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Article ; Online: Circulatory MicroRNAs in Plasma and Atrial Fibrillation in the General Population: The Rotterdam Study.

Geurts, Sven / Mens, Michelle M J / Bos, Maxime M / Ikram, M Arfan / Ghanbari, Mohsen / Kavousi, Maryam

2021 Volume 13, Issue 1

Abstract: Background: MicroRNAs (miRNAs), small non-coding RNAs regulating gene expression, have been shown to play an important role in cardiovascular disease. However, limited population-based data regarding the relationship between circulatory miRNAs in plasma ...

Abstract	Background: MicroRNAs (miRNAs), small non-coding RNAs regulating gene expression, have been shown to play an important role in cardiovascular disease. However, limited population-based data regarding the relationship between circulatory miRNAs in plasma and atrial fibrillation (AF) exist. Moreover, it remains unclear if the relationship differs by sex. We therefore aimed to determine the (sex-specific) association between plasma circulatory miRNAs and AF at the population level. Methods: Plasma levels of miRNAs were measured using a targeted next-generation sequencing method in 1999 participants from the population-based Rotterdam Study. Logistic regression and Cox proportional hazards models were used to assess the associations of 591 well-expressed miRNAs with the prevalence and incidence of AF. Models were adjusted for cardiovascular risk factors. We further examined the link between predicted target genes of the identified miRNAs. Results: The mean age was 71.7 years (57.1% women), 98 participants (58 men and 40 women) had prevalent AF at baseline. Moreover, 196 participants (96 men and 100 women) developed AF during a median follow-up of 9.0 years. After adjusting for multiple testing, miR-4798-3p was significantly associated with the odds of prevalent AF among men (odds ratio, 95% confidence interval, 0.39, 0.24-0.66, Conclusions: Plasma levels of miR-4798-3p were significantly associated with the odds of prevalent AF among men. Several target genes in relation to AF pathophysiology could potentially be regulated by miR-4798-3p that warrant further investigations in future experimental studies.
MeSH term(s)	Aged ; Atrial Fibrillation/genetics ; Circulating MicroRNA/genetics ; Female ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Male ; Oxidative Stress/genetics
Chemical Substances	Circulating MicroRNA
Language	English
Publishing date	2021-12-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13010011
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Article ; Online: Genetically Determined Higher TSH Is Associated With a Lower Risk of Diabetes Mellitus in Individuals With Low BMI.

Bos, Maxime M / van Vliet, Nicolien A / Mooijaart, Simon P / Noordam, Raymond / van Heemst, Diana

The Journal of clinical endocrinology and metabolism

2021 Volume 106, Issue 7, Page(s) e2502–e2511

Abstract: Context: Thyroid status is hypothesized to be causally related with the risk of diabetes mellitus (DM), but previous results were conflicting possibly because of a complex interaction between thyrotropin (TSH), body mass index (BMI) and DM.: Objective! ...

Abstract	Context: Thyroid status is hypothesized to be causally related with the risk of diabetes mellitus (DM), but previous results were conflicting possibly because of a complex interaction between thyrotropin (TSH), body mass index (BMI) and DM. Objective: This work aims to investigate the causal association between thyroid status with DM and glucose homeostasis and to what extent this association is dependent on BMI. Methods: A mendelian randomization study was conducted of European-ancestry participants from the UK Biobank population. The present study involved 408 895 individuals (mean age 57.4 years [SD 8.0], 45.9% men), of whom 19 773 had DM. Genetic variants for circulatory TSH, free thyroxine (fT4) concentrations and BMI to calculate weighted genetic risk scores. The main outcome measures included self-reported DM-stratified analyses by BMI. Analyses were repeated for nonfasting glucose and glycated hemoglobin A1c (HbA1c) among individuals without DM. Results: Genetically determined TSH and fT4 levels were not associated with risk of DM in the total UK Biobank population. However, in analyses stratified on genetically determined BMI, genetically determined higher TSH, and not fT4, was associated with a lower risk for DM only in the low BMI group (odds ratio 0.91; 95% CI, 0.85-0.98 in low BMI; P value for interaction = .06). Similar results were observed for glucose and HbA1c among individuals without DM. Conclusion: TSH, but not fT4, is a potential causal risk factor for DM in individuals with genetically determined low BMI highlighting potential protective effects of TSH only in low-risk populations.
MeSH term(s)	Adult ; Aged ; Blood Glucose/analysis ; Body Mass Index ; Diabetes Mellitus/epidemiology ; Diabetes Mellitus/genetics ; Female ; Genome-Wide Association Study ; Glycated Hemoglobin A/analysis ; Humans ; Male ; Mendelian Randomization Analysis ; Middle Aged ; Odds Ratio ; Polymorphism, Single Nucleotide ; Risk Factors ; Thyroid Function Tests ; Thyrotropin/blood ; Thyroxine/blood ; United Kingdom/epidemiology ; Whites/genetics
Chemical Substances	Blood Glucose ; Glycated Hemoglobin A ; Thyrotropin (9002-71-5) ; Thyroxine (Q51BO43MG4)
Language	English
Publishing date	2021-04-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/clinem/dgab277
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Article: Circulatory MicroRNAs in Plasma and Atrial Fibrillation in the General Population: The Rotterdam Study

