RESUMEN
Recent breakthroughs in human genetics and in information technologies have markedly expanded our understanding at the molecular level of the response to drugs, i.e., pharmacogenetics (PGx), across therapy areas. This review is restricted to PGx for cardiovascular (CV) drugs. First, we examined the PGx information in the labels approved by regulatory agencies in Europe, Japan, and North America and related recommendations from expert panels. Out of 221 marketed CV drugs, 36 had PGx information in their labels approved by one or more agencies. The level of annotations and recommendations varied markedly between agencies and expert panels. Clopidogrel is the only CV drug with consistent PGx recommendation (i.e., "actionable"). This situation prompted us to dissect the steps from discovery of a PGx association to clinical translation. We found 101 genome-wide association studies that investigated the response to CV drugs or drug classes. These studies reported significant associations for 48 PGx traits mapping to 306 genes. Six of these 306 genes are mentioned in the corresponding PGx labels or recommendations for CV drugs. Genomic analyses also highlighted the wide between-population differences in risk allele frequencies and the individual load of actionable PGx variants. Given the high attrition rate and the long road to clinical translation, additional work is warranted to identify and validate PGx variants for more CV drugs across diverse populations and to demonstrate the utility of PGx testing. To that end, pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond. SIGNIFICANCE STATEMENT: Despite spectacular breakthroughs in human molecular genetics and information technologies, consistent evidence supporting PGx testing in the cardiovascular area is limited to a few drugs. Additional work is warranted to discover and validate new PGx markers and demonstrate their utility. Pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond.
Asunto(s)
Fármacos Cardiovasculares , Enfermedades Cardiovasculares , Estudio de Asociación del Genoma Completo , Farmacogenética , Humanos , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/genética , Farmacogenética/métodos , Fármacos Cardiovasculares/uso terapéutico , Fármacos Cardiovasculares/farmacología , Estudio de Asociación del Genoma Completo/métodosRESUMEN
Whole genome sequencing (WGS) at high-depth (30X) allows the accurate discovery of variants in the coding and non-coding DNA regions and helps elucidate the genetic underpinnings of human health and diseases. Yet, due to the prohibitive cost of high-depth WGS, most large-scale genetic association studies use genotyping arrays or high-depth whole exome sequencing (WES). Here we propose a cost-effective method which we call "Whole Exome Genome Sequencing" (WEGS), that combines low-depth WGS and high-depth WES with up to 8 samples pooled and sequenced simultaneously (multiplexed). We experimentally assess the performance of WEGS with four different depth of coverage and sample multiplexing configurations. We show that the optimal WEGS configurations are 1.7-2.0 times cheaper than standard WES (no-plexing), 1.8-2.1 times cheaper than high-depth WGS, reach similar recall and precision rates in detecting coding variants as WES, and capture more population-specific variants in the rest of the genome that are difficult to recover when using genotype imputation methods. We apply WEGS to 862 patients with peripheral artery disease and show that it directly assesses more known disease-associated variants than a typical genotyping array and thousands of non-imputable variants per disease-associated locus.
RESUMEN
BACKGROUND: Twin studies show moderate heritability of sleep traits: 40% for insomnia symptoms and 46% for sleep duration. Genome-wide association studies (GWAS) have identified genetic variants involved in insomnia and sleep duration in adults, but it is unknown whether these variants affect sleep during early development. We assessed whether polygenic risk scores for insomnia (PRS-I) and sleep duration (PRS-SD) affect sleep throughout early childhood to adolescence. METHODS: We included 2,458 children of European ancestry (51% girls). Insomnia-related items of the Child Behavior Checklist were reported by mothers at child's age 1.5, 3, and 6 years. At 10-15 years, the Sleep Disturbance Scale for Children and actigraphy were assessed in a subsample (N = 975). Standardized PRS-I and PRS-SD (higher scores indicate genetic susceptibility for insomnia and longer sleep duration, respectively) were computed at multiple p-value thresholds based on largest GWAS to date. RESULTS: Children with higher PRS-I had more insomnia-related sleep problems between 1.5 and 15 years (BPRS-I < 0.001 = .09, 95% CI: 0.05; 0.14). PRS-SD was not associated with mother-reported sleep problems. A higher PRS-SD was in turn associated with longer actigraphically estimated sleep duration (BPRS-SD < 5e08 = .05, 95% CI: 0.001; 0.09) and more wake after sleep onset (BPRS-SD < 0.005 = .25, 95% CI: 0.04; 0.47) at 10-15 years, but these associations did not survive multiple testing correction. CONCLUSIONS: Children who are genetically predisposed to insomnia have more insomnia-like sleep problems, whereas those who are genetically predisposed to longer sleep have longer sleep duration, but are also more awake during the night in adolescence. This indicates that polygenic risk for sleep traits, based on GWAS in adults, affects sleep already in children.
