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Thyroid Signaling, Insulin Resistance, and 2 Diabetes Mellitus: A Mendelian Randomization Study

Abstract Context: Increasing evidence suggests an association between thyroid-stimulating hormone (TSH), free thyroxine (fT4), and deiodinases with insulin resistance and type 2 diabetes mellitus (T2D). Objective: We examined whether TSH and fT4 levels and deiodinases are causally associated with in... Full description

Journal Title: The Journal of Clinical Endocrinology & Metabolism 2017, Vol.102 (6), p.1960-1970
Main Author: Bos, Maxime M
Other Authors: Smit, Roelof A. J , Trompet, Stella , van Heemst, Diana , Noordam, Raymond
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: Washington, DC: Endocrine Society
ID: ISSN: 0021-972X
Link: https://www.ncbi.nlm.nih.gov/pubmed/28323940
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title: Thyroid Signaling, Insulin Resistance, and 2 Diabetes Mellitus: A Mendelian Randomization Study
format: Article
creator:
  • Bos, Maxime M
  • Smit, Roelof A. J
  • Trompet, Stella
  • van Heemst, Diana
  • Noordam, Raymond
subjects:
  • Abridged Index Medicus
  • Alleles
  • Blood Glucose - metabolism
  • Confidence intervals
  • Databases, Factual
  • Diabetes
  • Diabetes mellitus
  • Diabetes Mellitus, Type 2 - genetics
  • Diabetes Mellitus, Type 2 - metabolism
  • Genetic variance
  • Genetic Variation
  • Genetics
  • Genome-wide association studies
  • Genome-Wide Association Study
  • Genomes
  • Glucose
  • Glucose metabolism
  • Glycated Hemoglobin A - metabolism
  • Hemoglobin
  • Humans
  • Insulin
  • Insulin - metabolism
  • Insulin resistance
  • Insulin Resistance - genetics
  • Iodide Peroxidase - genetics
  • Mendelian Randomization Analysis
  • Metabolism
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins c-maf - genetics
  • Randomization
  • Signaling
  • Statistical analysis
  • Thyroid
  • Thyroid gland
  • Thyroid-stimulating hormone
  • Thyrotropin - metabolism
  • Thyroxine
  • Thyroxine - metabolism
  • Vascular Endothelial Growth Factor A - genetics
ispartof: The Journal of Clinical Endocrinology & Metabolism, 2017, Vol.102 (6), p.1960-1970
description: Abstract Context: Increasing evidence suggests an association between thyroid-stimulating hormone (TSH), free thyroxine (fT4), and deiodinases with insulin resistance and type 2 diabetes mellitus (T2D). Objective: We examined whether TSH and fT4 levels and deiodinases are causally associated with insulin resistance and T2D, using Mendelian randomization. Methods: We selected 20 genetic variants for TSH level and four for fT4 level (identified in a genome-wide association study (GWAS) meta-analysis of European-ancestry cohorts) as instrumental variables for TSH and fT4 levels, respectively. We used summary data from GWASs on the outcomes T2D [Diabetes, Genetics Replication and Meta-analysis (DIAGRAM), n = 12,171 cases and n = 56,862 control subjects] and glycemic traits in patients without diabetes [Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), n = 46,186 for fasting glucose and insulin and n = 46,368 for hemoglobin A1c]. To examine whether the associations between TSH/fT4 levels and the study outcomes were causal, we combined the effects of the genetic instruments. Furthermore, we examined the associations among 16 variants in DIO1, DIO2, DIO3, and T2D and glycemic traits. Results: We found no evidence for an association between the combined genetic instrumental variables for TSH and fT4 and the study outcomes. For example, we did not observe a genetically determined association between high TSH level and T2D (odds ratio, 0.91 per standard deviation TSH increase; 95% confidence interval, 0.78 to 1.07). Selected genetic variants in DIO1 (e.g., rs7527713) were associated with measures of insulin resistance. Conclusion: We found no evidence for a causal association between circulatory levels of TSH and fT4 with insulin resistance and T2D, but we found suggestive evidence that DIO1 affects glucose metabolism. Using summary statistics data from the MAGIC and DIAGRAM consortia, we did not find evidence supporting a causal association between TSH and fT4 serum concentration and increased insulin resistance.