Geurts, Sven / Mens, Michelle M. J. / Bos, Maxime M. / Ikram, M. Arfan / Ghanbari, Mohsen / Kavousi, Maryam

Genes. 2021 Dec. 22, v. 13, no. 1

2021

Abstract	Background: MicroRNAs (miRNAs), small non-coding RNAs regulating gene expression, have been shown to play an important role in cardiovascular disease. However, limited population-based data regarding the relationship between circulatory miRNAs in plasma and atrial fibrillation (AF) exist. Moreover, it remains unclear if the relationship differs by sex. We therefore aimed to determine the (sex-specific) association between plasma circulatory miRNAs and AF at the population level. Methods: Plasma levels of miRNAs were measured using a targeted next-generation sequencing method in 1999 participants from the population-based Rotterdam Study. Logistic regression and Cox proportional hazards models were used to assess the associations of 591 well-expressed miRNAs with the prevalence and incidence of AF. Models were adjusted for cardiovascular risk factors. We further examined the link between predicted target genes of the identified miRNAs. Results: The mean age was 71.7 years (57.1% women), 98 participants (58 men and 40 women) had prevalent AF at baseline. Moreover, 196 participants (96 men and 100 women) developed AF during a median follow-up of 9.0 years. After adjusting for multiple testing, miR-4798-3p was significantly associated with the odds of prevalent AF among men (odds ratio, 95% confidence interval, 0.39, 0.24–0.66, p-value = 0.000248). No miRNAs were significantly associated with incident AF. MiR-4798-3p could potentially regulate the expression of a number of AF-related genes, including genes involved in calcium and potassium handling in myocytes, protection of cells against oxidative stress, and cardiac fibrosis. Conclusions: Plasma levels of miR-4798-3p were significantly associated with the odds of prevalent AF among men. Several target genes in relation to AF pathophysiology could potentially be regulated by miR-4798-3p that warrant further investigations in future experimental studies.
Keywords	atrial fibrillation ; calcium ; confidence interval ; fibrosis ; gene expression ; microRNA ; myocytes ; odds ratio ; oxidative stress ; pathophysiology ; potassium ; regression analysis
Language	English
Dates of publication	2021-1222
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes13010011
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Article ; Online: Apolipoprotein E genotype, lifestyle and coronary artery disease: Gene-environment interaction analyses in the UK Biobank population.

Bos, Maxime M / de Vries, Lina / Rensen, Patrick Cn / Willems van Dijk, Ko / Blauw, Gerard Jan / van Heemst, Diana / Noordam, Raymond

Atherosclerosis

2021 Volume 328, Page(s) 33–37

Abstract: Background and aims: The APOE ε4 genotype has a higher risk for developing coronary artery disease (CAD), but there is preliminary evidence that antioxidative lifestyle factors interact with APOE genotype on CAD risk. Here, we assessed the effect ... ...

