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Molecular Aspects of Medicine Apr 2022In mammals and other air-breathing vertebrates that live at high altitude, adjustments in convective O transport via changes in blood hemoglobin (Hb) content and/or Hb-O... (Review)
Review
In mammals and other air-breathing vertebrates that live at high altitude, adjustments in convective O transport via changes in blood hemoglobin (Hb) content and/or Hb-O affinity can potentially mitigate the effects of arterial hypoxemia. However, there are conflicting views about the optimal values of such traits in hypoxia, partly due to the intriguing observation that hypoxia-induced acclimatization responses in humans and other predominantly lowland mammals are frequently not aligned in the same direction as evolved phenotypic changes in high-altitude natives. Here we review relevant theoretical and empirical results and we highlight experimental studies of rodents and humans that provide insights into the combination of hematological changes that help attenuate the decline in aerobic performance in hypoxia. For a given severity of hypoxia, experimental results suggest that optimal values for hematological traits are conditional on the states of other interrelated phenotypes that govern different steps in the O-transport pathway.
Topics: Acclimatization; Altitude; Animals; Hemoglobins; Humans; Hypoxia; Oxygen; Oxygen Consumption
PubMed: 34879970
DOI: 10.1016/j.mam.2021.101052 -
PLoS Pathogens Jun 2021Sickle-trait hemoglobin protects against severe Plasmodium falciparum malaria. Severe malaria is governed in part by the expression of the Plasmodium falciparum...
Sickle-trait hemoglobin protects against severe Plasmodium falciparum malaria. Severe malaria is governed in part by the expression of the Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) that are encoded by var genes, specifically those variants that bind Endothelial Protein C Receptor (EPCR). In this study, we investigate the effect of sickle-trait on parasite var gene expression and function in vitro and in field-collected parasites. We mapped var gene reads generated from RNA sequencing in parasite cultures in normal and sickle-cell trait blood throughout the asexual lifecycle. We investigated sickle-trait effect on PfEMP1 interactions with host receptors CD36 and EPCR using static adhesion assays and flow cytometry. Var expression in vivo was compared by assembling var domains sequenced from total RNA in parasites infecting Malian children with HbAA and HbAS. Sickle-trait did not alter the abundance or type of var gene transcripts in vitro, nor the abundance of overall transcripts or of var functional domains in vivo. In adhesion assays using recombinant host receptors, sickle-trait reduced adhesion by 73-86% to CD36 and 83% to EPCR. Similarly, sickle-trait reduced the surface expression of EPCR-binding PfEMP1. In conclusion, Sickle-cell trait does not directly affect var gene transcription but does reduce the surface expression and function of PfEMP1. This provides a direct mechanism for protection against severe malaria conferred by sickle-trait hemoglobin. Trial Registration: ClinicalTrials.gov Identifier: NCT02645604.
Topics: CD36 Antigens; Endothelial Protein C Receptor; Erythrocytes; Hemoglobin, Sickle; Humans; Malaria, Falciparum; Plasmodium falciparum; Protozoan Proteins; Sickle Cell Trait
PubMed: 34115805
DOI: 10.1371/journal.ppat.1009659 -
Lancet (London, England) Jan 2013Reliable estimates of populations affected by diseases are necessary to guide efficient allocation of public health resources. Sickle haemoglobin (HbS) is the most...
BACKGROUND
Reliable estimates of populations affected by diseases are necessary to guide efficient allocation of public health resources. Sickle haemoglobin (HbS) is the most common and clinically significant haemoglobin structural variant, but no contemporary estimates exist of the global populations affected. Moreover, the precision of available national estimates of heterozygous (AS) and homozygous (SS) neonates is unknown. We aimed to provide evidence-based estimates at various scales, with uncertainty measures.
METHODS
Using a database of sickle haemoglobin surveys, we created a contemporary global map of HbS allele frequency distribution within a Bayesian geostatistical model. The pairing of this map with demographic data enabled calculation of global, regional, and national estimates of the annual number of AS and SS neonates. Subnational estimates were also calculated in data-rich areas.
FINDINGS
Our map shows subnational spatial heterogeneities and high allele frequencies across most of sub-Saharan Africa, the Middle East, and India, as well as gene flow following migrations to western Europe and the eastern coast of the Americas. Accounting for local heterogeneities and demographic factors, we estimated that the global number of neonates affected by HbS in 2010 included 5,476,000 (IQR 5,291,000-5,679,000) AS neonates and 312,000 (294,000-330,000) SS neonates. These global estimates are higher than previous conservative estimates. Important differences predicted at the national level are discussed.
INTERPRETATION
HbS will have an increasing effect on public health systems. Our estimates can help countries and the international community gauge the need for appropriate diagnoses and genetic counselling to reduce the number of neonates affected. Similar mapping and modelling methods could be used for other inherited disorders.
