Intermediate expansions of a GAA repeat in the frataxin gene are not associated with type 2 diabetes or altered glucose-induced beta-cell function in Danish Caucasians.

Dalgaard, Louise Torp; Hansen, Torben; Urhammer, S.; Clausen, Jesper O.; Eiberg, Hans; Pedersen, Ole Dyg

doi:10.2337/diabetes.48.4.914

Cited by 20 publications

(12 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Nondiabetic FA patients exhibit normal basal insulin oscillations (M. Ristow et al, unpublished observations) and normal glucose-stimulated insulin secretion (13) but show some degree of insulin resistance (14,15). While studies on a possible association between the common type 2 diabetes and the frataxin GAA triplet repeat expansions in humans are inconclusive (16)(17)(18)(19)(20)(21), linkage of type 2 diabetes with the locus harboring the human frataxin gene at 9q13 was found in at least four different populations worldwide (22)(23)(24)(25), suggesting a role in the pathogenesis of common type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Frataxin deficiency in pancreatic islets causes diabetes due to loss of β cell mass

Ristow¹,

Mulder²,

Pomplun³

et al. 2003

J. Clin. Invest.

124

103

View full text Add to dashboard Cite

Section: Introductionmentioning

confidence: 99%

Frataxin deficiency in pancreatic islets causes diabetes due to loss of β cell mass

Ristow¹,

Mulder²,

Pomplun³

et al. 2003

J. Clin. Invest.

124

103

View full text Add to dashboard Cite

“…This observation is supported by previous studies that have clearly indicated an increased incidence of diabetes in FA-patients (17,18) together with normal or sometimes increased stimulus-coupled insulin secretion in FA-patients (19)(20)(21)(22) and obligate heterozygous carriers (18,22) of the GAA-tract expansion (i.e., >50 GAA repeats). On the other hand, population-based studies on premutations (i.e., >15 but <51 GAA repeats) and their association with common type 2 diabetes are as inconclusive (23)(24)(25)(26) as studies on the relevance of these premutations on transcription of the -based insulin sensitivity test (Y-axis, linear scale). Control subjects are represented by ᭺, whereas subjects with a heterozygous GAA expansion are represented by .…”

mentioning

confidence: 99%

Heterozygous expansion of the GAA tract of the X25/frataxin gene is associated with insulin resistance in humans.

et al. 2000

View full text Add to dashboard Cite

Friedreich's ataxia (FA) is an autosomal recessive disease that has been attributed to a GAA triplet repeat expansion in the first intron of the X25/frataxin gene. Impaired glucose tolerance is present in up to 39% of FA patients, and clinically apparent diabetes is seen in ~18% of the affected individuals. Subjects carrying the X25/frataxin GAA repeat in a heterozygous state do not develop FA and, therefore, represent an ideal model to study the underlying metabolic defects that contribute to the diabetes associated with this disorder. In the present study, we have compared 11 first-degree relatives of FA patients (i.e., parents or heterozygous siblings of FA patients) with matched normal control subjects to study the parameters of glucose metabolism. An oral glucose tolerance test revealed diabetes in one of the heterozygous subjects who was excluded from further analyses. Using an octreotide-based quantification of insulin sensitivity, 8 of the remaining 10 study subjects showed pronounced insulin resistance, reflecting a significant difference from the control group (P = 0.001). In conclusion, a heterozygous expansion of the X25/frataxin GAA repeat in healthy individuals is associated with insulin resistance and might be considered a genetic co-factor in the pathogenesis of mitochondrial subtypes of diabetes. Diabetes 49:1604-1607, 2000 F riedreich's ataxia (FA) is phenotypically characterized by progressive ataxia and other neurological alterations in association with hypertrophic cardiomyopathy. The vast majority of FA patients carry a homozygous expansion of an intronic GAA tract of the X25/frataxin gene (1) leading to interference with the transcription of the frataxin gene (2) and subsequently decreasing expression of the frataxin protein (3). Frataxin is expressed in a wide variety of tissues, exhibits mitchondrial localization, and appears to be essential for embryonic development (4) in mice. Frataxin is most abundant in tissues with high metabolic activity, including skeletal muscle and brown fat (5). The characterization of the yeast frataxin homolog suggests a central role in oxidative phosphorylation (6). Furthermore, frataxin was proposed to regulate mitochondrial iron content (7,8) and to decrease oxidative damage to the cell (9,10). Frataxin is a mitochondrial protein that is significantly reduced in FA patients because of decreased transcription subsequent to expanded intronic GAA repeats on both copies of the X25/frataxin gene. Heterozygous carriers for this expansion are phenotypically normal but presumably exhibit a decreased expression of frataxin (2,11). In the present study, these heterozygous individuals were evaluated for alterations in glucose metabolism, specifically incidence of diabetes and insulin resistance.First, first-degree relatives of FA patients were genotyped, as described in RESEARCH DESIGN AND METHODS, to assure the presence of GAA expansions, especially in siblings of the patients. Eleven subjects from 4 different unrelated families were analyzed (8 parents and 3 sibli...

