scholarly journals Impact of rare and common genetic variants on diabetes diagnosis by hemoglobin A1c in multi-ancestry cohorts: The Trans-Omics for Precision Medicine Program

2019 ◽  
Author(s):  
Chloé Sarnowski ◽  
Aaron Leong ◽  
Laura M Raffield ◽  
Peitao Wu ◽  
Paul S de Vries ◽  
...  
Keyword(s):  
African Americans ◽  
Precision Medicine ◽  
Hemoglobin A1c ◽  
Sequence Data ◽  
African Ancestry ◽  
Low Frequency ◽  
Diabetes Diagnosis ◽  
Common Genetic Variants ◽  
Patients With Diabetes ◽  
The Uk

AbstractHemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in patients with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K/FN3KRP in Europeans and G6PD in African-Americans and Hispanics) and discovered a new African-ancestry specific low-frequency variant (rs1039215 in HBG2/HBE1, minor allele frequency (MAF)=0.03). The most associated G6PD variant (p.Val98Met, rs1050828-T, MAF=12% in African-Americans, MAF=2% in Hispanics) lowered HbA1c (−0.88% in hemizygous males, −0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693 - p.Leu353Pro, MAF=0.5%; −0.98% in hemizygous males, −0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African-American cohorts and replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis.

scholarly journals Association of G6PD variants with hemoglobin A1c and impact on diabetes diagnosis in East Asian individuals

2020 ◽  
Vol 8 (1) ◽  
pp. e001091 ◽  
Author(s):  
Aaron Leong ◽  
Victor Jun Yu Lim ◽  
Chaolong Wang ◽  
Jin-Fang Chai ◽  
Rajkumar Dorajoo ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Minor Allele Frequency ◽  
Hemoglobin A1c ◽  
Fasting Glucose ◽  
African Ancestry ◽  
East Asian ◽  
Missense Variant ◽  
Minor Allele ◽  
Carrier Status ◽  
Diabetes Diagnosis

ObjectiveHemoglobin A1c (HbA1c) accuracy is important for diabetes diagnosis and estimation of overall glycemia. The G6PD-Asahi variant which causes glucose-6-phosphate dehydrogenase (G6PD) deficiency has been shown to lower HbA1c independently of glycemia in African ancestry populations. As different G6PD variants occur in Asian ancestry, we sought to identify Asian-specific G6PD variants associated with HbA1c.Research design and methodsIn eight Asian population-based cohorts, we performed imputation on the X chromosome using the 1000 Genomes reference panel and tested for association with HbA1c (10 005 East Asians and 2051 South Asians). Results were meta-analyzed across studies. We compared the proportion of individuals classified as having diabetes/pre-diabetes by fasting glucose ≥100 mg/dL or HbA1c ≥5.7% units among carriers and non-carriers of HbA1c-associated variants.ResultsThe strongest association was a missense variant (G6PD-Canton, rs72554665, minor allele frequency=2.2%, effect in men=−0.76% unit, 95% CI −0.88 to −0.64, p=1.25×10−27, n=2844). Conditional analyses identified a secondary distinct signal, missense variant (G6PD-Kaiping, rs72554664, minor allele frequency=1.6%, effect in men=−1.12 % unit, 95% CI −1.32 to −0.92, p=3.12×10−15, pconditional_Canton=7.57×10−11). Adjusting for glucose did not attenuate their effects. The proportion of individuals with fasting glucose ≥100 mg/dL did not differ by carrier status of G6PD-Canton (p=0.21). Whereas the proportion of individuals with HbA1c ≥5.7% units was lower in carriers (5%) compared with non-carriers of G6PD-Canton (30%, p=0.03).ConclusionsWe identified two G6PD variants in East Asian men associated with non-glycemic lowering of HbA1c. Carriers of these variants are more likely to be underdiagnosed for diabetes or pre-diabetes than non-carriers if screened by HbA1c without confirmation by direct glucose measurements.

scholarly journals Association of FMO3 Variants with Blood Pressure in the Atherosclerosis Risk in Communities Study

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Tyler S. Bryant ◽  
Priya Duggal ◽  
Bing Yu ◽  
Alanna C. Morrison ◽  
Tariq Shafi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
African Americans ◽  
Exome Sequencing ◽  
Meta Analysis ◽  
African Ancestry ◽  
Low Frequency ◽  
Atherosclerosis Risk In Communities ◽  
European Americans ◽  
Atherosclerosis Risk ◽  
Nitrogen Containing Compounds

