An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians.

Pratley, Richard E.; Thompson, David V.; Procházka, Michal; Baier, Leslie J.; Mott, David M.; Ravussin, Éric; Sakul, H.; Ehm, Margaret G.; Burns, Daniel K.; Foroud, Tatiana; Garvey, W. Timothy; Hanson, Robert L.; Knowler, William C.; Bennett, Peter H.; Bogardus, Clifton

doi:10.1172/jci1850

Cited by 206 publications

(169 citation statements)

References 35 publications

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“…The Thr394Thr -Gly482Ser haplotype was significantly associated with Type II diabetes, although individual SNPs were not. Taken together with the reported data showing that plasma fasting insulin is linked to chromosome 4p15.1 [6], where the PGC-1 gene is located [7], the results of the study suggest that the PGC-1 gene is implicated in the pathogenesis of Type II diabetes. exercise activity thermogenesis in resistance to fat gain in humans.…”

Section: Discussionsupporting

confidence: 83%

“…This hypothesis has been supported by a quantitative-trait linkage (QTL) analysis in Pima Indians that suggests linkage of basal insulin concentrations, an indicator of insulin sensitivity, to chromosome 4p15.1 [6], where the PGC-1 gene is located [7]. Therefore, we studied whether genetic variations in the PGC-1 gene might influence insulin resistance and susceptibility to Type II diabetes.…”

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confidence: 94%

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A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes

et al. 2002

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Aims/hypothesis. Peroxisome proliferator activated receptor γ coactivator-1 (PGC-1), a transcriptional coactivator of the nuclear receptor PPARγ, plays a role in adaptive thermogenesis and insulin sensitivity. Plasma fasting insulin has been linked to the chromosomal region where the PGC-1 gene is located. Thus, PGC-1 can be viewed as a functional and positional candidate for the susceptibility gene for Type II (non-insulindependent) diabetes mellitus. Methods. After screening the PGC-1 gene for single nucleotide polymorphisms (SNPs), we performed an association study using the newly detected SNPs in 537 Type II diabetic patients and 417 non-diabetic subjects. Results. We found three relatively frequent SNPs in the PGC-1 gene (IVS4-11T > C, Thr394Thr and Gly482Ser). There were significant differences in fasting insulin (Gly/Gly; 37.7 ± 1.43, Gly/Ser; 40.2 ± 1.21, Ser/Ser; 44.3 ± 1.82 pmol/l, p = 0.018) and insulin resistance index (Gly/Gly; 1.48 ± 0.06, Gly/Ser; 1.56 ± 0.05, Ser/Ser; 1.75 ± 0.08, p = 0.027) according to the genotype of the Gly482Ser polymorphism. The Thr394Thr -Gly482Ser haplotype was associated with Type II diabetes (p = 0.00003). Conclusion/interpretation. The results of this study suggested that the PGC-1 gene might be implicated in the pathogenesis of Type II diabetes. [Diabetologia (2002) 45:740-743]

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Section: Discussionsupporting

confidence: 83%

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confidence: 94%

A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes

et al. 2002

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“…Since insulin resistance is a pre-diabetic phenotype, it is thought that genes influencing this metabolic abnormality could be fewer than those contributing to the complex diabetic syndrome. Chromosomal regions harbouring susceptibility genes for pre-diabetic phenotypes [7] Type II (non-insulin-dependent) diabetes mellitus is an increasingly common metabolic disease involving abnormal regulation of carbohydrate and lipid metab-and diabetes [8] have been identified using linkage analyses in the Pima population.…”