Abstract	Background and aims: The APOE ε4 genotype has a higher risk for developing coronary artery disease (CAD), but there is preliminary evidence that antioxidative lifestyle factors interact with APOE genotype on CAD risk. Here, we assessed the effect modification of physical activity, oily fish and polyunsaturated fatty acid (PUFA) intake with APOE genotype on risk of incident CAD. Methods: The present study comprised 345,659 white European participants from UK Biobank (mean age: 56.5 years, 45.7% men) without a history of CAD. Information regarding physical activity, oily fish intake and PUFA intake was collected through questionnaires, and information on incident CAD through linkage with hospital admission records. Analyses were performed using Cox proportional hazard models adjusted for age and sex. Results: Higher physical activity level and oily fish intake were both associated with a lower incidence of CAD. However, these associations were similar across the different APOE genotypes (p-values for interaction > 0.05). Most notable, higher PUFA intake was associated with a lower CAD risk in APOE ε4 genotype carriers (hazard ratio: 0.76, 95% confidence interval: 0.63-0.92), and not in APOE ε3/ε3 genotype carriers (0.90; 0.79, 1.02), but without statistical evidence for effect modification (p-value Conclusions: While higher physical activity and high fish and PUFA intake were associated with a lower risk of incident CAD, no evidence for interaction of these lifestyle factors with APOE genotype was observed in UK Biobank participants. Interventions intended to reduce cardiovascular risk might therefore be similarly effective across the APOE genotype carriers.
MeSH term(s)	Animals ; Apolipoproteins E/genetics ; Biological Specimen Banks ; Coronary Artery Disease/diagnosis ; Coronary Artery Disease/epidemiology ; Coronary Artery Disease/genetics ; Female ; Gene-Environment Interaction ; Genotype ; Humans ; Life Style ; Male ; Middle Aged ; United Kingdom/epidemiology
Chemical Substances	ApoE protein, human ; Apolipoproteins E
Language	English
Publishing date	2021-05-27
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80061-2
ISSN	1879-1484 ; 0021-9150
ISSN (online)	1879-1484
ISSN	0021-9150
DOI	10.1016/j.atherosclerosis.2021.05.014
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Article ; Online: BMI-associated gene variants in

Ganeff, Ingeborg M M / Bos, Maxime M / van Heemst, Diana / Noordam, Raymond

Physiological genomics

2019 Volume 51, Issue 8, Page(s) 311–322

Abstract: Obesity is a causal risk factor for the development of age-related disease conditions, which includes Type 2 diabetes mellitus, cardiovascular disease, and dementia. In genome-wide association studies, genetic variation ... ...

Abstract	Obesity is a causal risk factor for the development of age-related disease conditions, which includes Type 2 diabetes mellitus, cardiovascular disease, and dementia. In genome-wide association studies, genetic variation in
MeSH term(s)	Adiposity/genetics ; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics ; Body Mass Index ; Brain Diseases/genetics ; Cardiovascular Diseases/genetics ; Diabetes Mellitus, Type 2/genetics ; Eating/genetics ; Energy Metabolism/genetics ; Genetic Pleiotropy ; Humans ; Obesity/genetics ; Polymorphism, Single Nucleotide/genetics
Chemical Substances	Alpha-Ketoglutarate-Dependent Dioxygenase FTO (EC 1.14.11.33) ; FTO protein, human (EC 1.14.11.33)
Language	English
Publishing date	2019-06-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2038823-8
ISSN	1531-2267 ; 1094-8341
ISSN (online)	1531-2267
ISSN	1094-8341
DOI	10.1152/physiolgenomics.00040.2019
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Zs.A 5697: Show issues

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Article ; Online: Association Between Sex-Specific Risk Factors and Risk of New-Onset Atrial Fibrillation Among Women.

Lu, Zuolin / Aribas, Elif / Geurts, Sven / Roeters van Lennep, Jeanine E / Ikram, M Arfan / Bos, Maxime M / de Groot, Natasja M S / Kavousi, Maryam

JAMA network open

2022 Volume 5, Issue 9, Page(s) e2229716

Abstract: Importance: Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with different epidemiological and pathophysiological processes for women vs men and a poorer prognosis for women. Further investigation of sex-specific risk factors ... ...

