Heritability estimates for beta cell function and features of the insulin resistance syndrome in UK families with an increased susceptibility to Type 2 diabetes

Mills, GW; Avery, P. J.; McCarthy, Mark I.; Hattersley, Andrew T.; Levy, Jonathan C.; Hitman, GA; Sampson, MJ; Walker, Mark

doi:10.1007/s00125-004-1338-2

Cited by 108 publications

(82 citation statements)

References 19 publications

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“…This is justified under the assumption that heritable precursors of type 2 diabetes will share the same genetic determinants as type 2 diabetes itself. Diabetes-related QTs are heritable in multiple ethnic groups (for examples, see [94][95][96]), and many also predict the subsequent development of diabetes (for examples, see [97][98][99]). In addition, genetic correlation has been demonstrated between type 2 diabetes and some QTs [100] and between various QTs [14, 37, 96, 100-102].…”

Section: Discussionmentioning

confidence: 99%

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

Lillioja

Wilton

2009

Diabetologia

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Aims/hypothesis Little of the genetic basis for type 2 diabetes has been explained, despite numerous genetic linkage studies and the discovery of multiple genes in genome-wide association (GWA) studies. To begin to resolve the genetic component of this disease, we searched for sites at which genetic results had been corroborated in different studies, in the expectation that replication among studies should direct us to the genomic locations of causative genes with more confidence than the results of individual studies. Methods We have mapped the physical location of results from 83 linkage reports (for type 2 diabetes and diabetes precursor quantitative traits [QTs, e.g. plasma insulin levels]) and recent large GWA reports (for type 2 diabetes) onto the same human genome sequence to identify replicated results in diabetes genetic 'hot spots'. Results Genetic linkage has been found at least ten times at 18 different locations, and at least five times in 56 locations. All replication clusters contained study populations from more than one ethnic background and most contained results for both diabetes and QTs. There is no close relationship between the GWA results and linkage clusters, and the nine best replication clusters have no nearby GWA result. Conclusions/interpretation Many of the genes for type 2 diabetes remain unidentified. This analysis identifies the broad location of yet to be identified genes on 6q, 1q, 18p, 2q, 20q, 17pq, 8p, 19q and 9q. The discrepancy between the linkage and GWA studies may be explained by the presence of multiple, uncommon, mildly deleterious polymorphisms scattered throughout the regulatory and coding regions of genes for type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

Lillioja

Wilton

2009

Diabetologia

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“…Twin [2][3][4][5] and family studies [6][7][8][9][10] support the notion that people who develop type 2 diabetes have a strong genetic predisposition, which may be partly conveyed through genetic effects on insulin resistance. Two twin studies, for instance, showed a significant genetic contribution to insulin sensitivity, assessed by euglycaemic-hyperinsulinaemic clamp with heritability estimates of 37% and 55% [11,12].…”

Section: Introductionmentioning

confidence: 89%

Genetic influences on the insulin response of the beta cell to different secretagogues

Simonis-Bik

Eekhoff

Moor³

et al. 2009

Diabetologia

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Aims/hypothesis The aim of the present study was to estimate the heritability of the beta cell insulin response to glucose and to glucose combined with glucagon-like peptide-1 (GLP-1) or with GLP-1 plus arginine. Methods This was a twin-family study that included 54 families from the Netherlands Twin Register. The participants were healthy twin pairs and their siblings of the same sex, aged 20 to 50 years. Insulin response of the beta cell was assessed by a modified hyperglycaemic clamp with additional GLP-1 and arginine. Insulin sensitivity index (ISI) was assessed by the euglycaemic-hyperinsulinaemic clamp. Multivariate structural equation modelling was used to obtain heritabilities and the genetic factors underlying individual differences in BMI, ISI and secretory responses of the beta cell. Results The heritability of insulin levels in response to glucose was 52% and 77% for the first and second phase, respectively, 53% in response to glucose+GLP-1 and 80% in response to an additional arginine bolus. Insulin responses to the administration of glucose, glucose+GLP-1 and glucose + GLP-1 + arginine were highly correlated (0.62

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“…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. In family studies, heritability estimates vary widely (8-72%), which may be partly due to ascertainment bias [10,11]. In a study of 89 randomly ascertained pedigrees, in which variance due to childhood household was also measured, the heritability of fasting glucose was 18% after adjustment for age, sex, BMI, and smoking [12].…”

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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Heritability estimates for beta cell function and features of the insulin resistance syndrome in UK families with an increased susceptibility to Type 2 diabetes

Cited by 108 publications

References 19 publications

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies

Genetic influences on the insulin response of the beta cell to different secretagogues

Heritability of fasting glucose levels in a young genetically isolated population

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