Asunto(s)
Trastornos del Inicio y del Mantenimiento del Sueño , Trastornos del Sueño-Vigilia , Adulto , Niño , Femenino , Adolescente , Humanos , Preescolar , Masculino , Estudio de Asociación del Genoma Completo , Sueño/genética , Predisposición Genética a la EnfermedadRESUMEN
A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.
Asunto(s)
Estudio de Asociación del Genoma Completo , Placenta , Femenino , Humanos , Embarazo , Peso al Nacer/genética , Desarrollo Fetal/genética , Insulina , Placenta/metabolismo , MasculinoRESUMEN
Osteoporosis is a multifactorial disease influenced by genetic and environmental factors, which contributes to an increased risk of bone fracture, but early diagnosis of this disease cannot be achieved using current techniques. We describe a generic platform for the targeted electrochemical genotyping of SNPs identified by genome-wide association studies to be associated with a genetic predisposition to osteoporosis. The platform exploits isothermal solid-phase primer elongation with ferrocene-labeled nucleoside triphosphates. Thiolated reverse primers designed for each SNP were immobilized on individual gold electrodes of an array. These primers are designed to hybridize to the SNP site at their 3'OH terminal, and primer elongation occurs only where there is 100% complementarity, facilitating the identification and heterozygosity of each SNP under interrogation. The platform was applied to real blood samples, which were thermally lysed and directly used without the need for DNA extraction or purification. The results were validated using Taqman SNP genotyping assays and Sanger sequencing. The assay is complete in just 15 min with a total cost of 0.3 per electrode. The platform is completely generic and has immense potential for deployment at the point of need in an automated device for targeted SNP genotyping with the only required end-user intervention being sample addition.
RESUMEN
The substantial investments in human genetics and genomics made over the past three decades were anticipated to result in many innovative therapies. Here we investigate the extent to which these expectations have been met, excluding cancer treatments. In our search, we identified 40 germline genetic observations that led directly to new targets and subsequently to novel approved therapies for 36 rare and 4 common conditions. The median time between genetic target discovery and drug approval was 25 years. Most of the genetically driven therapies for rare diseases compensate for disease-causing loss-of-function mutations. The therapies approved for common conditions are all inhibitors designed to pharmacologically mimic the natural, disease-protective effects of rare loss-of-function variants. Large biobank-based genetic studies have the power to identify and validate a large number of new drug targets. Genetics can also assist in the clinical development phase of drugs-for example, by selecting individuals who are most likely to respond to investigational therapies. This approach to drug development requires investments into large, diverse cohorts of deeply phenotyped individuals with appropriate consent for genetically assisted trials. A robust framework that facilitates responsible, sustainable benefit sharing will be required to capture the full potential of human genetics and genomics and bring effective and safe innovative therapies to patients quickly.
Asunto(s)
Desarrollo de Medicamentos , Genética Humana , Terapia Molecular Dirigida , Humanos , Aprobación de Drogas/estadística & datos numéricos , Desarrollo de Medicamentos/estadística & datos numéricos , Terapias en Investigación/estadística & datos numéricos , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/estadística & datos numéricos , Enfermedades Raras/genética , Enfermedades Raras/terapia , Mutación de Línea Germinal , Factores de TiempoRESUMEN
Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases.