FUNDING
The Wellcome Trust.
Topics: Africa South of the Sahara; Gene Frequency; Global Health; Hemoglobin, Sickle; Heterozygote; Homozygote; Humans; Infant, Newborn; Population Dynamics; Sickle Cell Trait
PubMed: 23103089
DOI: 10.1016/S0140-6736(12)61229-X -
Frontiers in Endocrinology 2023The aim of our study is to estimate the associations and causalities of glucose metabolism traits of fasting blood glucose (FBG), fasting insulin (FINS), glycosylated...
PURPOSE
The aim of our study is to estimate the associations and causalities of glucose metabolism traits of fasting blood glucose (FBG), fasting insulin (FINS), glycosylated hemoglobin (HbA1c), and 2-h glucose post-challenge (2hGlu) with sleep traits consisting of excessive daytime sleepiness (EDS), insomnia, and sleep duration.
METHODS
We employed standard quantitative analysis procedures to assess the associations between sleep traits and glucose metabolism. Moreover, we acquired published genome-wide association studies (GWAS) summary statistics for these traits and conducted Mendelian randomization (MR) analyses to estimate their causal directions and effects. Inverse variance weighting (IVW) was employed as the primary approach, followed by sensitivity analyses.
RESULTS
A total of 116 studies with over 840,000 participants were included in the quantitative analysis. Our results revealed that participants with abnormal glucose metabolism had higher risks for EDS (OR [95% CI] = 1.37 [1.10,1.69]), insomnia (OR [95% CI] = 1.65 [1.24,2.20]), and both short and long sleep duration (OR [95% CI] = 1.35 [1.12,1.63]; OR [95% CI] = 1.38 [1.13,1.67] respectively). In addition, individuals with these sleep traits exhibited alterations in several glycemic traits compared with non-affected controls. In MR analysis, the primary analysis demonstrated causal effects of 2hGlu on risks of EDS (OR [95% CI] = 1.022 [1.002,1.042]) and insomnia (OR [95% CI] = 1.020[1.001,1.039]). Furthermore, FINS was associated with short sleep duration (OR [95% CI] = 1.043 [1.018,1.068]), which reversely presented a causal influence on HbA1c (β [95% CI] = 0.131 [0.022,0.239]). These results were confirmed by sensitivity analysis.
CONCLUSION
Our results suggested mutual risk and causal associations between the sleep traits and glycemic traits, shedding new light on clinical strategies for preventing sleep disorders and regulating glucose metabolism. Future studies targeting these associations may hold a promising prospect for public health.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Genome-Wide Association Study; Glycated Hemoglobin; Sleep; Causality; Glucose; Sleep Wake Disorders
PubMed: 38027156
DOI: 10.3389/fendo.2023.1227372 -
Indian Journal of Pathology &... 2023β-thalassemia trait is usually diagnosed by raised hemoglobin A (HbA). The presence of megaloblastic anemia can cause an increase in HbA and create a diagnostic...
CONTEXT
β-thalassemia trait is usually diagnosed by raised hemoglobin A (HbA). The presence of megaloblastic anemia can cause an increase in HbA and create a diagnostic dilemma. Here, we have analyzed the effect of vitamin B12 and folic acid supplementation on HbA and diagnosis of β-thalassemia trait in cases of megaloblastic anemia with raised HbA.
MATERIALS AND METHODS
Cases of megaloblastic anemia with raised HbA on high-performance liquid chromatography (HPLC) were supplemented with vitamin B12 and folic acid. Post-treatment evaluation was done after 2 months. Cases showing adequate hematological response were subjected to statistical analysis. Based on post-treatment HbA value, the cases were diagnosed as normal, borderline raised HbA, or β-thalassemia trait. Pre- and post-treatment values of red cell parameters and HbA were analyzed.
RESULTS
There was a significant decrease in HbA value after vitamin B12 and folic acid supplementation. The diagnosis was changed in 70.97% of the cases after treatment. The chance of inconclusive diagnosis was decreased from more than 50% to less than 10%. Pre-treatment mean corpuscular volume (MCV) and HbA% showed a significant difference between the thalassemic and normal groups.
CONCLUSIONS
Megaloblastic anemia can lead to false-positive diagnosis of β-thalassemia trait on HPLC. Repeat HPLC should be done after adequate supplementation of vitamin B12 and folic acid in cases of megaloblastic anemia with raised HbA. Red cell parameters are not helpful to suspect β-thalassemia trait in presence of megaloblastic anemia. However, HbA% on HPLC can be a useful parameter to suspect or exclude β-thalassemia trait in cases of megaloblastic anemia.