Abstract	Importance: Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide, with different epidemiological and pathophysiological processes for women vs men and a poorer prognosis for women. Further investigation of sex-specific risk factors associated with AF development in women is warranted. Objective: To investigate the linear and potential nonlinear associations between sex-specific risk factors and the risk of new-onset AF in women. Design, setting, and participants: This population-based cohort study obtained data from the 2006 to 2010 UK Biobank study, a cohort of more than 500 000 participants aged 40 to 69 years. Participants were women without AF and history of hysterectomy and/or bilateral oophorectomy at baseline. Median follow-up period for AF onset was 11.6 years, and follow-up ended on October 3, 2020. Exposures: Self-reported, sex-specific risk factors, including age at menarche, history of irregular menstrual cycle, menopause status, age at menopause, years after menopause, age at first live birth, years after last birth, history of spontaneous miscarriages, history of stillbirths, number of live births, and total reproductive years. Main outcomes and measures: The primary outcome was new-onset AF, which was defined by the use of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code I48. Results: A total of 235 191 women (mean [SD] age, 55.7 [8.1] years) were included in the present study. During follow-up, 4629 (2.0%) women experienced new-onset AF. In multivariable-adjusted models, history of irregular menstrual cycle was associated with higher AF risk (hazard ratio [HR], 1.34; 95% CI, 1.01-1.79). Both early menarche (age 7-11 years; HR, 1.10 [95% CI, 1.00-1.21]) and late menarche (age 13-18 years; HR, 1.08 [95% CI, 1.00-1.17]) were associated with AF incidence. Early menopause (age 35-44 years; HR, 1.24 [95% CI, 1.10-1.39]) and delayed menopause (age ≥60 years; HR, 1.34 [95% CI, 1.10-1.78]) were associated with higher risk of AF. Compared with women with 1 to 2 live births, those with 0 live births (HR, 1.13; 95% CI, 1.04-1.24) or 7 or more live births (HR, 1.67; 95% CI, 1.03-2.70) both had significantly higher AF risk. Conclusions and relevance: Results of this study suggest that irregular menstrual cycles, nulliparity, and multiparity were associated with higher risk of new-onset AF among women. The results highlight the importance of taking into account the reproductive history of women in devising screening strategies for AF prevention.
MeSH term(s)	Atrial Fibrillation/complications ; Atrial Fibrillation/etiology ; Cohort Studies ; Female ; Humans ; Incidence ; Male ; Menopause ; Middle Aged ; Risk Factors
Language	English
Publishing date	2022-09-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2022.29716
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Article ; Online: Autoimmune diseases and new-onset atrial fibrillation: a UK Biobank study.

Tilly, Martijn J / Geurts, Sven / Zhu, Fang / Bos, Maxime M / Ikram, M Arfan / de Maat, Moniek P M / de Groot, Natasja M S / Kavousi, Maryam

Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology

2022 Volume 25, Issue 3, Page(s) 804–811

Abstract: Aims: The underlying mechanisms of atrial fibrillation (AF) are largely unknown. Inflammation may underlie atrial remodelling. Autoimmune diseases, related to increased systemic inflammation, may therefore be associated with new-onset AF.: Methods and ...

Abstract	Aims: The underlying mechanisms of atrial fibrillation (AF) are largely unknown. Inflammation may underlie atrial remodelling. Autoimmune diseases, related to increased systemic inflammation, may therefore be associated with new-onset AF. Methods and results: Participants from the population-based UK Biobank were screened for rheumatic fever, gastrointestinal autoimmune diseases, autoimmune diseases targeting the musculoskeletal system and connective tissues, and neurological autoimmune diseases. Between 2006 and 2022, participants were followed for incident AF. Cox proportional hazards regression analyses were performed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) to quantify associations. 494 072 participants free from AF were included (median age 58.0 years, 54.8% women). After a median of 12.8 years, 27 194 (5.5%) participants were diagnosed with new-onset AF. Rheumatic fever without heart involvement (HR, 95% CI: 1.47, 1.26-1.72), Crohn's disease (1.23, 1.05-1.45), ulcerative colitis (1.17, 1.06-1.31), rheumatoid arthritis (1.39, 1.28-1.51), polyarteritis nodosa (1.82, 1.04-3.09), systemic lupus erythematosus (1.82, 1.41-2.35), and systemic sclerosis (2.32, 1.57-3.44) were associated with a larger AF risk. In sex-stratified analyses, rheumatic fever without heart involvement, multiple sclerosis, Crohn's disease, seropositive rheumatoid arthritis, psoriatic and enteropathic arthropathies, systemic sclerosis and ankylosing spondylitis were associated with larger AF risk in women, whereas only men showed a larger AF risk associated with ulcerative colitis. Conclusions: Various autoimmune diseases are associated with new-onset AF, more distinct in women. Our findings elaborate on the pathophysiological differences in autoimmunity and AF risk between men and women.
MeSH term(s)	Male ; Humans ; Female ; Middle Aged ; Atrial Fibrillation/diagnosis ; Atrial Fibrillation/epidemiology ; Crohn Disease ; Colitis, Ulcerative ; Rheumatic Fever ; Biological Specimen Banks ; Autoimmune Diseases/diagnosis ; Autoimmune Diseases/epidemiology ; Inflammation ; Scleroderma, Systemic ; United Kingdom/epidemiology ; Risk Factors ; Incidence
Language	English
Publishing date	2022-12-21
Publishing country	England
Document type	Journal Article
ZDB-ID	1449879-0
ISSN	1532-2092 ; 1099-5129
ISSN (online)	1532-2092
ISSN	1099-5129
DOI	10.1093/europace/euac244
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Article ; Online: Disentangling the association between kidney function and atrial fibrillation: a bidirectional Mendelian randomization study.