Flavin containing monooxygenase 3 [FMO3] encodes dimethylaniline monooxygenase [N-oxide-forming] 3, which breaks down nitrogen-containing compounds, and has been implicated in blood pressure regulation. Studies have reported conflicting results of the association of a common nonsynonymous variant, E158K (rs2266782), with hypertension. We examined the associations of E158K, along with rare and low frequency exonic variants (minor allele frequency [MAF]<5%) in FMO3 with hypertension, systolic blood pressure (SBP), and diastolic blood pressure (DBP). We included 7,350 European Americans and 2,814 African Americans in the Atherosclerosis Risk in Communities (ARIC) study with exome sequencing of FMO3. The association of FMO3 variants with SBP and DBP was tested using single variant and gene-based tests followed by the replication or interrogation of significant variants in ancestry-specific cohorts based on Bonferroni corrected thresholds. E158K had significant association with higher SBP in African Americans in ARIC (p=0.03), and two low frequency variants had significant association with higher SBP in African Americans (rs200985584, MAF 0.1%, p=0.0003) and European Americans (rs75904274, MAF 1.7%, p=0.006). These associations were not significant with additional samples: E158K in a meta-analysis of SBP of African ancestry (N=30,841, p=0.43) that included ARIC participants and the two low frequency variants in an independent ancestry-specific exome sequencing study of blood pressure (rs200985584, p=0.94; rs75904274, p=0.81). Our study does not support the association of E158K and low frequency variants in FMO3 with blood pressure and demonstrates the importance of replication in genetic studies.

Influence of Diabetes Duration and Glycemic Control on Dementia: A Cohort Study

2021 ◽  
Author(s):  
Fu-Rong Li ◽  
Hai-Lian Yang ◽  
Rui Zhou ◽  
Jia-Zhen Zheng ◽  
Guo-Chong Chen ◽  
...  
Keyword(s):  
Glycemic Control ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Diabetes Duration ◽  
Self Report ◽  
Diabetes Diagnosis ◽  
Duration Of Diabetes ◽  
Incident Dementia ◽  
Patients With Diabetes ◽  
The Uk

Abstract Background To investigate the influence of diabetes duration and glycemic control, assessed by glycated hemoglobin (HbA1c) levels, on risk of incident dementia. Methods The present study is a prospective study of 461,563 participants from the UK Biobank. The age at diabetes diagnosis was determined by self-report. Diabetes duration was calculated as baseline age minus age at diagnosis. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% confidential intervals (CIs). Results During a median follow-up of 8.1 y, 2,233 dementia cases were recorded. As compared with normoglycemic individuals, individuals with diabetes had higher risk of all-cause dementia, and the risk increased with increasing duration of diabetes; compared with participants with diabetes duration of &lt;5 y, the multivariable-adjusted HRs (95% CIs) were 1.49 (1.12-1.97), 1.71 (1.21-2.41), and 2.15 (1.60-2.90) for those with diabetes durations ≥5 to &lt; 10, ≥10 to &lt;15, and ≥ 15 y, respectively (P for trend &lt; 0.001). Among participants with diabetes, those with both longer diabetes duration (diabetes duration ≥10 y) and poor glycemic control (HbA1c ≥8%) had the highest risk of All-cause dementia (multivariable-adjusted HR =2.07, 95% CI 1.45, 2.94), compared with patients with shorter duration of diabetes and better glycemic control (diabetes duration &lt;10 y and HbA1c &lt;8%). Conclusions Diabetes duration appeared to be associated with the risk of incident dementia due to factors beyond glycemic control. Clinicians should consider not only glycemic control but also diabetes duration in dementia risk assessments for patients with diabetes.

scholarly journals Financial Resources and Biomarkers of Aging in the National Health and Aging Trends Study

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 589-589
Author(s):  
Laura Samuel ◽  
Laken Roberts ◽  
Danielle Boyce ◽  
Melissa Hladek ◽  
Sarah LaFave ◽  
...  
Keyword(s):  
Hemoglobin A1c ◽  
Income Group ◽  
Cross Sectional Study ◽  
Financial Strain ◽  
Diabetes Diagnosis ◽  
Lower Income ◽  
Sampling Weights ◽  
Cross Sectional ◽  
Lower Income Group ◽  
Biomarkers Of Aging