Topics: Humans; beta-Thalassemia; Hemoglobin A2; Anemia, Megaloblastic; Vitamin B 12; Folic Acid
PubMed: 37077076
DOI: 10.4103/ijpm.ijpm_233_21 -
Human Genetics Aug 2023The co-occurrence of migraine and glycemic traits has long been reported in observational epidemiological studies, but it has remained unknown how they are linked... (Meta-Analysis)
Meta-Analysis
The co-occurrence of migraine and glycemic traits has long been reported in observational epidemiological studies, but it has remained unknown how they are linked genetically. We used large-scale GWAS summary statistics on migraine, headache, and nine glycemic traits in European populations to perform cross-trait analyses to estimate genetic correlation, identify shared genomic regions, loci, genes, and pathways, and test for causal relationships. Out of the nine glycemic traits, significant genetic correlation was observed for fasting insulin (FI) and glycated haemoglobin (HbA1c) with both migraine and headache, while 2-h glucose was genetically correlated only with migraine. Among 1703 linkage disequilibrium (LD) independent regions of the genome, we found pleiotropic regions between migraine and FI, fasting glucose (FG), and HbA1c, and pleiotropic regions between headache and glucose, FI, HbA1c, and fasting proinsulin. Cross-trait GWAS meta-analysis with glycemic traits, identified six novel genome-wide significant lead SNPs with migraine, and six novel lead SNPs with headache (P < 5.0 × 10 and P < 1 × 10), all of which were LD-independent. Genes with a nominal gene-based association (P ≤ 0.05) were significantly enriched (overlapping) across the migraine, headache, and glycemic traits. Mendelian randomisation analyses produced intriguing, but inconsistent, evidence for a causal relationship between migraine and headache with multiple glycemic traits; and consistent evidence suggesting increased fasting proinsulin levels may causally decrease the risk of headache. Our findings indicate that migraine, headache, and glycemic traits share a common genetic etiology and provide genetic insights into the molecular mechanisms contributing to their comorbid relationship.
Topics: Humans; Proinsulin; Glycated Hemoglobin; Genome-Wide Association Study; Migraine Disorders; Insulin; Fasting; Headache; Glucose; Polymorphism, Single Nucleotide
PubMed: 36808568
DOI: 10.1007/s00439-023-02532-6 -
Human Molecular Genetics Oct 2017Glycaemic traits such as fasting and post-challenge glucose and insulin measures, as well as glycated haemoglobin (HbA1c), are used to diagnose and monitor diabetes.... (Review)
Review
Glycaemic traits such as fasting and post-challenge glucose and insulin measures, as well as glycated haemoglobin (HbA1c), are used to diagnose and monitor diabetes. These traits are risk factors for cardiovascular disease even below the diabetic threshold, and their study can additionally yield insights into the pathophysiology of type 2 diabetes. To date, a diverse set of genetic approaches have led to the discovery of over 97 loci influencing glycaemic traits. In this review, we will focus on recent advances in the genetic aetiology of glycaemic traits, and the resulting biological insights. We will provide a brief overview of results ranging from common, to low- and rare-frequency variant-trait association studies, studies leveraging the diversity across populations, and studies harnessing the power of genetic and genomic approaches to gain insights into the biological underpinnings of these traits.
Topics: Blood Glucose; Diabetes Mellitus; Diabetes Mellitus, Type 2; Fasting; Glycated Hemoglobin; Humans; Hyperglycemia; Insulin
PubMed: 28977447
DOI: 10.1093/hmg/ddx293 -
Diabetes Oct 2022We conducted a Mendelian randomization analysis to differentiate associations of four glycemic indicators with a broad range of atherosclerotic and thrombotic diseases....
We conducted a Mendelian randomization analysis to differentiate associations of four glycemic indicators with a broad range of atherosclerotic and thrombotic diseases. Independent genetic variants associated with fasting glucose (FG), 2 h glucose after an oral glucose challenge (2hGlu), fasting insulin (FI), and glycated hemoglobin (HbA1c) at the genome-wide significance threshold were used as instrumental variables. Summary-level data for 12 atherosclerotic and 4 thrombotic outcomes were obtained from large genetic consortia and the FinnGen and UK Biobank studies. Higher levels of genetically predicted glycemic traits were consistently associated with increased risk of coronary atherosclerosis-related diseases and symptoms. Genetically predicted glycemic traits except HbA1c showed positive associations with peripheral artery disease risk. Genetically predicted FI levels were positively associated with risk of ischemic stroke and chronic kidney disease. Genetically predicted FG and 2hGlu were positively associated with risk of large artery stroke. Genetically predicted 2hGlu levels showed positive associations with risk of small vessel stroke. Higher levels of genetically predicted glycemic traits were not associated with increased risk of thrombotic outcomes. Most associations for genetically predicted levels of 2hGlu and FI remained after adjustment for other glycemic traits. Increase in glycemic status appears to increase risks of coronary and peripheral artery atherosclerosis but not thrombosis.
Topics: Atherosclerosis; Blood Glucose; Genome-Wide Association Study; Glycated Hemoglobin; Humans; Insulin; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Stroke
PubMed: 35499407
DOI: 10.2337/db21-0905 -
Frontiers in Endocrinology 2022The effect of hyperglycemia on periodontitis is mainly based on observational studies, and inconsistent results were found whether periodontal treatment favors glycemic...
PURPOSE
The effect of hyperglycemia on periodontitis is mainly based on observational studies, and inconsistent results were found whether periodontal treatment favors glycemic control. The two-way relationship between periodontitis and hyperglycemia needs to be further elucidated. This study aims to evaluate the causal association of periodontitis with glycemic traits using bi-directional Mendelian randomization (MR) approach.
METHODS
Summary statistics were sourced from large-scale genome-wide association study conducted for fasting glucose (N = 133,010), HbA1c (N = 123,665), type 2 diabetes (T2D, N = 659,316), and periodontitis (N = 506,594) among European ancestry. The causal relationship was estimated using the inverse-variance weighted (IVW) model and further validated through extensive complementary and sensitivity analyses.
RESULTS
Overall, IVW showed that a genetically higher level of fasting glucose was significantly associated with periodontitis (OR = 1.119; 95% CI = 1.045-1.197; = 0.007) after removing the outlying instruments. Such association was robust and consistent through other MR models. Limited evidence was found suggesting the association of HbA1C with periodontitis after excluding the outliers (IVW OR = 1.123; 95% CI = 1.026-1.229; = 0.048). These linkages remained statistically significant in multivariate MR analyses, after adjusting for body mass index. The reverse direction MR analyses did not exhibit the causal association of genetic liability to periodontitis with any of the glycemic trait tested.
CONCLUSIONS
Our MR study reaffirms previous findings and extends evidence to substantiate the causal effect of hyperglycemia on periodontitis. Future studies with robust genetic instruments are needed to confirm the causal association of periodontitis with glycemic traits.
Topics: Blood Glucose; Diabetes Mellitus, Type 2; Fasting; Genome-Wide Association Study; Glucose; Glycated Hemoglobin; Humans; Hyperglycemia; Mendelian Randomization Analysis; Periodontitis; Polymorphism, Single Nucleotide
PubMed: 35992145
DOI: 10.3389/fendo.2022.860274 -
American Journal of Hypertension Sep 2023Previous studies have found associations of red blood cell (RBC) traits (hemoglobin and RBC count) with blood pressure; whether these associations are causal is unknown.
BACKGROUND
Previous studies have found associations of red blood cell (RBC) traits (hemoglobin and RBC count) with blood pressure; whether these associations are causal is unknown.
METHODS
We performed cross-sectional analyses in the Lifelines Cohort Study (n = 167,785). Additionally, we performed bidirectional 2 sample Mendelian randomization (MR) analyses to explore the causal effect of the 2 traits on systolic (SBP) and diastolic blood pressure (DBP), using genetic instrumental variables regarding hemoglobin and RBC identified in UK Biobank (n = 350,475) and International Consortium of Blood Pressure studies for SBP and DBP (n = 757,601).
RESULTS
In cross-sectional analyses, we observed positive associations with hypertension and blood pressure for both hemoglobin (odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.16-1.20 for hypertension; B = 0.11, 95% CI: 0.11-0.12 for SBP; B = 0.11, 95% CI: 0.10-0.11 for DBP, all per SD) and RBC (OR = 1.14, 95% CI: 1.12-1.16 for hypertension; B = 0.11, 95% CI: 0.10-0.12 for SBP; B = 0.08, 95% CI: 0.08-0.09 for DBP, all per SD). MR analyses suggested that higher hemoglobin and RBC cause higher DBP (inverse-variance weighted B = 0.11, 95% CI: 0.07-0.16 for hemoglobin; B = 0.07, 95% CI: 0.04-0.10 for RBC, all per SD). Reverse MR analyses (all per SD) suggested causal effects of DBP on both hemoglobin (B = 0.06, 95% CI: 0.03-0.09) and RBC (B = 0.08, 95% CI: 0.04-0.11). No significant effects on SBP were found.
CONCLUSIONS
Our results suggest bidirectional causal relationships of hemoglobin and RBC with DBP, but not with SBP.
Topics: Humans; Blood Pressure; Cohort Studies; Cross-Sectional Studies; Hypertension; Erythrocytes; Hemoglobins; Genome-Wide Association Study
PubMed: 37432331
DOI: 10.1093/ajh/hpad061