HbA1c Levels Are Genetically Determined Even in Type 1 Diabetes

Snieder, Harold; Sawtell, P. A.; Ross, Lindsey; Walker, James; Spector, Tim D.; Leslie, Richard

doi:10.2337/diabetes.50.12.2858

Cited by 178 publications

(123 citation statements)

References 29 publications

(20 reference statements)

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“…First, they demonstrate a contrast between GSPs, which are not inherited, and A1C, which is inherited. This observation limits the range of candidate mechanisms that could account for the heritability of A1C (9). Second, these findings demonstrate that a measure, the GG, which captures the variation of A1C in a population beyond that which is attributable to blood glucose variation, also captures a proportion of the heritability of A1C based on quantitative genetic modeling.…”

Section: Quantitative Genetic Model Fittingmentioning

confidence: 85%

“…McCarter et al (8) found that HGI was likewise reproducible over time and that retinopathy and nephropathy risk were predicted by the HGI determined on numerous extended capillary glucose profiles throughout the duration of the Diabetes Control and Complications Trial. Evidence from both healthy and diabetic twins indicates that A1C levels are genetically determined, which provides an independent line of evidence that A1C is in part determined by factors other than glycemic control (9). Given the two independent lines of evidence about A1C variance and heritability (7-9), a logical question that arises is whether the heritable components of A1C are associated preferentially with the GG fraction or the GSPs fraction of the A1C variance, as this would narrow the range of mechanisms involved and inform candidate gene studies.…”

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confidence: 84%

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Evidence for Independent Heritability of the Glycation Gap (Glycosylation Gap) Fraction of HbA1c in Nondiabetic Twins

et al. 2006

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OBJECTIVE -HbA 1c (A1C) is substantially determined by genetic factors not shared in common with glucose. Fractions of the variance in A1C, the glycation gap (GG; previously called the glycosylation gap) and the hemoglobin glycosylation index, correlate with diabetes complications. We therefore tested whether GG (measured A1C Ϫ A1C predicted from glycated serum proteins [GSPs]) was genetically determined and whether it accounted for the heritability of A1C.RESEARCH DESIGN AND METHODS -We conducted a classic twin study on A1C and GSP collected in 40 and 46 pairs of monozygotic and dizygotic healthy female twins, respectively. The predicted A1C was based on the regression line between A1C and GSP in a separate population spanning the pathophysiologic range.RESULTS -GG was more strongly correlated between monozygotic (r ϭ 0.65) than dizygotic (r ϭ 0.48) twins, adjusted for age and BMI. The best-fitting quantitative genetic model adjusted for age and BMI showed that 69% of population variance in GG is heritable, while the remaining 31% is due to unique environmental influences. In contrast, GSP was similarly correlated between monozygotic (r ϭ 0.55) and dizygotic (r ϭ 0.49) twins, hence not genetically determined. GG was strongly correlated to A1C (r ϭ 0.48), attributable mostly to genetic factors. About one-third of the heritability of A1C is shared with GG; the remainder is specific to A1C.CONCLUSIONS -Heritability of the GG accounts for about one-third of the heritability of A1C. By implication, there are gene(s) that preferentially affect erythrocyte lifespan or glucose and/or nonenzymatic glycation or deglycation in the intracellular, rather than extracellular, compartment. Diabetes Care 29:1739 -1743, 2006V ariation between different measures of glycemic control within subjects with diabetes is a common clinical finding (1-4). Yudkin et al. (5) and Gould et al. (6) described persistent differences between HbA 1c (A1C) and blood glucose in nondiabetic subjects and categorized these differences as "high glycator" and "low glycator" subsets. This observation has recently led to efforts to fractionate the variance in A1C to determine whether there are components that are more closely related to glycemic control and components that seem to remain constant despite variations in glycemic control. The strategy taken to fractionate the variance in A1C has been to examine the relationship between A1C and other measures of glycemic control, including, in one instance, glycated serum proteins (GSPs) using the measure fructosamine (i.e., resulting in a measure identified as the glycation gap [GG; previously called the glycosylation gap]) and in the other instance, by the mean of capillary blood glucose measured throughout the day (yielding a measure referred to as the hemoglobin glycation index [HGI]). Cohen et al. (7) reported that the GG is reproducible over time, despite variation in glycemic control reflected in A1C and GSPs. GG correlated with the development of diabetic nephropathy in a retrospective study. McCarter ...

