Contribution of genetic ancestry and polygenic risk score in meeting vitamin B12 needs in healthy Brazilian children and adolescents.
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ABSTRACT:
SUBMITTER: Fuzo CA
PROVIDER: S-EPMC8184816 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundWe previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.Materials and methodsGenotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.ResultsCF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.ConclusionWe identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.
| S-EPMC8669040 | biostudies-literature
Project description:Background and aimsFamilial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of LDL-C leading to premature cardiovascular disease (CAD). Only about 40% of individuals with a clinical diagnosis of FH have a causative genetic variant identified, and a proportion of genetically negative cases may have a polygenic cause rather than a still unidentified monogenic cause. This work aims to evaluate and validate the role of a polygenic risk score (PRS) associated with hypercholesterolemia in a Brazilian FH cohort and its clinical implications.MethodsWe analyzed a previously derived PRS of 12 and 6 SNPs (Single Nucleotide Polymorphism) in 684 FH individuals (491 mutation-negative [FH/M-], 193 mutation-positive [FH/M+]) and in 1605 controls. Coronary artery calcium (CAC) score was also evaluated.ResultsThe PRS was independently associated with LDL-C in control individuals (p < 0.001). Within this group, in individuals in the highest quartile of the 12 SNPs PRS, the odds ratio for CAC score >100 was 1.7 (95% CI: 1.01-2.88, p = 0.04) after adjustment for age and sex. Subjects in the FH/M- group had the highest mean score in both 12 and 6 SNPs PRS (38.25 and 27.82, respectively) when compared to the other two groups (p = 2.2 × 10-16). Both scores were also higher in the FH/M+ group (36.48 and 26.26, respectively) when compared to the control group (p < 0.001 for the two scores) but inferior to the FH/M- group. Within FH individuals, the presence of a higher PRS score was not associated with LDL-C levels or with CAD risk.ConclusionA higher PRS is associated with significantly higher levels of LDL-C and it is independently associated with higher CAC in the Brazilian general population. A polygenic cause can explain a fraction of FH/M- individuals but does not appear to be a modulator of the clinical phenotype among FH individuals, regardless of mutation status.
| S-EPMC9833269 | biostudies-literature
Project description:It is unknown whether the impact of high diet quality and physical activity depends on the level of polygenic risk score (PRS) in different ancestries. Our cross-sectional study utilized de-identified data from 1987-2010 for self-reported European Americans (n = 6575) and African Americans (n = 1606). The high-risk PRS increased ASCVD risk by 59% (Risk Ratio (RR) = 1.59; 95% Confidence Interval:1.16-2.17) in the highest tertile for African Americans and by 15% (RR = 1.15; 1.13-1.30) and 18% (RR = 1.18; 1.04-1.35) in the second and highest tertiles compared to the lowest tertile in European Americans. Within the highest PRS tertiles, high physical activity-diet combinations (Dietary Approaches to Stop High Blood Pressure (DASH), Mediterranean, or Southern) reduced ASCVD risks by 9% (RR = 0.91; 0.85-0.96) to 15% (RR = 0.85; 0.80-0.90) in European Americans; and by 13% (RR = 0.87; 0.78-0.97) and 18% (RR = 0.82; 0.72-0.95) for DASH and Mediterranean diets, respectively, in African Americans. Top molecular pathways included fructose metabolism and catabolism linked to obesity, insulin resistance, and type 2 diabetes. Additional molecular pathways for African Americans were Vitamin D linked to depression and aging acceleration and death signaling associated with cancer. Effects of high diet quality and high physical activity can counterbalance the influences of genetically high-risk PRSs on ASCVD risk, especially in African Americans.
| S-EPMC10893526 | biostudies-literature
Project description:Polygenic Scores (PSs) describe the genetic component of an individual's quantitative phenotype or their susceptibility to diseases with a genetic basis. Currently, PSs rely on population-dependent contributions of many associated alleles, with limited applicability to understudied populations and recently admixed individuals. Here we introduce a combination of local ancestry deconvolution and partial PS computation to account for the population-specific nature of the association signals in individuals with admixed ancestry. We demonstrate partial PS to be a proxy for the total PS and that a portion of the genome is enough to improve susceptibility predictions for the traits we test. By combining partial PSs from different populations, we are able to improve trait predictability in admixed individuals with some European ancestry. These results may extend the applicability of PSs to subjects with a complex history of admixture, where current methods cannot be applied.