Asunto(s)
Densidad Ósea , Craneosinostosis , Animales , Densidad Ósea/genética , Estudio de Asociación del Genoma Completo , Pez Cebra/genética , Cráneo , Craneosinostosis/genética , Factores de Transcripción/genéticaRESUMEN
BACKGROUND AND OBJECTIVES: Low bone mineral density (BMD) and dementia commonly co-occur in older individuals, with bone loss accelerating in patients with dementia due to physical inactivity and poor nutrition. However, uncertainty persists over the extent to which bone loss already exists before onset of dementia. Therefore, we investigated how dementia risk was affected by BMD at various skeletal regions in community-dwelling older adults. METHODS: In a prospective population-based cohort study, BMD at the femoral neck, lumbar spine, and total body and the trabecular bone score (TBS) were obtained using dual-energy X-ray absorptiometry in 3,651 participants free from dementia between 2002 and 2005. Persons at risk of dementia were followed up until January 1, 2020. For analyses of the association between BMD at baseline and the risk of incident dementia, we used Cox proportional hazards regression analyses, adjusting for age, sex, educational attainment, physical activity, smoking status, body mass index, systolic and diastolic blood pressure, cholesterol level, high-density lipoprotein cholesterol, history of comorbidities (stroke and diabetes mellitus), and APOE genotype. RESULTS: Among the 3,651 participants (median age 72.3 ± 10.0 years, 57.9% women), 688 (18.8%) developed incident dementia during a median of 11.1 years, of whom 528 (76.7%) developed Alzheimer disease (AD). During the whole follow-up period, participants with lower BMD at the femoral neck (per SD decrease) were more likely to develop all-cause dementia (hazard ratio [HR] total follow-up 1.12, 95% CI 1.02-1.23) and AD (HRtotal follow-up 1.14, 95% CI 1.02-1.28). Within the first 10 years after baseline, the risk of dementia was greatest for groups with the lowest tertile of BMD (femoral neck BMD, HR0-10 years 2.03; 95% CI 1.39-2.96; total body BMD, HR0-10 years 1.42; 95% CI 1.01-2.02; and TBS, HR0-10 years 1.59; 95% CI 1.11-2.28). DISCUSSION: In conclusion, participants with low femoral neck and total body BMD and low TBS were more likely to develop dementia. Further studies should focus on the predictive ability of BMD for dementia.
Asunto(s)
Enfermedades Óseas Metabólicas , Demencia , Humanos , Femenino , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Masculino , Densidad Ósea/fisiología , Estudios de Cohortes , Estudios Prospectivos , Absorciometría de Fotón , Vértebras Lumbares , Colesterol , Demencia/diagnóstico por imagen , Demencia/epidemiologíaRESUMEN
BACKGROUND: Looking older for one's chronological age is associated with a higher mortality rate. Yet it remains unclear how perceived facial age relates to morbidity and the degree to which facial ageing reflects systemic ageing of the human body. OBJECTIVES: To investigate the association between ΔPA and age-related morbidities of different organ systems, where ΔPA represents the difference between perceived age (PA) and chronological age. METHODS: We performed a cross-sectional analysis on data from the Rotterdam Study, a population-based cohort study in the Netherlands. High-resolution facial photographs of 2679 men and women aged 51.5-87.8â years of European descent were used to assess PA. PA was estimated and scored in 5-year categories using these photographs by a panel of men and women who were blinded for chronological age and medical history. A linear mixed model was used to generate the mean PAs. The difference between the mean PA and chronological age was calculated (ΔPA), where a higher (positive) ΔPA means that the person looks younger for their age and a lower (negative) ΔPA that the person looks older. ΔPA was tested as a continuous variable for association with ageing-related morbidities including cardiovascular, pulmonary, ophthalmological, neurocognitive, renal, skeletal and auditory morbidities in separate regression analyses, adjusted for age and sex (model 1) and additionally for body mass index, smoking and sun exposure (model 2). RESULTS: We observed 5-year higher ΔPA (i.e. looking younger by 5â years for one's age) to be associated with less osteoporosis [odds ratio (OR) 0.76, 95% confidence interval (CI) 0.62-0.93], less chronic obstructive pulmonary disease (OR 0.85, 95% CI 0.77-0.95), less age-related hearing loss (model 2; B = -0.76, 95% CI -1.35 to -0.17) and fewer cataracts (OR 0.84, 95% CI 0.73-0.97), but with better global cognitive functioning (g-factor; model 2; B = 0.07, 95% CI 0.04-0.10). CONCLUSIONS: PA is associated with multiple morbidities and better cognitive function, suggesting that systemic ageing and cognitive ageing are, to an extent, externally visible in the human face.
