Multiple Non-glycemic Genomic Loci Are Newly Associated with Blood Level of Glycated Hemoglobin in East Asians (original) (raw)
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PLoS ONE, 2013
Glycated hemoglobin A 1C (HbA 1C ) level is used as a diagnostic marker for diabetes mellitus and a predictor of diabetes associated complications. Genome-wide association studies have identified genetic variants associated with HbA 1C level. Most of these studies have been conducted in populations of European ancestry. Here we report the findings from a meta-analysis of genome-wide association studies of HbA 1C levels in 6,682 non-diabetic subjects of Chinese, Malay and South Asian ancestries. We also sought to examine the associations between HbA 1C associated SNPs and microvascular complications associated with diabetes mellitus, namely chronic kidney disease and retinopathy. A cluster of 6 SNPs on chromosome 17 showed an association with HbA 1C which achieved genome-wide significance in the Malays but not in Chinese and Asian Indians. No other variants achieved genome-wide significance in the individual studies or in the meta-analysis. When we investigated the reproducibility of the findings that emerged from the European studies, six loci out of fifteen were found to be associated with HbA 1C with effect sizes similar to those reported in the populations of European ancestry and P-value ≤ 0.05. No convincing associations with chronic kidney disease and retinopathy were identified in this study.
PLoS medicine, 2017
Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics perf...
Hemoglobin 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 vari...
BMC Medical Genetics, 2011
Background: Chronic hyperglycemia confers increased risk for long-term diabetes-associated complications and repeated hemoglobin A1c (HbA1c) measures are a widely used marker for glycemic control in diabetes treatment and follow-up. A recent genome-wide association study revealed four genetic loci, which were associated with HbA1c levels in adults with type 1 diabetes. We aimed to evaluate the effect of these loci on glycemic control in type 2 diabetes. Methods: We genotyped 1,486 subjects with type 2 diabetes from a Norwegian population-based cohort (HUNT2) for single-nucleotide polymorphisms (SNPs) located near the BNC2, SORCS1, GSC and WDR72 loci. Through regression models, we examined their effects on HbA1c and non-fasting glucose levels individually and in a combined genetic score model.
Annals of Human Genetics, 2010
SummaryGenome‐wide association (GWA) studies have identified around 20 common genetic variants influencing the risk of type 2 diabetes (T2D). Likewise, a number of variants have been associated with diabetes‐related quantitative glycaemic traits, but to date the overlap between these genes and variants has been low. The majority of genetic studies have focused on fasting plasma glucose levels; however, this measure is highly variable. We have conducted a GWA meta‐analysis of glycated haemoglobin (HbA1C) levels within three healthy nondiabetic populations. This phenotype provides an estimate of mean glucose levels over 2–3 months and is a more stable predictor of future diabetes risk. Participants were from three isolated populations: the Orkney Isles in the north of Scotland, the Dalmatian islands of Vis, and Korčula in Croatia (total of 1782 nondiabetic subjects). Association was tested in each population and results combined by meta‐analysis. The strongest association was with the...
BMJ Open Diabetes Research & Care
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%...
Hemoglobin Variant HbE Found in Two South Asian Diabetic Patients
Internal Medicine, 2009
Glycohemoglobin, also known as hemoglobin (Hb) A1c, is a marker of long-term glycemic control in patients with diabetes. We present two South-Asian diabetic patients whose HbA1c peaks were not measurable using high performance liquid chromatography (HPLC). Further investigations showed that these patients were homozygous for a hemoglobin variant, HbE (β26 Glu Lys). Because of the increasing numbers of immigrants in Japan, area-specific hemoglobinopathies are now encountered more frequently than before. Thus, if discrepant results are found on an HbA1c assay or if the HbA1c value cannot be measured, such patients should be screened for hemoglobinopathies and alternative measurements for monitoring diabetes should be considered.
Diabetic Medicine, 2012
Aims Genetic variation at the rs560887 locus of the glucose-6-phosphatase, catalytic 2 gene (G6PC2) is known to affect regulation of fasting glycaemia. We determined the rs560887 genotype of patients with monogenic diabetes and glucokinase gene mutations (GCK-MODY) and correlated the genotypes with HbA 1c levels. Methods Patients from families with GCK-MODY were recruited from two large cohorts from Poland (n = 128) and the Czech Republic (n = 154). Genotypes at the rs560887 polymorphic site in G6PC2 were examined using real-time quantitative polymerase chain reaction. The effect of rs560887 genotype on age at diagnosis of GCK-MODY and initial HbA 1c levels were evaluated separately within both cohorts. Following that, a meta-analysis of rs560887 genotype-HbA 1c associations of both Polish and Czech cohorts was performed to confirm homogeneity of findings and validate cohort-specific results. Results GG homozygosity at rs560887 was associated with marginally elevated HbA 1c levels (P = 0.07 in both cohorts). The effects observed in both groups were very homogeneous (Q = 0.18; P = 0.68). Meta-analysis showed that GG homozygosity at rs560887 was associated with mean HbA 1c levels higher by 2.4 mmol ⁄ mol (0.24%), 95% CI 0.5-4.4 mmol ⁄ mol (0.05-0.44%) than in individuals with other genotypes. Additionally, meta-analysis of both cohorts showed that GG homozygous individuals had higher odds of reaching the 48 mmol ⁄ mol (6.5%) diagnostic threshold of diabetes; (odds ratio 1.90; 95% CI 1.07-3.36; P = 0.03). No such effects were observed for age at diagnosis of diabetes. Conclusions Variation at the rs560887 locus of G6PC2 is associated with worse glycated haemoglobin levels in individuals with GCK mutations; GG homozygotes are more likely to meet diagnostic criteria for diabetes based on HbA 1c level.