Geurts, Sven / van der Burgh, Anna C / Bos, Maxime M / Ikram, M Arfan / Stricker, Bruno H C / Deckers, Jaap W / Hoorn, Ewout J / Chaker, Layal / Kavousi, Maryam

International journal of cardiology

2022 Volume 355, Page(s) 15–22

Abstract: Background: The potential bidirectional causal association between kidney function and atrial fibrillation (AF) remains unclear.: Methods: We conducted a bidirectional two-sample Mendelian randomization (MR) analysis. From multiple genome-wide ... ...

Abstract	Background: The potential bidirectional causal association between kidney function and atrial fibrillation (AF) remains unclear. Methods: We conducted a bidirectional two-sample Mendelian randomization (MR) analysis. From multiple genome-wide association studies (GWAS), we retrieved genetic variants associated with kidney function (estimated glomerular filtration rate based on creatinine (eGFRcreat), blood urea nitrogen (BUN), chronic kidney disease (CKD stage ≥G3): n = 1,045,620, eGFR based on cystatin C: n = 24,063-32,861, urine albumin-to-creatinine ratio (UACR), and microalbuminuria: n = 564,257), and AF (n = 1,030,836). The inverse-variance weighted method was used as our main analysis. Results: MR analyses supported a causal effect of CKD (n = 9 SNPs, odds ratio (OR): 1.10, 95% confidence interval (CI): 1.04-1.17, p-value = 1.97 × 10 Conclusions: Our results supported a bidirectional causal association between kidney function and AF. The shared genetic architecture between kidney dysfunction and AF might represent potential important therapeutic targets to prevent both conditions in the general population.
MeSH term(s)	Atrial Fibrillation/diagnosis ; Atrial Fibrillation/epidemiology ; Atrial Fibrillation/genetics ; Genome-Wide Association Study ; Glomerular Filtration Rate/genetics ; Humans ; Kidney ; Mendelian Randomization Analysis ; Polymorphism, Single Nucleotide/genetics
Language	English
Publishing date	2022-03-09
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	779519-1
ISSN	1874-1754 ; 0167-5273
ISSN (online)	1874-1754
ISSN	0167-5273
DOI	10.1016/j.ijcard.2022.03.004
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Article ; Online: Coronary Artery Calcium Score and Polygenic Risk Score for the Prediction of Coronary Heart Disease Events.

Khan, Sadiya S / Post, Wendy S / Guo, Xiuqing / Tan, Jingyi / Zhu, Fang / Bos, Daniel / Sedaghati-Khayat, Bahar / van Rooij, Jeroen / Aday, Aaron / Allen, Norrina B / Bos, Maxime M / Uitterlinden, André G / Budoff, Matthew J / Lloyd-Jones, Donald M / Mosley, Jonathan D / Rotter, Jerome I / Greenland, Philip / Kavousi, Maryam

JAMA

2023 Volume 329, Issue 20, Page(s) 1768–1777

Abstract: Importance: Coronary artery calcium score and polygenic risk score have each separately been proposed as novel markers to identify risk of coronary heart disease (CHD), but no prior studies have directly compared these markers in the same cohorts.: ... ...