Asunto(s)
Envejecimiento , Envejecimiento de la Piel , Anciano , Persona de Mediana Edad , Masculino , Humanos , Femenino , Estudios de Cohortes , Estudios Transversales , Facies , MorbilidadRESUMEN
BACKGROUND: Increasing evidence suggests that sarcopenia and a higher systemic immune-inflammation index (SII) are linked with morbidity in patients with COPD. However, whether these two conditions contribute to all-cause mortality in middle-aged and older patients with COPD or asthma is unclear. Therefore, we investigated the association between sarcopenia, SII, COPD or asthma and all-cause mortality in a large-scale population-based setting. METHODS: Between 2009 and 2014, 4482 participants (aged >55â years; 57.3% female) from the population-based Rotterdam Study were included. COPD and asthma patients were diagnosed clinically and based on spirometry. Six study groups were defined according to the presence or absence of COPD or asthma and sarcopenia. Cox regression models were used to assess all-cause mortality in the study groups, adjusted for sex, age, body mass index, SII, smoking, oral corticosteroid use and comorbidities. In addition, all participants were categorised into sex-specific quartiles of SII, and mortality in these groups was compared. RESULTS: Over a median follow-up of 6.1â years (interquartile range 5.0-7.2 years), 466 (10.4%) persons died. Independent of the presence of sarcopenia, participants with COPD had a higher risk of all-cause mortality (hazard ratio (HR) 2.13, 95% CI 1.46-3.12 and HR 1.70, 95% CI 1.32-2.18 for those with and without sarcopenia, respectively). Compared to lower SII levels, higher SII levels increased mortality risk even in people without sarcopenia, COPD or asthma. CONCLUSION: Middle-aged and older people with COPD, higher SII levels or sarcopenia had an independently increased mortality risk. Our study suggests prognostic usefulness of routinely evaluating sarcopenia and SII in older people with COPD or asthma.
RESUMEN
Vitamin D supplementation can prevent and cure nutritional rickets in infants and children. Preclinical and observational data suggest that the vitamin D endocrine system has a wide spectrum of skeletal and extra-skeletal activities. There is consensus that severe vitamin D deficiency (serum 25-hydroxyvitamin D (25OHD) concentration <30 nmol/l) should be corrected, whereas most guidelines recommend serum 25OHD concentrations of >50 nmol/l for optimal bone health in older adults. However, the causal link between vitamin D and many extra-skeletal outcomes remains unclear. The VITAL, ViDA and D2d randomized clinical trials (combined number of participants >30,000) indicated that vitamin D supplementation of vitamin D-replete adults (baseline serum 25OHD >50 nmol/l) does not prevent cancer, cardiovascular events, falls or progression to type 2 diabetes mellitus. Post hoc analysis has suggested some extra-skeletal benefits for individuals with vitamin D deficiency. Over 60 Mendelian randomization studies, designed to minimize bias from confounding, have evaluated the consequences of lifelong genetically lowered serum 25OHD concentrations on various outcomes and most studies have found null effects. Four Mendelian randomization studies found an increased risk of multiple sclerosis in individuals with genetically lowered serum 25OHD concentrations. In conclusion, supplementation of vitamin D-replete individuals does not provide demonstrable health benefits. This conclusion does not contradict older guidelines that severe vitamin D deficiency should be prevented or corrected.
Asunto(s)
Diabetes Mellitus Tipo 2 , Raquitismo , Deficiencia de Vitamina D , Anciano , Niño , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Suplementos Dietéticos , Humanos , Lactante , Raquitismo/inducido químicamente , Raquitismo/tratamiento farmacológico , Vitamina D/uso terapéutico , Deficiencia de Vitamina D/tratamiento farmacológicoRESUMEN
BACKGROUND: Accumulation of advanced glycation end-products (AGEs) in skeletal muscle has been implicated in development of sarcopenia. AIM: To obtain further insight in the pathophysiology of sarcopenia, we studied its relationship with skin AGEs in the general population. METHODS: In a cross-sectional analysis, 2744 participants of northern European background, mean age 74.1 years, were included from the Rotterdam Study. Skin AGEs were measured as skin autofluorescence (SAF) using AGE ReaderTM, appendicular skeletal mass index (ASMI) using insight dual-energy X-ray absorptiometry, hand grip strength (HGS) using a hydraulic hand dynamometer, and, in a subgroup, gait speed (GS) measured on an electronic walkway (n = 2080). We defined probable sarcopenia (low HGS) and confirmed sarcopenia (low HGS and low ASMI) based on the European Working Group on Sarcopenia in Older People (EWGSOP2) revised criteria cutoffs. Multivariate linear and logistic regression were performed adjusting for age, sex, body fat percentage, height, renal function, diabetes, and smoking status. RESULTS: The prevalence of low ASMI was 7.7%; probable sarcopenia, 24%, slow GS, 3%; and confirmed sarcopenia, 3.5%. SAF was inversely associated with ASMI [ß -0.062 (95% CI -0.092, -0.032)], HGS [ß -0.051 (95% CI -0.075, -0.026)], and GS [ß -0.074 (95% CI -0.116, -0.033)]. A 1-unit increase in SAF was associated with higher odds of probable sarcopenia [odds ratio (OR) 1.36 (95% CI 1.09, 1.68)] and confirmed sarcopenia [OR 2.01 (95% CI 1.33, 3.06)]. CONCLUSION: Higher skin AGEs are associated with higher sarcopenia prevalence. We call for future longitudinal studies to explore the role of SAF as a potential biomarker of sarcopenia.