| S-EPMC7118071 | biostudies-literature
Project description:BackgroundVitamin B12 deficiency in children may be associated with (severe) neurological manifestations, therefore recognition is important. Diagnosing vitamin B12 deficiency in children is challenging. This study aimed to investigate plasma methylmalonic acid, holotranscobalamin, and total cobalamin in children 0-18 years of age and to estimate age-dependent reference intervals.MethodsPlasma vitamin B12 markers were measured in collected plasma samples of 170 children 0-18 years visiting a local primary care laboratory. All had within-reference hemoglobin and MCV values. Pediatric plasma vitamin B12 biomarkers were measured and reference values were derived thereof.ResultsPlasma methylmalonic acid was higher in young children, in particular between 1 and 6 months of age; total cobalamin and holotranscobalamin were highest from 0.5 to 4 years and decreased till 10 years of age. Plasma holotranscobalamin was highly correlated with plasma total cobalamin; their ratio was independent of age. Plasma methylmalonic acid was slightly more related to total cobalamin than to holotranscobalamin. A large proportion of mainly young children would be misclassified when adult references are applied.ConclusionsPediatric reference values for cobalamin markers are necessary to allow for early recognition and monitoring of children suspect of (clinical) cobalamin deficiency.ImpactWe analyzed three plasma vitamin B12 status markers, i.e., total cobalamin, holotranscobalamin, and methylmalonic acid, in the plasma of 170 children 0-18 years of age and were able to derive reference intervals thereof. Recognition of vitamin B12 deficiency in children is important but challenging as pediatric reference intervals for plasma vitamin B12 status markers, particularly plasma holotranscobalamin, are not well described. We think that our results may help early recognition and monitoring of children suspect of (clinical) vitamin B12 deficiency.
| S-EPMC8651506 | biostudies-literature
Project description:Glaucoma is a progressive and irreversible blindness-causing disease. However, the underlying genetic factors and molecular mechanisms remain poorly understood. Previous genome-wide association studies (GWAS) have made tremendous progress on the SNP-based disease association and characterization. However, most of them were conducted for Europeans. Since differential genetic characteristics among ethnic groups were evident in glaucoma, it is worthwhile to complete its genetic landscape from the larger cohorts of Asian individuals. Here, we present a GWAS based on the Taiwan Biobank. Among 1013 glaucoma patients and 36,562 controls, we identified a total of 138 independent glaucoma-associated SNPs at the significance level of p < 1 × 10-5. After clumping genetically linked SNPs (LD clumping), 134 independent SNPs with p < 10-4 were recruited to construct a Polygenic Risk Score (PRS). The model achieved an area under the receiver operating characteristic curve (AUC) of 0.8387 (95% CI = [0.8269-0.8506]), and those within the top PRS quantile had a 45.48-fold increased risk of glaucoma compared with those within the lowest quantile. The PRS model was validated with an independent cohort that achieved an AUC of 0.7283, thereby showing the effectiveness of our polygenic risk score in predicting individuals in the Han Chinese population with higher glaucoma risks.
| S-EPMC8618593 | biostudies-literature
Project description:We have analyzed 247 Brazilian mtDNAs for hypervariable segment (HVS)-I and selected restriction fragment-length-polymorphism sites, to assess their ancestry in different continents. The total sample showed nearly equal amounts of Native American, African, and European matrilineal genetic contribution but with regional differences within Brazil. The mtDNA pool of present-day Brazilians clearly reflects the imprints of the early Portuguese colonization process (involving directional mating), as well as the recent immigrant waves (from Europe) of the last century. The subset of 99 mtDNAs from the southeastern region encompasses nearly all mtDNA haplogroups observed in the total Brazilian sample; for this regional subset, HVS-II was analyzed, providing, in particular, some novel details of the African mtDNA phylogeny.
| S-EPMC1287189 | biostudies-other
Project description:BackgroundIt is controversial whether B12 deficiency causes dementia or B12 treatment can prevent dementia.ObjectiveTo assess associations between low plasma (P-)B12 levels, B12 treatment, and risk of Alzheimer's disease (AD; primary outcome) and all-cause or vascular dementia (secondary outcomes).MethodsWe conducted a population-based cohort study using Danish registry data to assess associations between low P-B12 levels, high-dose injection or oral B12 treatment, and risk of dementia (study period 2000-2013). The primary P-B12 cohort included patients with a first-time P-B12 measurement whose subsequent B12 treatment was recorded. The secondary B12 treatment cohort included patients with a first-time B12 prescription and P-B12 measurement within one year before this prescription. For both cohorts, patients with low P-B12 levels (<200 pmol/L) were propensity score-matched 1:1 with patients with normal levels (200-600 pmol/L). We used multivariable Cox regression to compute 0-15-year hazard ratios for dementia.ResultsFor low P-B12 and normal P-B12 level groups, we included 53,089 patients in the primary P-B12 cohort and 13,656 patients in the secondary B12 treatment cohort. In the P-B12 cohort, hazard ratios for AD centered around one, regardless of follow-up period or treatment during follow-up. In the B12 treatment cohort, risk of AD was unaffected by low pre-treatment P-B12 levels, follow-up period and type of B12 treatment. Findings were similar for all-cause and vascular dementia.ConclusionWe found no associatio1n between low P-B12 levels and dementia. Associations were unaffected by B12 treatment. Results do not support routine screening for B12 deficiency in patients with suspected dementia.