show abstract

“…25 In these calculations we assumed an intermediate GAA-repeat frequency of B30% as reported in Scandinavians 15 and an odds ratio (OR) of 3.3 in carriers vs noncarriers, as reported in the initial positive study by Ristow et al 18 We further assumed a T2D disease prevalence of B6%. Under these parameters, we estimate that B130 trios and B150 cases and B100 controls would provide 95% power to reject the null hypothesis of no association at ao0.05 under a dominant model.…”

Section: Discussionmentioning

confidence: 99%

Haplotype construction of the FRDA gene and evaluation of its role in type II diabetes

et al. 2005

View full text Add to dashboard Cite

A GAA-repeat in the X25 gene is causing Friedreich's ataxia (FRDA), a common neurodegenerative disease and 420% of FRDA patients develop type II diabetes (T2D). Linkage has previously been detected between T2D and chromosome 9p13-q21, the region that harbours the X25 gene, but association studies of this gene in T2D have been contradicting. Here, we examined whether genetic variation in the X25 gene is associated with risk for T2D. The GAA-repeat and 18 single nucleotide polymorphisms (SNPs) covering the X25 gene were genotyped in 220 trios in which the affected offspring had abnormal glucose tolerance. Any nominally significant findings were examined in an independent sample consisting of 523 individuals with T2D and 326 healthy controls. Previously reported results were analysed together with our data using a meta-analysis approach. There was no association between the GAA-repeat and T2D susceptibility in our study, which was supported by the meta-analysis including all previous publications. One SNP (rs2498429), 8.2 kb downstream of X25, was nominally associated with T2D in the trios (P ¼ 0.02) and showed a trend of association in the same direction in the case-controls (P ¼ 0.08; combined permuted P ¼ 0.01). Further analysis showed that the nine-marker haplotype containing the rare allele of rs2498429 was nominally associated with T2D in the trios (Po0.01) as well as in the case -controls (P ¼ 0.03). In conclusions, this study excludes a role of genetic variation within the X25 gene, but instead suggests that genetic variation downstream the X25 gene, may increase risk for T2D.

show abstract

Intermediate expansions of a GAA repeat in the frataxin gene are not associated with type 2 diabetes or altered glucose-induced beta-cell function in Danish Caucasians.

Cited by 20 publications

References 2 publications

Frataxin deficiency in pancreatic islets causes diabetes due to loss of β cell mass

Frataxin deficiency in pancreatic islets causes diabetes due to loss of β cell mass

Heterozygous expansion of the GAA tract of the X25/frataxin gene is associated with insulin resistance in humans.

Haplotype construction of the FRDA gene and evaluation of its role in type II diabetes

Contact Info

Product

Resources

About