language: eng
source:
identifier: ISSN: 0021-972X
fulltext: no_fulltext
issn:
  • 0021-972X
  • 1945-7197
url: Link


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titleThyroid Signaling, Insulin Resistance, and 2 Diabetes Mellitus: A Mendelian Randomization Study
creatorBos, Maxime M ; Smit, Roelof A. J ; Trompet, Stella ; van Heemst, Diana ; Noordam, Raymond
creatorcontribBos, Maxime M ; Smit, Roelof A. J ; Trompet, Stella ; van Heemst, Diana ; Noordam, Raymond
descriptionAbstract Context: Increasing evidence suggests an association between thyroid-stimulating hormone (TSH), free thyroxine (fT4), and deiodinases with insulin resistance and type 2 diabetes mellitus (T2D). Objective: We examined whether TSH and fT4 levels and deiodinases are causally associated with insulin resistance and T2D, using Mendelian randomization. Methods: We selected 20 genetic variants for TSH level and four for fT4 level (identified in a genome-wide association study (GWAS) meta-analysis of European-ancestry cohorts) as instrumental variables for TSH and fT4 levels, respectively. We used summary data from GWASs on the outcomes T2D [Diabetes, Genetics Replication and Meta-analysis (DIAGRAM), n = 12,171 cases and n = 56,862 control subjects] and glycemic traits in patients without diabetes [Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), n = 46,186 for fasting glucose and insulin and n = 46,368 for hemoglobin A1c]. To examine whether the associations between TSH/fT4 levels and the study outcomes were causal, we combined the effects of the genetic instruments. Furthermore, we examined the associations among 16 variants in DIO1, DIO2, DIO3, and T2D and glycemic traits. Results: We found no evidence for an association between the combined genetic instrumental variables for TSH and fT4 and the study outcomes. For example, we did not observe a genetically determined association between high TSH level and T2D (odds ratio, 0.91 per standard deviation TSH increase; 95% confidence interval, 0.78 to 1.07). Selected genetic variants in DIO1 (e.g., rs7527713) were associated with measures of insulin resistance. Conclusion: We found no evidence for a causal association between circulatory levels of TSH and fT4 with insulin resistance and T2D, but we found suggestive evidence that DIO1 affects glucose metabolism. Using summary statistics data from the MAGIC and DIAGRAM consortia, we did not find evidence supporting a causal association between TSH and fT4 serum concentration and increased insulin resistance.
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languageeng
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subjectAbridged Index Medicus ; Alleles ; Blood Glucose - metabolism ; Confidence intervals ; Databases, Factual ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Type 2 - genetics ; Diabetes Mellitus, Type 2 - metabolism ; Genetic variance ; Genetic Variation ; Genetics ; Genome-wide association studies ; Genome-Wide Association Study ; Genomes ; Glucose ; Glucose metabolism ; Glycated Hemoglobin A - metabolism ; Hemoglobin ; Humans ; Insulin ; Insulin - metabolism ; Insulin resistance ; Insulin Resistance - genetics ; Iodide Peroxidase - genetics ; Mendelian Randomization Analysis ; Metabolism ; Odds Ratio ; Polymorphism, Single Nucleotide ; Proto-Oncogene Proteins c-maf - genetics ; Randomization ; Signaling ; Statistical analysis ; Thyroid ; Thyroid gland ; Thyroid-stimulating hormone ; Thyrotropin - metabolism ; Thyroxine ; Thyroxine - metabolism ; Vascular Endothelial Growth Factor A - genetics
ispartofThe Journal of Clinical Endocrinology & Metabolism, 2017, Vol.102 (6), p.1960-1970
rights
0Copyright © 2017 Endocrine Society 2017
1Copyright © Oxford University Press 2015
2Copyright © 2017 by the Endocrine Society
3Copyright © 2017 Endocrine Society
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1Smit, Roelof A. J
2Trompet, Stella
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4Noordam, Raymond
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1The Journal of Clinical Endocrinology & Metabolism
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descriptionAbstract Context: Increasing evidence suggests an association between thyroid-stimulating hormone (TSH), free thyroxine (fT4), and deiodinases with insulin resistance and type 2 diabetes mellitus (T2D). Objective: We examined whether TSH and fT4 levels and deiodinases are causally associated with insulin resistance and T2D, using Mendelian randomization. Methods: We selected 20 genetic variants for TSH level and four for fT4 level (identified in a genome-wide association study (GWAS) meta-analysis of European-ancestry cohorts) as instrumental variables for TSH and fT4 levels, respectively. We used summary data from GWASs on the outcomes T2D [Diabetes, Genetics Replication and Meta-analysis (DIAGRAM), n = 12,171 cases and n = 56,862 control subjects] and glycemic traits in patients without diabetes [Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), n = 46,186 for fasting glucose and insulin and n = 46,368 for hemoglobin A1c]. To examine whether the associations between TSH/fT4 levels and the study outcomes were causal, we combined the effects of the genetic instruments. Furthermore, we examined the associations among 16 variants in DIO1, DIO2, DIO3, and T2D and glycemic traits. Results: We found no evidence for an association between the combined genetic instrumental variables for TSH and fT4 and the study outcomes. For example, we did not observe a genetically determined association between high TSH level and T2D (odds ratio, 0.91 per standard deviation TSH increase; 95% confidence interval, 0.78 to 1.07). Selected genetic variants in DIO1 (e.g., rs7527713) were associated with measures of insulin resistance. Conclusion: We found no evidence for a causal association between circulatory levels of TSH and fT4 with insulin resistance and T2D, but we found suggestive evidence that DIO1 affects glucose metabolism. Using summary statistics data from the MAGIC and DIAGRAM consortia, we did not find evidence supporting a causal association between TSH and fT4 serum concentration and increased insulin resistance.