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Section: Quantitative Genetic Model Fittingmentioning

confidence: 85%

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confidence: 84%

Evidence for Independent Heritability of the Glycation Gap (Glycosylation Gap) Fraction of HbA1c in Nondiabetic Twins

et al. 2006

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“…46,47 Whereas some authors interpret data as indicating minimal biologic variation in HbA1c between individuals, 4 others have found evidence for more marked differences resulting from poorly understood genetic factors. 48,49 After the elucidation of the nature of nonenzymatic glycation, 50,51 glycation rates have been shown to be subject to variation between individuals by factors that are independent of glucose concentration, including pH, 32 inorganic phosphate, 52 oxidative stress, 53 deglycation, 43,54 and Schiff base inhibitors. 55 These techniques used here, in combination with frequent blood glucose sampling, could evaluate the importance of these factors.…”

Section: Hba1c Synthesis Ratementioning

confidence: 99%

Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c

Cohen

Franco²,

Khera

et al. 2008

Blood

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Although red blood cell (RBC) life span is a known determinant of percentage hemoglobin A1c (HbA1c), its variation has been considered insufficient to affect clinical decisions in hematologically normal persons. However, an unexplained discordance between HbA1c and other measures of glycemic control can be observed that could be, in part, the result of differences in RBC life span. To explore the hypothesis that variation in RBC life span could alter measured HbA1c sufficiently to explain some of this discordance, we determined RBC life span using a biotin label in 6 people with diabetes and 6 nondiabetic controls.

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“…The heritability estimate shows how much of the phenotypic variance is attributable to the average effects of genes [6]. For fasting glucose, heritability studies in Northern Europe have mostly been done using twin registers, in which heritability estimates ranged from 38 to 51% [7][8][9]. Heritability estimates tend to be higher among twins than in extended pedigrees because of greater similarities in early-life environment and behavioural patterns among twins.…”

Section: Introductionmentioning

confidence: 99%

Heritability of fasting glucose levels in a young genetically isolated population

et al. 2006

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Aims/hypothesis: The heritability of fasting glucose levels in Northern European populations has been examined previously in twins and samples of small pedigrees. In this study the heritability of fasting plasma glucose (FPG) was estimated in participants in the Erasmus Rucphen Family study, who were members of a single pedigree from a young genetic isolate. We also studied the relationship between FPG and components of the metabolic syndrome. Methods: FPG, lipid, blood pressure and body composition measurements were completed for 852 participants without diabetic medication. The most significant predictors of FPG were used as covariates in heritability estimation. The sibship effect, which is a composite of genetic dominance and shared early-life environmental effects, was included as a random effect. Results: The age-and sex-adjusted heritability of log normal-transformed FPG was 36.6%. When further adjusted for metabolic risk factors, namely body composition parameters, systolic blood pressure, triglycerides and cholesterol:HDL ratio, the heritability estimate rose to 42.8%. After adjustment for the sibship effect, the additive component of heritability was estimated to be 28.3% (ageand sex-adjusted) and 24.9% (full model). Conclusions/ interpretation: Genes control a significant proportion of the variance in FPG levels. Adjustment for other metabolic risk factors did not substantially change the heritability estimate, which suggests that a large part of the variance in FPG levels is due to genes that act through pathways that are independent of those controlling body composition, blood pressure and lipid levels.

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HbA1c Levels Are Genetically Determined Even in Type 1 Diabetes

Cited by 178 publications

References 29 publications

Evidence for Independent Heritability of the Glycation Gap (Glycosylation Gap) Fraction of HbA1c in Nondiabetic Twins

Evidence for Independent Heritability of the Glycation Gap (Glycosylation Gap) Fraction of HbA1c in Nondiabetic Twins

Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c

Heritability of fasting glucose levels in a young genetically isolated population

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