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confidence: 99%

Microarray profiling of skeletal muscle tissues from equally obese, non-diabetic insulin-sensitive and insulin-resistant Pima Indians

et al. 2002

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Aims/hypothesis. We carried out global transcript profiling to identify differentially expressed skeletal muscle genes in insulin resistance, a major risk factor for Type II (non-insulin-dependent) diabetes mellitus. This approach also complemented the ongoing genomic linkage analyses to identify genes linked to insulin resistance and diabetes in Pima Indians. Methods. We compared gene expression profiles of skeletal muscle tissues from 18 insulin-sensitive versus 17 insulin-resistant equally obese, non-diabetic Pima Indians using oligonucleotide arrays consisting of about 40,600 transcripts of known genes and expressed sequence tags, and analysed the results with the Wilcoxon rank sum test. We verified the mRNA expression of ten differentially (best-ranked) and ten similarly (worst-ranked) genes using quantitative Real Time PCR.Results. There were 185 differentially expressed transcripts by the rank sum test. The differential expressions of two out of the ten best-ranked genes were confirmed and the similar expressions of all ten worstranked genes were reproduced. Conclusion/interpretation. Of the 185 differentially expressed transcripts, 20 per cent were true positives and some could generate new hypotheses about the aetiology or pathophysiology of insulin resistance. Furthermore, differentially expressed genes in chromosomal regions with linkage to diabetes and insulin resistance serve as new diabetes susceptibility genes. [Diabetologia (2002[Diabetologia ( ) 45:1584[Diabetologia ( -1593

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“…These difficulties are encountered in all cross-sectional studies. The overlapping regions of linkage observed for the diabetes-related phenotypes in Pima [23] and Finnish [26] families, and the Framingham Offspring [6] and Heart Studies [25], support the existence of genes affecting fasting serum insulin concentrations on chromosomes 19 and 5 and fasting serum glucose on chromosome 13.…”

Section: Discussionmentioning

confidence: 78%

“…Regions of linkage in several reports overlap with those observed in this HyperGEN analysis. On chromosome 19, linkage was detected at 18 cM for fasting insulin in Pima Indians (LOD 1.33) [23], and for type 2 diabetes and glucose intolerance in young-onset French families at 36 cM (LOD 1.26) [24]. Linkage with fasting glucose, and combined fasting and non-fasting glucose, was detected on chromosome 5 at 0 cM in the Framingham Offspring Study (LOD 1.09) [6], and Framingham Heart Study (LOD 1.65) [25].…”

Section: Discussionmentioning

confidence: 99%

Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families

et al. 2005

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Aims/hypothesis: The heritability of fasting serum insulin and glucose concentrations in non-diabetic members of multiplex hypertensive families is unknown. Methods: We calculated the familial aggregation of fasting serum glucose and insulin concentrations and performed a genome-wide scan to assess whether quantitative trait loci contribute to these phenotypes in 2,412 non-diabetic individuals from 1,030 families enrolled in the Hypertension Genetic Epidemiology Network (HyperGEN) in the Family Blood Pressure Program. Results: The heritability (±SE) of fasting serum insulin was 0.47±0.085 in European Americans and 0.28±0.08 in African Americans (p<0.0001 for both), after adjusting for age, sex, and BMI. A genomewide scan for fasting serum insulin yielded a maximum log of the odds (LOD) score of 2.36 on chromosome 5 at 20 cM (p=0.0004) in European Americans, and an LOD score of 2.28 on chromosome 19 at 11 cM (p=0.0004) in African Americans. The heritability of fasting serum glucose was 0.5109±0.08 in the former and 0.29±0.09 in the latter (p<0.0003 for both) after adjusting for age, sex and BMI. A genome-wide scan for fasting serum glucose revealed a maximum LOD score of 2.07 on chromosome 5 at 26 cM (p=0.0009) in European Americans. Conclusions/ interpretation: These analyses demonstrate the marked heritability of fasting serum insulin and glucose concentrations in families enriched for the presence of members with hypertension. They suggest that genes associated with fasting serum insulin concentration are present on chromosomes 19 and 5, and that genes associated with fasting serum glucose concentration are on chromosome 5, in families enriched for hypertension.

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An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians.

Cited by 206 publications

References 35 publications

A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes

A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes

Microarray profiling of skeletal muscle tissues from equally obese, non-diabetic insulin-sensitive and insulin-resistant Pima Indians

Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families

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