Abstract Lower income and financial strain (i.e. difficulty making ends meet) are associated with worse aging biomarkers, but evidence among nationally representative samples is limited. This cross-sectional study tested whether income to poverty ratio (analyzed separately for those &lt;500% vs. ≥500% poverty threshold) and financial strain are associated with biomarkers of aging among NHATS participants aged ≥65 years (n=4,648), adjusting for age, race/ethnicity, gender, smoking, BMI, and diabetes diagnosis for hemoglobin A1c. Sampling weights were applied. Among those with incomes &lt;500% poverty, higher income was associated with lower hemoglobin A1c (b= -0.0196, p=0.007), CMV (b= -0.0689, p&lt;0.001) and CRP (b= -0.0428, p=0.012). Among those with incomes ≥500%, higher income was associated with lower IL-6 (b= -0.0001, p=0.023) and lower CMV (b= -0.0001, p&lt;0.001). Financial strain was not associated with biomarkers. Income is more strongly associated with biomarkers among the lower income group, calling for special attention to this vulnerable population.

scholarly journals Impact of the UK COVID‐19 pandemic on HbA1c testing and its implications for diabetes diagnosis and management

2021 ◽  
Vol 75 (4) ◽  
Author(s):  
David Holland ◽  
Adrian H. Heald ◽  
Mike Stedman ◽  
Lewis Green ◽  
Jonathan Scargill ◽  
...  
Keyword(s):  
Diabetes Diagnosis ◽  
Diagnosis And Management ◽  
The Uk

Occurrence and Origin of Supernumerary Chromosomes in Partamona (Hymenoptera: Apidae: Meliponini)

2016 ◽  
Vol 150 (1) ◽  
pp. 68-75 ◽  
Author(s):  
Diana P. Machado ◽  
Elder A. Miranda ◽  
Mariana C. Dessi ◽  
Camila P. Sabadini ◽  
Marco A. Del Lama
Keyword(s):  
High Frequency ◽  
Scar Marker ◽  
Sequence Data ◽  
Low Frequency ◽  
B Chromosomes ◽  
First Report ◽  
Supernumerary Chromosomes

Samples from 861 colonies of 12 Partamona species from 125 Brazilian localities were analysed for a SCAR marker specific to the B chromosomes of P. helleri. We identified the SCAR marker in 6 of the 12 species analysed, including 2 (P. gregaria and P. chapadicola) from the pearsoni clade. This is the first report on the presence of this marker in Partamona species that are not included in the cupira clade, which indicates that the B chromosomes probably are more widespread in this genus than previously thought. The analysis revealed a high frequency of the SCAR marker in the samples of P. helleri (0.47), P. cupira (0.46), and P. rustica (0.29), and a low frequency in P. aff. helleri (0.06). The frequency of the marker in P. helleri was correlated with the latitude of the sampling locality, decreasing from north to south. Sequence data on the SCAR marker from 50 individuals of the 6 species in which the presence of this marker was shown revealed a new scenario for the origin of the B chromosomes in Partamona.

Diabetes Mellitus in Patients With Cystic Fibrosis: Effect on Survival

PEDIATRICS ◽  
1990 ◽  
Vol 86 (3) ◽  
pp. 374-377
Author(s):  
J. Reisman ◽  
M. Corey ◽  
G. Canny ◽  
H. Levison
Keyword(s):  
Diabetes Mellitus ◽  
Cystic Fibrosis ◽  
Survival Analysis ◽  
Nutritional Status ◽  
Pulmonary Function ◽  
Survival Data ◽  
Diabetes Diagnosis ◽  
Patients With Diabetes ◽  
Insulin Dependent ◽  
Sick Children

