLs). The Turkish variant was initially considered to be a distinct genetic entity, with clinical presentation similar to that of other forms of late-infantile-onset NCL (LINCL), including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death. However, Turkish variant LINCL was recently found to be genetically heterogeneous, because mutations in two genes, CLN6 and CLN8, were identified to underlie the disease phenotype in a subset of patients. After a genomewide scan with single-nucleotide-polymorphism markers and homozygosity mapping in nine Turkish families and one Indian family, not linked to any of the known NCL loci, we mapped a novel variant LINCL locus to chromosome 4q28.1-q28.2 in five families. We identified six different mutations in the MFSD8 gene (previously denoted "MGC33302"), which encodes a novel polytopic 518-amino acid membrane protein that belongs to the major facilitator superfamily of transporter proteins. MFSD8 is expressed ubiquitously, with several alternatively spliced variants. Like the majority of the previously identified NCL proteins, MFSD8 localizes mainly to the lysosomal compartment. However, the function of MFSD8 remains to be elucidated. Analysis of the genome-scan data suggests the existence of at least three more genes in the remaining five families, further corroborating the great genetic heterogeneity of LINCLs.     

Unwinding fibril formation of medin, the peptide of the most common form of human amyloid

Medin amyloid affects the medial layer of the thoracic aorta of most people above 50 years of age. The consequences of this amyloid are not completely known but the deposits may contribute to diseases such as thoracic aortic aneurysm and dissection or to the general diminished elasticity of blood vessels seen in elderly people. We show that the 50-amino acid residue peptide medin forms amyloid-like fibrils in vitro. With the use of Congo red staining, Thioflavin T fluorescence, electron microscopy, and a solid-phase binding assay on different synthetic peptides, we identified the last 18-19 amino acid residues to constitute the amyloid-promoting region of medin. We also demonstrate that the two C-terminal phenylalanines, previously suggested to be of importance for amyloid formation, are not required for medin amyloid formation.