Asunto(s)
Productos Finales de Glicación Avanzada/análisis , Imagen Óptica/métodos , Sarcopenia/epidemiología , Piel/diagnóstico por imagen , Absorciometría de Fotón , Anciano , Anciano de 80 o más Años , Estudios Transversales , Femenino , Productos Finales de Glicación Avanzada/metabolismo , Fuerza de la Mano , Humanos , Masculino , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/metabolismo , Países Bajos/epidemiología , Prevalencia , Estudios Prospectivos , Medición de Riesgo/métodos , Sarcopenia/diagnóstico , Sarcopenia/metabolismo , Sarcopenia/patología , Piel/metabolismoRESUMEN
A synoptic overview of scientific methods applied in bone and associated research fields across species has yet to be published. Experts from the EU Cost Action GEMSTONE ("GEnomics of MusculoSkeletal Traits translational Network") Working Group 2 present an overview of the routine techniques as well as clinical and research approaches employed to characterize bone phenotypes in humans and selected animal models (mice and zebrafish) of health and disease. The goal is consolidation of knowledge and a map for future research. This expert paper provides a comprehensive overview of state-of-the-art technologies to investigate bone properties in humans and animals - including their strengths and weaknesses. New research methodologies are outlined and future strategies are discussed to combine phenotypic with rapidly developing -omics data in order to advance musculoskeletal research and move towards "personalised medicine".
Asunto(s)
Huesos/metabolismo , Genómica/métodos , Fenómenos Fisiológicos Musculoesqueléticos/genética , Animales , Huesos/patología , Redes Reguladoras de Genes/fisiología , Humanos , Ratones , Modelos Animales , Fenotipo , Proteómica/métodos , Pez CebraRESUMEN
CONTEXT: Recent studies have shown that ß-blocker (BB) users have a decreased risk of fracture and higher bone mineral density (BMD) compared to nonusers, likely due to the suppression of adrenergic signaling in osteoblasts, leading to increased BMD. There is also variability in the effect size of BB use on BMD in humans, which may be due to pharmacogenomic effects. OBJECTIVE: To investigate potential single-nucleotide variations (SNVs) associated with the effect of BB use on femoral neck BMD, we performed a cross-sectional analysis using clinical data, dual-energy x-ray absorptiometry, and genetic data from the Framingham Heart Study's (FHS) Offspring Cohort. We then sought to validate our top 4 genetic findings using data from the Rotterdam Study, the BPROOF Study, the Malta Osteoporosis Fracture Study (MOFS), and the Hertfordshire Cohort Study. METHODS: We used sex-stratified linear mixed models to determine SNVs that had a significant interaction effect with BB use on femoral neck (FN) BMD across 11 gene regions. We also evaluated the association of our top SNVs from the FHS with microRNA (miRNA) expression in blood and identified potential miRNA-mediated mechanisms by which these SNVs may affect FN BMD. RESULTS: One variation (rs11124190 in HDAC4) was validated in females using data from the Rotterdam Study, while another (rs12414657 in ADRB1) was validated in females using data from the MOFS. We performed an exploratory meta-analysis of all 5 studies for these variations, which further validated our findings. CONCLUSION: This analysis provides a starting point for investigating the pharmacogenomic effects of BB use on BMD measures.