Patient data obtained from the cystic fibrosis clinic of the Hospital for Sick Children (Toronto, Canada) over the period 1977 to 1988 were analyzed to compare the diabetic and nondiabetic cystic fibrosis patients. The pulmonary function, nutritional status, and survival data for 713 patients who attended the clinic over the 11-year period are reported. Insulin-dependent diabetes was found to exist in 37 (5.2%) of 713 patients. The patient age at time of diabetes diagnosis ranged from 2 to 34 years, with a mean ± SD of 20.0 ± 7.4 years. Patients who died in both the diabetic and nondiabetic groups had worse pulmonary and nutritional status than the surviving patients, but there were no significant differences between the diabetic and nondiabetic groups in those who died or in those who remained alive. Survival analysis showed a similar prognosis in the diabetic and nondiabetic groups. It is concluded that cystic fibrosis patients with diabetes are, for their age, not different from patients without diabetes with respect to pulmonary function, nutritional status, and survival.

scholarly journals The Effect of Biracial Status and Color on Crystallized Intelligence in the U.S.-Born African–European American Population

Psych ◽  
2019 ◽  
Vol 1 (1) ◽  
pp. 44-54
Author(s):  
John Fuerst ◽  
Richard Lynn ◽  
Emil Kirkegaard
Keyword(s):  
African Americans ◽  
Cognitive Ability ◽  
African Ancestry ◽  
Significant Negative Correlation ◽  
European Ancestry ◽  
European American ◽  
Crystallized Intelligence ◽  
Black And White ◽  
Nationally Representative ◽  
Sub Saharan

The relationship between biracial status, color, and crystallized intelligence was examined in a nationally representative sample of adult Black and White Americans. First, it was found that self-identifying biracial individuals, who were found to be intermediate in color and in self-reported ancestry, had intermediate levels of crystallized intelligence relative to self-identifying White (mostly European ancestry) and Black (mostly sub-Saharan African ancestry) Americans. The results were transformed to an IQ scale: White (M = 100.00, N = 7569), primarily White–biracial (M = 96.07, N = 43, primarily Black–biracial (M = 94.14 N = 50), and Black (M = 89.81, N = 1381). Next, among self-identifying African Americans, a statistically significant negative correlation of r = −0.102 (N = 637) was found between interviewer-rated darker facial color and vocabulary scores. After correction for the reliability of the measures, this correlation increased to r = −0.21. Corrections for the validity of color as an index of African ancestry would raise this correlation to around r = −0.48. This association among self-identifying African Americans was not accounted for by confounding factors, such as region of residence and interviewer race, or by parental socioeconomic status and individual educational attainment. In the multivariate models, the standardized betas for color and crystallized intelligence among African Americans ranged from β = −0.112 to β = −0.142. Based on the coefficients from the multivariate analysis, it was further found that cognitive ability was a significant mediator in the context of color and education, while education was not in the context of color and cognitive ability. It is concluded that these results further substantiate the statistical relation between intelligence and biogeographic ancestry in African and European American populations.

scholarly journals Assessing the contribution of rare-to-common protein-coding variants to circulating metabolic biomarker levels via 412,394 UK Biobank exome sequences

2021 ◽  
Author(s):  
Abhishek Nag ◽  
Lawrence Middleton ◽  
Ryan S Dhindsa ◽  
Dimitrios Vitsios ◽  
Eleanor M Wigmore ◽  
...  
Keyword(s):  
Gene Networks ◽  
Rare Variants ◽  
Association Studies ◽  
Low Frequency ◽  
Genome Wide Association Studies ◽  
Uk Biobank ◽  
Protein Coding ◽  
The Uk ◽  
Metabolic Biomarkers ◽  
Coding Variants

Genome-wide association studies have established the contribution of common and low frequency variants to metabolic biomarkers in the UK Biobank (UKB); however, the role of rare variants remains to be assessed systematically. We evaluated rare coding variants for 198 metabolic biomarkers, including metabolites assayed by Nightingale Health, using exome sequencing in participants from four genetically diverse ancestries in the UKB (N=412,394). Gene-level collapsing analysis, that evaluated a range of genetic architectures, identified a total of 1,303 significant relationships between genes and metabolic biomarkers (p<1x10-8), encompassing 207 distinct genes. These include associations between rare non-synonymous variants in GIGYF1 and glucose and lipid biomarkers, SYT7 and creatinine, and others, which may provide insights into novel disease biology. Comparing to a previous microarray-based genotyping study in the same cohort, we observed that 40% of gene-biomarker relationships identified in the collapsing analysis were novel. Finally, we applied Gene-SCOUT, a novel tool that utilises the gene-biomarker association statistics from the collapsing analysis to identify genes having similar biomarker fingerprints and thus expand our understanding of gene networks.

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