| S-EPMC7990402 | biostudies-literature
Project description:Vitamin D, used here to refer to both 25-hydroxyvitamin D, the main circulating form of the vitamin, and 1,25-hydroxyvitamin D, the biologically active form, has been shown to influence brain development and function. Consistent with these findings, low levels of vitamin D have been implicated in various mental disorders, including depression, schizophrenia, and autism. Recently, a shared variance across multiple categories of mental health disorders has been identified and shown to be genetically influenced. This shared variance, thought to represent a general risk for psychopathology, has been termed the p factor. Individuals with high p factor scores are characterized by high neuroticism and low agreeableness and conscientiousness. Here, we investigated the links between vitamin D polygenic scores - derived from the latest genome-wide association study of circulating vitamin D (25-hydroxyvitamin D) levels - the Big Five personality traits (neuroticism, agreeableness, conscientiousness, openness-to-experience, and extraversion), and the p factor, in a sample of 522 (278 women, mean age 20 ± 1 years) non-Hispanic Caucasians. Vitamin D polygenic scores were significantly and negatively associated with neuroticism and the p factor, even after correcting for multiple comparisons, and controlling for sex, age, ancestry, socioeconomic status, and body mass index. Based on previous research implicating neuroticism as a risk factor for psychopathology, mediation was tested. Results showed a significant indirect effect from the vitamin D polygenic score to the p factor via neuroticism. Our findings support a genetic link between vitamin D levels, neuroticism, and the p factor, but due to the cross-sectional nature of our data, future studies are needed to clarify the causal associations between these phenotypes.
| S-EPMC7107583 | biostudies-literature
Project description:Backgroundβ-Blockers (BBs) are mainstay therapy for heart failure with reduced ejection fraction. However, individual patient responses to BB vary, which may be partially due to genetic variation. The goal of this study was to derive and validate the first polygenic response predictor (PRP) for BB survival benefit in heart failure with reduced ejection fraction patients.MethodsDerivation and validation analyses were performed in n=1436 total HF patients of European descent and with ejection fraction <50%. The PRP was derived in a random subset of the Henry Ford Heart Failure Pharmacogenomic Registry (n=248) and then validated in a meta-analysis of the remaining patients from Henry Ford Heart Failure Pharmacogenomic Registry (n=247), the TIME-CHF (Trial of Intensified Versus Standard Medical Therapy in Elderly Patients With Congestive Heart Failure; n=431), and HF-ACTION trial (Heart Failure: a Controlled Trial Investigating Outcomes of Exercise Training; n=510). The PRP was constructed from a genome-wide analysis of BB×genotype interaction predicting time to all-cause mortality, adjusted for Meta-Analysis Global Group in Chronic Heart Failure score, genotype, level of BB exposure, and BB propensity score.ResultsFive-fold cross-validation summaries out to 1000 single-nucleotide polymorphisms identified optimal prediction with a 44 single-nucleotide polymorphism score and cutoff at the 30th percentile. In validation testing (n=1188), greater BB exposure was associated with reduced all-cause mortality in patients with low PRP score (n=251; hazard ratio, 0.19 [95% CI, 0.04-0.51]; P=0.0075) but not high PRP score (n=937; hazard ratio, 0.84 [95% CI, 0.53-1.3]; P=0.448)-a difference that was statistically significant (P interaction, 0.0235). Results were consistent regardless of atrial fibrillation, ejection fraction (≤40% versus 41%-50%), or when examining cardiovascular death.ConclusionsAmong patients of European ancestry with heart failure with reduced ejection fraction, a PRP distinguished patients who derived substantial survival benefit from BB exposure from a larger group that did not. Additional work is needed to prospectively test clinical utility and to develop PRPs for other population groups and other medications.
| S-EPMC7738407 | biostudies-literature