9 research outputs found
Vitamin B-12 deficiency stimulates osteoclastogenesis via increased homocysteine and methylmalonic acid
No full textThe risk of nutrient deficiencies increases with age in our modern Western society, and vitamin B(12) deficiency is especially prevalent in the elderly and causes increased homocysteine (Hcy) and methylmalonic acid (MMA) levels. These three factors have been recognized as risk factors for reduced bone mineral density and increased fracture risk, though mechanistic evidence is still lacking. In the present study, we investigated the influence of B(12), Hcy, and MMA on differentiation and activity of bone cells. B(12) deficiency did not affect the onset of osteoblast differentiation, maturation, matrix mineralization, or adipocyte differentiation from human mesenchymal stem cells (hMSCs). B(12) deficiency caused an increase in the secretion of Hcy and MMA into the culture medium by osteoblasts, but Hcy and MMA appeared to have no effect on hMSC osteoblast differentiation. We further studied the effect of B(12), Hcy, and MMA on the formation of multinucleated tartrate-resistant acid phosphatase-positive osteoclasts from mouse bone marrow. We observed that B(12) did not show an effect on osteoclastogenesis. However, Hcy as well as MMA were found to induce osteoclastogenesis in a dose-dependent manner. On the basis of these results, we conclude that B(12) deficiency may lead to decreased bone mass by increased osteoclast formation due to increased MMA and Hcy levels
Folic acid and reduction of plasma homocysteine concentrations in older adults: a dose-response study.
No full textBACKGROUND: Elevated homocysteine concentrations, a likely risk factor for cardiovascular disease, can be lowered effectively with folic acid. The minimum dose of folic acid required for maximal reduction of homocysteine concentrations is not yet known reliably. OBJECTIVE: We aimed to determine the lowest folic acid dose that decreases plasma homocysteine concentrations adequately in healthy older adults. DESIGN: A dose-response trial with a randomized, double-blind, parallel-group, placebo-controlled design was carried out among 316 Dutch men and women aged 50-75 y. Subjects received daily for 12 wk either a placebo or 1 of the 6 following folic acid doses: 50, 100, 200, 400, 600, or 800 micro g. The relative changes in plasma homocysteine concentration in response to increasing doses of folic acid were used to calculate the dose-response curve. An adequate dose of folic acid was defined as the dose that induced >or= 90% of the maximal reduction in homocysteine concentration. RESULTS: The relative decrease in plasma homocysteine concentration was associated exponentially with increasing doses of folic acid. From the dose-response curve, the adequate daily dose of folic acid was estimated to be 392 micro g, which decreased plasma homocysteine concentrations 22%. CONCLUSION: In older adults, daily supplementation with folic acid effectively lowers plasma homocysteine concentrations, and a daily dose of approximately 400 micro g is the minimum dose required for adequate homocysteine reduction
The long-term effectiveness of efavirenz-based combination antiretroviral therapy, the impact of pharmacogenomics and pharmacokinetic interaction of artemisinin-based antimalarial therapy on efavirenz exposure among Ghanaian HIV-infected patients
No full textDr. Fred Stephen Sarfo, The long-term effectiveness of efavirenz-based combination antiretroviral therapy, the impact of pharmacogenomics and pharmacokinetic interaction of artemisinin-based antimalarial therapy on efavirenz exposure among Ghanaian HIV-infected patients. PhD dissertation, Durham University, January 2013.
Introduction: In sub-Saharan Africa, HIV treatment is initiated with combination of antiretroviral medications comprising of a backbone of either stavudine or zidovudine plus lamivudine with a non-nucleoside reverse transcriptase inhibitor of either efavirenz or nevirapine. Efavirenz is highly efficacious, durable and well tolerated. The risk for toxicity of efavirenz is determined by several factors including single nucleotide polymorphisms in the hepatic enzymes responsible for its metabolism and concurrently administered medications such as antimalarials, which share common metabolic pathways. The aims of this dissertation are to assess the long-term effectiveness of efavirenz-based antiretroviral therapy and the impact of pharmogenomics and pharmacokinetic interactions of artemisinin-based antimalarial therapy on efavirenz exposure among Ghanaian HIV-infected patients.
Methods: The effectiveness of efavirenz- compared with nevirapine-based antiretroviral therapy was assessed retrospectively in nearly 4000 patients starting treatment between 2004 and 2010. The main outcome measure was a composite of toxicity, disease progression and attrition, and CD4 count changes. A prospective pharmacokinetic study of artesunate and efavirenz was conducted among 22 HIV-infected and 21 controls. Plasma efavirenz and artesunate/ dihydroartemisinin concentrations were measured using validated and standardised methods. Genotyping for single nucleotide polymorphisms in CYP2B6 G516T, T983C; CYP2A6*9B, UGT2B7*735 and *802 as well as CAR rs2307424 were performed for 800 patients with real-time polymerase chain reaction with allelic discrimination.
Results: Antiretroviral therapy was associated with robust CD4 increases. Efavirenz was comparable with nevirapine in composite outcomes but better tolerated. Artesunate was well tolerated when administered to HIV-infected patients on efavirenz. Single nucleotide polymorphisms in the CYP2B6 G516T and T983C were associated with increased plasma efavirenz concentrations.
Conclusions/Recommendation: Among this Ghanaian cohort, both efavirenz and nevirapine-based antiretroviral therapy were effective. The better tolerability of efavirenz compared with nevirapine means it can be safely used as the preferred first line non-nucleoside reverse transcriptase inhibitor in sub-Saharan Africa
Defining the role of common variation in the genomic and biological architecture of adult human height.
No full textDefining the role of common variation in the genomic and biological architecture of adult human height.
No full textUsing genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants
Biological interpretation of genome-wide association studies using predicted gene functions
No full textThe main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes.</p
New genetic loci link adipose and insulin biology to body fat distribution
No full textBody fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.</p
Defining the role of common variation in the genomic and biological architecture of adult human height.
No full textUsing genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants
New genetic loci link adipose and insulin biology to body fat distribution
No full textBody fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms
