Genetic determinants of variability in glycated hemoglobin (HbA(1c)) in humans: review of recent progress and prospects for use in diabetes care.
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SUBMITTER: Soranzo N
PROVIDER: S-EPMC3207128 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundRecent epidemiological studies indicate that only 30-50% of undiagnosed type 2 diabetes mellitus (T2DM) patients are identified using glycated hemoglobin (HbA1c) and elevated fasting plasma glucose (FPG) levels. Thus, novel biomarkers for early diagnosis and prognosis are urgently needed for providing early and personalized treatment.MethodsHere, we studied the glycation degrees of 27 glycation sites representing nine plasma proteins in 48 newly diagnosed male T2DM patients and 48 non-diabetic men matched for age (range 35-65 years). Samples were digested with trypsin and enriched for glycated peptides using boronic acid affinity chromatography. Quantification relied on mass spectrometry (multiple reaction monitoring) using isotope-labelled peptides as internal standard.ResultsThe combination of glycated lysine-141 of haptoglobin (HP K141) and HbA1c provided a sensitivity of 94%, a specificity of 98%, and an accuracy of 96% to identify T2DM. A set of 15 features considering three glycation sites in human serum albumin, HP K141, and 11 routine laboratory measures of T2DM, metabolic syndrome, obesity, inflammation, and insulin resistance provided a sensitivity of 98%, a specificity of 100%, and an accuracy of 99% for newly diagnosed T2DM patients.ConclusionsOur studies demonstrated the great potential of glycation sites in plasma proteins providing an additional diagnostic tool for T2DM and elucidating that the combination of these sites with HbA1c and FPG could improve the diagnosis of T2DM.
| S-EPMC5370432 | biostudies-literature
Project description:BackgroundCombining HbA1c with glycated albumin (GA) may improve detection of dysglycaemia. As BMI correlates positively with HbA1c and negatively with GA, HbA1c may be more effective in obese and GA in nonobese individuals.MethodsTo relate these findings to Africans, we assessed in 1274 South Africans living in CapeTown (male 26%; age 48±16y; BMI 28.7 kg/m2 (range 15.6-73.8); obesity 39.9% and no prior diabetes history) the: (1) correlation of BMI with HbA1c and GA, (2) ability of HbA1c and GA separately and jointly, to detect OGTT-diagnosed dysglycaemia (diabetes plus prediabetes). Data collection took place between 2014 and 2016 in the City of Cape Town. Dysglycaemia was diagnosed by glucose criteria for the OGTT. Youden index was used to optimize diagnostic thresholds for HbA1c and GA.FindingsNormal glucose tolerance, prediabetes and diabetes occurred in 76%, 17% and 7%, respectively. BMI positively correlated with HbA1c [r = 0·34 [95%CI: 0·29,0·39)] and negatively with GA [-0·08 (0·13,0·03)]. For HbA1c the optimal threshold by Youden-index for dysglycaemia diagnosis was: 6·0% (95%CI: 5·8,6·2) and for GA: 13·44% (12·72,14·71). In the nonobese, obese and total cohort, HbA1c-alone detected: 51% (42-60), 72% (65,78), 63% (57,68), respectively; GA-alone detected 55% (52% (46,63), 52% (44, 59) and 53% (47,53), respectively; whereas: HbA1c+GA detected: 69% (60,76), 82% (75,87) and 76% (71, 81). Therefore, for the total cohort detection of dysglycaemia HbA1c-alone vs HbA1c+GA detected 63% (57,68) vs 76% (71,81).InterpretationThe opposite correlations of HbA1c and GA with BMI have now been demonstrated in an African-based population. Improving detection of dysglycaemia by combining HbA1c and GA has important implications for diabetes risk screening.FundingAES is supported by the intramural programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Minority Health and Health Disparities of the National Institutes of Health (NIH, Bethesda, Maryland, USA). DBS is supported by the intramural program of the Clinical Center of NIH. The South African Medical Research Council (SAMRC) funded the VMH study with funds from the National Treasury under its Economic Competitiveness and Support Package (MRC-RFA-UFSP-01-2013/VMH Study).
| S-EPMC9249545 | biostudies-literature
Project description:Glycated hemoglobin (HbA1c) is an important measure of glycemia in diabetes. HbA1c is influenced by environmental and genetic factors both in people with and in people without diabetes. We performed a genome-wide association study (GWAS) for HbA1c in a Finnish type 1 diabetes (T1D) cohort, FinnDiane. Top results were examined for replication in T1D cohorts DCCT/EDIC, WESDR, CACTI, EDC, and RASS, and a meta-analysis was performed. Three SNPs in high linkage disequilibrium on chromosome 13 near relaxin family peptide receptor 2 (RXFP2) were associated with HbA1c in FinnDiane at genome-wide significance (P < 5 × 10-8). The minor alleles of rs2085277 and rs1360072 were associated with higher HbA1c also in the meta-analysis with RASS (P < 5 × 10-8), where these variants had minor allele frequencies ?1%. Furthermore, these SNPs were associated with HbA1c in an East Asian population without diabetes (P ? 0.013). A weighted genetic risk score created from 55 HbA1c-associated variants from the literature was associated with HbA1c in FinnDiane but explained only a small amount of variation. Understanding the genetic basis of glycemic control and HbA1c may lead to better prevention of diabetes complications.
| S-EPMC6425874 | biostudies-literature
Project description:AimHigher haemoglobin levels and differences in glucose metabolism have been reported among high-altitude residents, which may influence the diagnostic performance of HbA1c . This study explores the relationship between HbA1c and fasting plasma glucose (FPG) in populations living at sea level and at an altitude of > 3000 m.MethodsData from 3613 Peruvian adults without a known diagnosis of diabetes from sea-level and high-altitude settings were evaluated. Linear, quadratic and cubic regression models were performed adjusting for potential confounders. Receiver operating characteristic (ROC) curves were constructed and concordance between HbA1c and FPG was assessed using a Kappa index.ResultsAt sea level and high altitude, means were 13.5 and 16.7 g/dl (P > 0.05) for haemoglobin level; 41 and 40 mmol/mol (5.9% and 5.8%; P < 0.01) for HbA1c ; and 5.8 and 5.1 mmol/l (105 and 91.3 mg/dl; P < 0.001) for FPG, respectively. The adjusted relationship between HbA1c and FPG was quadratic at sea level and linear at high altitude. Adjusted models showed that, to predict an HbA1c value of 48 mmol/mol (6.5%), the corresponding mean FPG values at sea level and high altitude were 6.6 and 14.8 mmol/l (120 and 266 mg/dl), respectively. An HbA1c cut-off of 48 mmol/mol (6.5%) had a sensitivity for high FPG of 87.3% (95% confidence interval (95% CI) 76.5 to 94.4) at sea level and 40.9% (95% CI 20.7 to 63.6) at high altitude.ConclusionThe relationship between HbA1c and FPG is less clear at high altitude than at sea level. Caution is warranted when using HbA1c to diagnose diabetes mellitus in this setting.
| S-EPMC5432378 | biostudies-literature
Project description:BackgroundInsulin resistance and metabolic dysfunction have been associated with asthma risk and asthma severity.ObjectiveTo examine the association between glycated hemoglobin A1c (HbA1c), asthma-related hospitalizations, and lung function measures among adults in the United Kingdom.MethodsA cross-sectional study was conducted of 47,606 adults aged 40 to 69 years who participated in the UK Biobank and had asthma but no diagnosis of diabetes mellitus. HbA1c level was analyzed as a continuous measure and also categorized as normal (<42 mmol/mol) or as consistent with prediabetes/diabetes (≥42 mmol/mol). An asthma-related hospitalization was defined as ever having had a hospitalization with an International Classification of Diseases, Ninth/Tenth Revision, Clinical Modification code of a main diagnosis compatible with asthma (International Classification of Diseases, Ninth Revision, Clinical Modification code 493.x or International Classification of Diseases, Tenth Revision, Clinical Modification codes J45.x and J46.x). Logistic or linear regression was used for the multivariable analysis of asthma hospitalizations and lung function measures (FEV1, forced vital capacity [FVC], and FEV1/FVC). All models were adjusted for age, sex, ethnic background, body mass index, average annual household income, current smoking status, pack-years of smoking, fasting time, and C-reactive protein level.ResultsBoth HbA1c level (odds ratio, 1.03; 95% CI, 1.01-1.04) and an HbA1c level in the prediabetes/diabetes range (odds ratio, 1.68; 95% CI, 1.18-2.41) were associated with 1 or more asthma hospitalizations. Moreover, both HbA1c level and an HbA1c level in the prediabetes/diabetes range were significantly and inversely associated with FEV1 and FVC.ConclusionsHbA1c is linked to asthma-related hospitalizations and small decrements in FEV1 and FVC among British adults with asthma but no diagnosis of diabetes mellitus.
| S-EPMC7655696 | biostudies-literature
Project description:Arachnids exhibit tremendous species richness and adaptations of biomedical, industrial, and agricultural importance. Yet genomic resources for arachnids are limited, with the first few spider and scorpion genomes becoming accessible in the last four years. We review key insights from these genome projects, and recommend additional genomes for sequencing, emphasizing taxa of greatest value to the scientific community. We suggest greater sampling of spiders whose genomes are understudied but hold important protein recipes for silk and venom production. We further recommend arachnid genomes to address significant evolutionary topics, including the phenotypic impact of genome duplications. A barrier to high-quality arachnid genomes are assemblies based solely on short-read data, which may be overcome by long-range sequencing and other emerging methods.
| S-EPMC6658092 | biostudies-literature
Project description:ObjectivesTo examine the accuracy of glycated haemoglobin A1c (HbA1c) in detecting type 2 diabetes and impaired fasting glucose among adults living in Malawi.DesignA diagnostic validation study of HbA1c. Fasting plasma glucose (FPG) ?7.0?mmol/L was the reference standard for type 2 diabetes, and FPG between 6.1 and 6.9?mmol/L as impaired fasting glucose.Participants3645 adults (of whom 63% were women) recruited from two demographic surveillance study sites in urban and rural Malawi. This analysis excluded those who had a previous diagnosis of diabetes or had history of taking diabetes medication.ResultsHbA1c demonstrated excellent validity to detect FPG-defined diabetes, with an area under the receiver operating characteristic (AUROC) curve of 0.92 (95% CI 0.90 to 0.94). At HbA1c ?6.5% (140 mg/dL), sensitivity was 78.7% and specificity was 94.0%. Subgroup AUROCs ranged from 0.86 for participants with anaemia to 0.94 for participants in urban Malawi. There were clinical and metabolic differences between participants with true diabetes versus false positives when HbA1c was ?6.5% (140 mg/dL).ConclusionsThe findings from this study provide justification to use HbA1c to detect type 2 diabetes. As HbA1c testing is substantially less burdensome to patients than either FPG testing or oral glucose tolerance testing, it represents a useful option for expanding access to diabetes care in sub-Saharan Africa.
| S-EPMC5942411 | biostudies-literature
Project description:IntroductionAlthough poor glycemic control is associated with dementia, it is unknown if variability in glycemic control, even in those with optimal glycosylated hemoglobin A1c (HbA1c) levels, increases dementia risk.MethodsAmong 171,964 people with type 2 diabetes, we evaluated the hazard of dementia association with long-term HbA1c variability using five operationalizations, including standard deviation (SD), adjusting for demographics and comorbidities.ResultsThe mean baseline age was 61 years (48% women). Greater HbA1c SD was associated with greater dementia hazard (adjusted hazard ratio = 1.15 [95% confidence interval: 1.12, 1.17]). In stratified analyses, higher HbA1c SD quintiles were associated with greater dementia hazard among those with a mean HbA1c < 6% (P = 0.0004) or 6% to 8% (P < 0.0001) but not among those with mean HbA1c ≥ 8% (P = 0.42).DiscussionGreater HbA1c variability is associated with greater dementia risk, even among those with HbA1c concentrations at ideal clinical targets. These findings add to the importance and clinical impact of recommendations to minimize glycemic variability.HighlightsWe observed a cohort of 171,964 people with type 2 diabetes (mean age 61 years). This cohort was based in Northern California between 1996 and 2018. We examined the association between glycosylated hemoglobin A1c (HbA1c) variability and dementia risk. Greater HbA1c variability was associated with greater dementia hazard. This was most evident among those with normal-low mean HbA1c concentrations.
| S-EPMC11350038 | biostudies-literature
Project description:We previously showed that a common genetic variant leads to a remarkably increased risk of type 2 diabetes (T2D) in the small and historically isolated Greenlandic population. Motivated by this, we aimed at discovering novel genetic determinants for glycated hemoglobin (HbA1C) and at estimating the effect of known HbA1C-associated loci in the Greenlandic population. We analyzed genotype data from 4049 Greenlanders generated using the Illumina Cardio-Metabochip. We performed the discovery association analysis by an additive linear mixed model. To estimate the effect of known HbA1C-associated loci, we modeled the effect in the European and Inuit ancestry proportions of the Greenlandic genome (EAPGG and IAPGG, respectively). After correcting for multiple testing, we found no novel significant associations. When we investigated loci known to associate with HbA1C levels, we found that the lead variant in the GCK locus associated significantly with HbA1C levels in the IAPGG ([Formula: see text]). Furthermore, for 10 of 15 known HbA1C loci, the effects in IAPGG were similar to the previously reported effects. Interestingly, the ANK1 locus showed a statistically significant ancestral population differential effect, with opposing directions of effect in the two ancestral populations. In conclusion, we found only 1 of the 15 known HbA1C loci to be significantly associated with HbA1C levels in the IAPGG and that two-thirds of the loci showed similar effects in Inuit as previously found in European and East Asian populations. Our results shed light on the genetic effects across ethnicities.
| S-EPMC5974304 | biostudies-literature
Project description:In this paper, we discuss the recent progress made in aluminum gallium nitride (AlGaN) nanowire ultraviolet (UV) light-emitting diodes (LEDs). The AlGaN nanowires used for such LED devices are mainly grown by molecular beam epitaxy (MBE) and metalorganic chemical vapor deposition (MOCVD); and various foreign substrates/templates have been investigated. Devices on Si so far exhibit the best performance, whereas devices on metal and graphene have also been investigated to mitigate various limitations of Si substrate, e.g., the UV light absorption. Moreover, patterned growth techniques have also been developed to grow AlGaN nanowire UV LED structures, in order to address issues with the spontaneously formed nanowires. Furthermore, to reduce the quantum confined Stark effect (QCSE), nonpolar AlGaN nanowire UV LEDs exploiting the nonpolar nanowire sidewalls have been demonstrated. With these recent developments, the prospects, together with the general challenges of AlGaN nanowire UV LEDs, are discussed in the end.
| S-EPMC7074201 | biostudies-literature