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0Abridged Index Medicus
1Alleles
2Blood Glucose - metabolism
3Confidence intervals
4Databases, Factual
5Diabetes
6Diabetes mellitus
7Diabetes Mellitus, Type 2 - genetics
8Diabetes Mellitus, Type 2 - metabolism
9Genetic variance
10Genetic Variation
11Genetics
12Genome-wide association studies
13Genome-Wide Association Study
14Genomes
15Glucose
16Glucose metabolism
17Glycated Hemoglobin A - metabolism
18Hemoglobin
19Humans
20Insulin
21Insulin - metabolism
22Insulin resistance
23Insulin Resistance - genetics
24Iodide Peroxidase - genetics
25Mendelian Randomization Analysis
26Metabolism
27Odds Ratio
28Polymorphism, Single Nucleotide
29Proto-Oncogene Proteins c-maf - genetics
30Randomization
31Signaling
32Statistical analysis
33Thyroid
34Thyroid gland
35Thyroid-stimulating hormone
36Thyrotropin - metabolism
37Thyroxine
38Thyroxine - metabolism
39Vascular Endothelial Growth Factor A - genetics
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titleThyroid Signaling, Insulin Resistance, and 2 Diabetes Mellitus: A Mendelian Randomization Study
authorBos, Maxime M ; Smit, Roelof A. J ; Trompet, Stella ; van Heemst, Diana ; Noordam, Raymond
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1Alleles
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3Confidence intervals
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5Diabetes
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7Diabetes Mellitus, Type 2 - genetics
8Diabetes Mellitus, Type 2 - metabolism
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abstractAbstract Context: Increasing evidence suggests an association between thyroid-stimulating hormone (TSH), free thyroxine (fT4), and deiodinases with insulin resistance and type 2 diabetes mellitus (T2D). Objective: We examined whether TSH and fT4 levels and deiodinases are causally associated with insulin resistance and T2D, using Mendelian randomization. Methods: We selected 20 genetic variants for TSH level and four for fT4 level (identified in a genome-wide association study (GWAS) meta-analysis of European-ancestry cohorts) as instrumental variables for TSH and fT4 levels, respectively. We used summary data from GWASs on the outcomes T2D [Diabetes, Genetics Replication and Meta-analysis (DIAGRAM), n = 12,171 cases and n = 56,862 control subjects] and glycemic traits in patients without diabetes [Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), n = 46,186 for fasting glucose and insulin and n = 46,368 for hemoglobin A1c]. To examine whether the associations between TSH/fT4 levels and the study outcomes were causal, we combined the effects of the genetic instruments. Furthermore, we examined the associations among 16 variants in DIO1, DIO2, DIO3, and T2D and glycemic traits. Results: We found no evidence for an association between the combined genetic instrumental variables for TSH and fT4 and the study outcomes. For example, we did not observe a genetically determined association between high TSH level and T2D (odds ratio, 0.91 per standard deviation TSH increase; 95% confidence interval, 0.78 to 1.07). Selected genetic variants in DIO1 (e.g., rs7527713) were associated with measures of insulin resistance. Conclusion: We found no evidence for a causal association between circulatory levels of TSH and fT4 with insulin resistance and T2D, but we found suggestive evidence that DIO1 affects glucose metabolism. Using summary statistics data from the MAGIC and DIAGRAM consortia, we did not find evidence supporting a causal association between TSH and fT4 serum concentration and increased insulin resistance.
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pubEndocrine Society
pmid28323940
doi10.1210/jc.2016-2816
oafree_for_read