RESUMEN
BACKGROUND: Elevated plasma homocysteine has been found to be associated with an increased risk of osteoporosis, especially hip and vertebral fractures. The plasma concentration of homocysteine is dependent on the activities of several B vitamin-dependent enzymes, such as methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), and cystathionine ß-synthase (CBS). OBJECTIVES: We investigated whether genetic variants in some of the genes involved in 1 carbon metabolism modify the association of B vitamin-related measures with bone mineral density (BMD) and strength. METHODS: We measured several B vitamins and biomarkers in participants of the Framingham Offspring Study, and performed analyses of methylmalonic acid (MMA) continuously and <210 nmol/L; pyridoxal-5'-phosphate; vitamin B-12 continuously and ≥258 pmol/L; and folate. The outcomes of interest included areal and volumetric BMD, measured by DXA and quantitative computed tomography (QCT), respectively. We evaluated associations between the bone measures and interactions of single nucleotide polymorphism with a B vitamin or biomarker in Framingham participants (n = 4310 for DXA and n = 3127 for QCT). For analysis of DXA, we validated the association results in the B-PROOF cohort (n = 1072). Bonferroni-corrected locus-wide significant thresholds were defined to account for multiple testing. RESULTS: The interactions between rs2274976 and vitamin B-12 and rs34671784 and MMA <210 nmol/L were associated with lumbar spine BMD, and the interaction between rs6586281 and vitamin B-12 ≥258 pmol/L was associated with femoral neck BMD. For QCT-derived traits, 62 interactions between genetic variants and B vitamins and biomarkers were identified. CONCLUSIONS: Some genetic variants in the 1-carbon methylation pathway modify the association of B vitamin and biomarker concentrations with bone density and strength. These interactions require further replication and functional validation for a mechanistic understanding of the role of the 1-carbon metabolism pathway on BMD and risks of fracture.
Asunto(s)
Densidad Ósea/fisiología , Variación Genética , Ácido Metilmalónico/sangre , Complejo Vitamínico B/sangre , Adolescente , Adulto , Anciano , Densidad Ósea/genética , Niño , Preescolar , Femenino , Ácido Fólico/sangre , Ácido Fólico/metabolismo , Genotipo , Humanos , Masculino , Ácido Metilmalónico/metabolismo , Persona de Mediana Edad , Vitamina B 12/sangre , Vitamina B 12/metabolismo , Vitamina B 6/sangre , Vitamina B 6/metabolismo , Complejo Vitamínico B/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Previous studies have suggested that insufficient concentrations of vitamin D are associated with dental caries in primary teeth, but evidence remains inconclusive. OBJECTIVES: We assessed the longitudinal associations between prenatal, perinatal, and early childhood serum 25-hydroxyvitamin D concentrations [25(OH)D] and the risk of dental caries in 6-year-old children. METHODS: This research was conducted within the Generation R Study, a large, multi-ethnic, prospective cohort study located in Rotterdam, the Netherlands. Dental caries were assessed in children using the decayed-missing-filled-primary teeth index at a mean age of 6.1 years (90% range, 4.8-9.1). We measured serum total 25(OH)D concentrations at 3 time points: prenatally (at 18-24 weeks of gestation), perinatally (at birth), and during early childhood (at age 6 years). We performed logistic regression analyses to determine the longitudinal association of serum 25(OH)D concentrations with caries risks in 5257 children. Additionally, we constructed a Genetic Risk Score (GRS) for the genetic predispositions to serum total 25(OH)D concentrations based on 6 vitamin D-related single nucleotide polymorphisms in a subsample of 3385 children. RESULTS: Children with severe prenatal and early childhood serum 25(OH)D deficiencies (<25 nmol/L) were more likely to be diagnosed with caries [OR, 1.56 (95% CI, 1.18-2.06) and 1.58 (95% CI, 1.10-2.25), respectively] than children with optimal concentrations (≥75 nmol/L). After adjustment for residuals of serum 25(OH)D concentrations at other time points, only the early childhood serum 25(OH)D concentration was inversely associated with the caries risk at 6 years (OR, 0.97; 95% CI, 0.95-0.98). However, our GRS analysis showed that children who are genetically predisposed to have lower serum 25(OH)D concentrations do not have a higher risk of developing caries in primary teeth. CONCLUSIONS: Our study suggests a weak association between serum 25(OH)D concentrations and risks of caries in primary teeth. Based on our results, we do not recommend vitamin D supplementation for the prevention of dental caries in children.