Abstract	Importance: Coronary artery calcium score and polygenic risk score have each separately been proposed as novel markers to identify risk of coronary heart disease (CHD), but no prior studies have directly compared these markers in the same cohorts. Objective: To evaluate change in CHD risk prediction when a coronary artery calcium score, a polygenic risk score, or both are added to a traditional risk factor-based model. Design, setting, and participants: Two observational population-based studies involving individuals aged 45 years through 79 years of European ancestry and free of clinical CHD at baseline: the Multi-Ethnic Study of Atherosclerosis (MESA) study involved 1991 participants at 6 US centers and the Rotterdam Study (RS) involved 1217 in Rotterdam, the Netherlands. Exposure: Traditional risk factors were used to calculate CHD risk (eg, pooled cohort equations [PCEs]), computed tomography for the coronary artery calcium score, and genotyped samples for a validated polygenic risk score. Main outcomes and measures: Model discrimination, calibration, and net reclassification improvement (at the recommended risk threshold of 7.5%) for prediction of incident CHD events were assessed. Results: The median age was 61 years in MESA and 67 years in RS. Both log (coronary artery calcium+1) and polygenic risk score were significantly associated with 10-year risk of incident CHD (hazards ratio per SD, 2.60; 95% CI, 2.08-3.26 and 1.43; 95% CI, 1.20-1.71, respectively), in MESA. The C statistic for the coronary artery calcium score was 0.76 (95% CI, 0.71-0.79) and for the polygenic risk score, 0.69 (95% CI, 0.63-0.71). The change in the C statistic when each was added to the PCEs was 0.09 (95% CI, 0.06-0.13) for the coronary artery calcium score, 0.02 (95% CI, 0.00-0.04) for the polygenic risk score, and 0.10 (95% CI, 0.07-0.14) for both. Overall categorical net reclassification improvement was significant when the coronary artery calcium score (0.19; 95% CI, 0.06-0.28) but was not significant when the polygenic risk score (0.04; 95% CI, -0.05 to 0.10) was added to the PCEs. Calibration of the PCEs and models with coronary artery calcium and/or polygenic risk scores was adequate (all χ2<20). Subgroup analysis stratified by the median age demonstrated similar findings. Similar findings were observed for 10-year risk in RS and in longer-term follow-up in MESA (median, 16.0 years). Conclusions and relevance: In 2 cohorts of middle-aged to older adults from the US and the Netherlands, the coronary artery calcium score had better discrimination than the polygenic risk score for risk prediction of CHD. In addition, the coronary artery calcium score but not the polygenic risk score significantly improved risk discrimination and risk reclassification for CHD when added to traditional risk factors.
MeSH term(s)	Aged ; Humans ; Middle Aged ; Atherosclerosis/diagnostic imaging ; Calcium ; Coronary Disease/diagnostic imaging ; Coronary Vessels/diagnostic imaging ; Coronary Vessels/pathology ; Risk Factors ; Risk Assessment
Chemical Substances	Calcium (SY7Q814VUP)
Language	English
Publishing date	2023-05-23
Publishing country	United States
Document type	Journal Article ; Multicenter Study ; Observational Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2958-0
ISSN	1538-3598 ; 0254-9077 ; 0002-9955 ; 0098-7484
ISSN (online)	1538-3598
ISSN	0254-9077 ; 0002-9955 ; 0098-7484
DOI	10.1001/jama.2023.7575
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Article ; Online: Thyroid Signaling, Insulin Resistance, and 2 Diabetes Mellitus: A Mendelian Randomization Study.

Bos, Maxime M / Smit, Roelof A J / Trompet, Stella / van Heemst, Diana / Noordam, Raymond

The Journal of clinical endocrinology and metabolism

2017 Volume 102, Issue 6, Page(s) 1960–1970

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 ... ...

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.
MeSH term(s)	Alleles ; Blood Glucose/metabolism ; Databases, Factual ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Genetic Variation ; Genome-Wide Association Study ; Glycated Hemoglobin/metabolism ; Humans ; Insulin/metabolism ; Insulin Resistance/genetics ; Iodide Peroxidase/genetics ; Mendelian Randomization Analysis ; Odds Ratio ; Polymorphism, Single Nucleotide ; Proto-Oncogene Proteins c-maf/genetics ; Thyrotropin/metabolism ; Thyroxine/metabolism ; Vascular Endothelial Growth Factor A/genetics ; Iodothyronine Deiodinase Type II
Chemical Substances	Blood Glucose ; Glycated Hemoglobin A ; Insulin ; MAF protein, human ; Proto-Oncogene Proteins c-maf ; VEGFA protein, human ; Vascular Endothelial Growth Factor A ; hemoglobin A1c protein, human ; Thyrotropin (9002-71-5) ; iodothyronine deiodinase type I (EC 1.11.1.-) ; iodothyronine deiodinase type III (EC 1.11.1.-) ; Iodide Peroxidase (EC 1.11.1.8) ; Thyroxine (Q51BO43MG4)
Language	English
Publishing date	2017-03-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/jc.2016-2816
Database	MEDical Literature Analysis and Retrieval System OnLINE

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