Asunto(s)
Caries Dental , Deficiencia de Vitamina D , Niño , Preescolar , Caries Dental/epidemiología , Caries Dental/etiología , Femenino , Humanos , Recién Nacido , Estudios Longitudinales , Países Bajos/epidemiología , Embarazo , Estudios Prospectivos , Vitamina D , Deficiencia de Vitamina D/complicaciones , VitaminasRESUMEN
Sarcopenia is a heterogeneous skeletal muscle disorder involving the loss of muscle mass and function. However, the prevalence of sarcopenia based on the most recent definition remains to be determined in older people with chronic airway diseases. The aim was to evaluate sarcopenia prevalence and association with chronic airway diseases and its lung function in an older population, using the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria. We performed a cross-sectional analysis in 5082 participants (mean age 69.0±8.8â years, 56% females) from the Rotterdam Study. Participants with interpretable spirometry and an available assessment of sarcopenia were included. The appendicular skeletal muscle mass index (ASMI) and handgrip strength (HGS) were assessed using dual-energy X-ray absorptiometry (DXA) and a hydraulic hand dynamometer, respectively. We analysed the association between sarcopenia and chronic airway diseases by using regression models adjusted for age, sex, smoking status, total fat percentage and other relevant confounders. Participants with chronic airway diseases had higher prevalence of probable sarcopenia (12.0%, 95% CI 10.2-13.8) and confirmed sarcopenia (3.0%, 95% CI 2.1-3.9) than without. Chronic airway diseases were associated with "probable sarcopenia" (OR 1.28, 95% CI 1.02-1.60), "confirmed sarcopenia" (OR 2.13, 95% CI 1.33-3.43), reduced HGS (ß -0.51 (-0.90--0.11)) and reduced ASMI (ß -0.19 (-0.25--0.14)). Forced expiratory volume in 1 s <80% was associated with lower HGS (ß -1.03 (-1.75--0.31)) and lower ASMI (ß -0.25 (-0.36--0.15)) than forced expiratory volume in 1 s ≥80%. Sarcopenia was prevalent and associated with chronic airway diseases among older population. These results suggest the need for early diagnosis of sarcopenia in older people with chronic airway diseases by applying EWGSOP2 recommendations.
RESUMEN
Low muscle strength is an important heritable indicator of poor health linked to morbidity and mortality in older people. In a genome-wide association study meta-analysis of 256,523 Europeans aged 60 years and over from 22 cohorts we identify 15 loci associated with muscle weakness (European Working Group on Sarcopenia in Older People definition: n = 48,596 cases, 18.9% of total), including 12 loci not implicated in previous analyses of continuous measures of grip strength. Loci include genes reportedly involved in autoimmune disease (HLA-DQA1 p = 4 × 10-17), arthritis (GDF5 p = 4 × 10-13), cell cycle control and cancer protection, regulation of transcription, and others involved in the development and maintenance of the musculoskeletal system. Using Mendelian randomization we report possible overlapping causal pathways, including diabetes susceptibility, haematological parameters, and the immune system. We conclude that muscle weakness in older adults has distinct mechanisms from continuous strength, including several pathways considered to be hallmarks of ageing.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Debilidad Muscular/genética , Sarcopenia/genética , Anciano , Anciano de 80 o más Años , Envejecimiento/genética , Estudios de Cohortes , Europa (Continente) , Femenino , Factor 5 de Diferenciación de Crecimiento/genética , Cadenas alfa de HLA-DQ/genética , Humanos , Masculino , Persona de Mediana Edad , Fuerza Muscular/genética , Fuerza Muscular/fisiología , Debilidad Muscular/fisiopatología , Polimorfismo de Nucleótido Simple , Sarcopenia/fisiopatologíaRESUMEN
OBJECTIVE: The role of vitamin D in OA is unclear and previous epidemiological studies have provided inconsistent results. We conducted a two-sample Mendelian randomization (MR) study to investigate the causal relationship between genetically determined serum vitamin D levels and hip/knee OA. METHODS: Six single-nucleotide polymorphisms (SNPs) associated with vitamin D levels in the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits Consortium were selected as instrumental variables. Summary statistics of the SNPs effects on OA were derived from the Iceland and UK Biobank, comprising 23 877 knee OA cases, 17 151 hip OA cases and >562 000 controls. The control samples match the OA cases in age, sex and county of origin. RESULTS: The MR analyses showed no causal association between genetically determined vitamin D levels and knee OA [odds ratio (OR) 1.03 (95% CI 0.84, 1.26)] or hip OA [OR 1.06 (95% CI 0.83, 1.35)]. CONCLUSION: Genetic variations associated with low vitamin D serum levels are not associated with increased risk of hip or knee OA in community-dwelling older adults, suggesting that vitamin D levels are not causally linked to OA. It is therefore unlikely that vitamin D supplementation protects against hip or knee OA.