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Zethelius, Björn
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Publications (10 of 114) Show all publications
Graae, A.-S., Grarup, N., Ribel-Madsen, R., Lystbaek, S. H., Boesgaard, T., Staiger, H., . . . Holst, B. (2019). ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations. Diabetes, 68(3), 502-514
Open this publication in new window or tab >>ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations
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2019 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, no 3, p. 502-514Article in journal (Refereed) Published
Abstract [en]

The ADAMTS9 rs4607103 C allele is one of the few gene variants proposed to increase the risk of type 2 diabetes through an impairment of insulin sensitivity. We show that the variant is associated with increased expression of the secreted ADAMTS9 and decreased insulin sensitivity and signaling in human skeletal muscle. In line with this, mice lacking Adamts9 selectively in skeletal muscle have improved insulin sensitivity. The molecular link between ADAMTS9 and insulin signaling was characterized further in a model where ADAMTS9 was overexpressed in skeletal muscle. This selective over expression resulted in decreased insulin signaling presumably mediated through alterations of the integrin 131 signaling pathway and disruption of the intracellular cytoskeletal organization. Furthermore, this led to impaired mitochondria! function in mouse muscle-an observation found to be of translational character because humans carrying the ADAMTS9 risk allele have decreased expression of mitochondrial markers. Finally, we found that the link between ADAMTS9 overexpression and impaired insulin signaling could be due to accumulation of harmful lipid intermediates. Our findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and type 2 diabetes and point to inhibition of ADAMTS9 as a potential novel mode of treating insulin resistance.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-379022 (URN)10.2337/db18-0418 (DOI)000459677400006 ()30626608 (PubMedID)
Available from: 2019-03-12 Created: 2019-03-12 Last updated: 2019-03-12Bibliographically approved
Rawshani, A., Rawshani, A., Sattar, N., Franzen, S., McGuire, D. K., Eliasson, B., . . . Gudbjornsdottir, S. (2019). Relative Prognostic Importance and Optimal Levels of Risk Factors for Mortality and Cardiovascular Outcomes in Type 1 Diabetes Mellitus. Circulation, 139(16), 1900-1912
Open this publication in new window or tab >>Relative Prognostic Importance and Optimal Levels of Risk Factors for Mortality and Cardiovascular Outcomes in Type 1 Diabetes Mellitus
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2019 (English)In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 139, no 16, p. 1900-1912Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The strength of association and optimal levels for risk factors related to excess risk of death and cardiovascular outcomes in type 1 diabetes mellitus have been sparsely studied. METHODS: In a national observational cohort study from the Swedish National Diabetes Register from 1998 to 2014, we assessed relative prognostic importance of 17 risk factors for death and cardiovascular outcomes in individuals with type 1 diabetes mellitus. We used Cox regression and machine learning analyses. In addition, we examined optimal cut point levels for glycohemoglobin, systolic blood pressure, and low-density lipoprotein cholesterol. Patients with type 1 diabetes mellitus were followed up until death or study end on December 31, 2013. The primary outcomes were death resulting from all causes, fatal/nonfatal acute myocardial infarction, fatal/nonfatal stroke, and hospitalization for heart failure. RESULTS: Of 32 611 patients with type 1 diabetes mellitus, 1809 (5.5%) died during follow-up over 10.4 years. The strongest predictors for death and cardiovascular outcomes were glycohemoglobin, albuminuria, duration of diabetes mellitus, systolic blood pressure, and low-density lipoprotein cholesterol. Glycohemoglobin displayed approximate to 2% higher risk for each 1-mmol/mol increase (equating to approximate to 22% per 1% glycohemoglobin difference), whereas low-density lipoprotein cholesterol was associated with 35% to 50% greater risk for each 1-mmol/L increase. Microalbuminuria or macroalbuminuria was associated with 2 to 4 times greater risk for cardiovascular complications and death. Glycohemoglobin <53 mmol/mol (7.0%), systolic blood pressure <140 mm Hg, and low-density lipoprotein cholesterol <2.5 mmol/L were associated with significantly lower risk for outcomes observed. CONCLUSIONS: Glycohemoglobin, albuminuria, duration of diabetes mellitus, systolic blood pressure, and low-density lipoprotein cholesterol appear to be the most important predictors for mortality and cardiovascular outcomes in patients with type 1 diabetes mellitus. Lower levels for glycohemoglobin, systolic blood pressure, and low-density lipoprotein cholesterol than contemporary guideline target levels appear to be associated with significantly lower risk for outcomes.

Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2019
Keywords
cardiovascular disease, cerebrovascular disorders, diabetes mellitus, type 1, glycated hemoglobin A, heart failure, mortality, risk factors
National Category
Endocrinology and Diabetes Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-387557 (URN)10.1161/CIRCULATIONAHA.118.037454 (DOI)000469321500007 ()30798638 (PubMedID)
Funder
Swedish Research Council, 2013-5187Swedish Heart Lung Foundation, 2017-0839Swedish Association of Local Authorities and Regions
Available from: 2019-06-25 Created: 2019-06-25 Last updated: 2019-06-25Bibliographically approved
Franzon, K., Zethelius, B., Cederholm, T. & Kilander, L. (2019). The impact of muscle function, muscle mass and sarcopenia on independent ageing in very old Swedish men. BMC Geriatrics, 19, Article ID 153.
Open this publication in new window or tab >>The impact of muscle function, muscle mass and sarcopenia on independent ageing in very old Swedish men
2019 (English)In: BMC Geriatrics, ISSN 1471-2318, E-ISSN 1471-2318, Vol. 19, article id 153Article in journal (Refereed) Published
Abstract [en]

Background Preserved functions of daily life and cognition are cornerstones of independent aging, which is crucial for maintaining a high quality of life. The aim of this study was to examine the impact of sarcopenia, and its underlying components, on independent ageing in a cohort study of very old men.

Methods The presence of sarcopenia and independent ageing at a mean age of 87 was investigated in 287 men from the Uppsala Longitudinal Study of Adult Men. Five years later 127 men were re-evaluated for independent ageing. Sarcopenia was defined by two different definitions from the European Working Group on Sarcopenia in Older People. In the first definition sarcopenia was defined as skeletal muscle index < 7.26 kg/m2 and either gait speed ≤0.8 m/s or hand grip strength < 30 kg. In the later up-dated definition, HGS < 27 kg and/or chair stand test > 15 s defines probable sarcopenia, which is confirmed by SMI < 7.0 kg/m2. Independent ageing was defined as a Mini-Mental State Examination score of ≥25 points, absence of diagnosed dementia, community-dwelling, independency in personal care and ability to walk outdoors alone.

Results Sarcopenia at baseline was observed in 21% (60/287) and 20% (58/287), respectively, due to definition. The prevalence of independent ageing was 83% (239/288) at baseline and 69% (87/127) five years later. None of the sarcopenia diagnoses were associated with independent ageing. In contrast, gait speed was both in cross-sectional (odds ratio (OR) per one standard deviation increase 2.15, 95% confidence interval (CI) 1.47–3.15), and in longitudinal multivariate analyses (OR 1.84, 95% CI 1.19–2.82). In the cross-sectional analysis also higher hand grip strength was associated with independent ageing (OR 1.58, 95% CI 1.12–2.22), while a slower chair stand test was inversely associated (OR 0.61, 95% CI 0.43–0.86). Muscle mass; i.e. skeletal muscle index, was not associated with independent ageing.

Conclusions For very old men, especially a higher gait speed, but also a higher hand grip strength and a faster chair stand test, were associated with independent ageing, while skeletal muscle index alone, and the composite sarcopenia phenotype measured with two different definitions, were not.

Keywords
Sarcopenia, EWGSOP1, EWGSOP2, Muscle mass, Muscle function, Gait speed, Hand grip strength, Chair stand test, Independent ageing
National Category
Geriatrics
Research subject
Geriatrics
Identifiers
urn:nbn:se:uu:diva-380155 (URN)10.1186/s12877-019-1142-y (DOI)000469459000001 ()31142271 (PubMedID)
Available from: 2019-03-25 Created: 2019-03-25 Last updated: 2019-06-20Bibliographically approved
Crawley, D., Chamberlain, F., Garmo, H., Rudman, S., Zethelius, B., Holmberg, L., . . . Van Hemelrijck, M. (2018). A systematic review of the literature exploring the interplay between prostate cancer and type two diabetes mellitus. ecancermedicalscience, 12, Article ID 802.
Open this publication in new window or tab >>A systematic review of the literature exploring the interplay between prostate cancer and type two diabetes mellitus
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2018 (English)In: ecancermedicalscience, ISSN 1754-6605, E-ISSN 1754-6605, Vol. 12, article id 802Article, review/survey (Refereed) Published
Abstract [en]

Prostate cancer (PCa) and type two diabetes mellitus (T2DM) are both increasing prevalent conditions and often occur concurrently. However, the relationship between the two is more complex than just two prevalent conditions co-existing. This review systematically explores the literature around the interplay between the two conditions. It covers the impact of pre-existing T2DM on PCa incidence, grade and stage, as well as exploring the impact of T2DM on PCa outcomes and mortality and the interaction between T2DM and PCa treatments.

Keywords
type two diabetes, prostate cancer, review
National Category
Cancer and Oncology Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-350200 (URN)10.3332/ecancer.2018.802 (DOI)000423854500001 ()29456619 (PubMedID)
Available from: 2018-05-08 Created: 2018-05-08 Last updated: 2018-05-08Bibliographically approved
Crawley, D., Garmo, H., Rudman, S., Stattin, P., Zethelius, B., Holmberg, L., . . . Van Hemelrijck, M. (2018). Association between type 2 diabetes, curative treatment and survival in men with intermediate- and high-risk localized prostate cancer.. BJU International, 121(2), 209-216
Open this publication in new window or tab >>Association between type 2 diabetes, curative treatment and survival in men with intermediate- and high-risk localized prostate cancer.
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2018 (English)In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 121, no 2, p. 209-216Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: To investigate whether curative prostate cancer (PCa) treatment was received less often by men with both PCa and Type 2 diabetes mellitus (T2DM) as little is known about the influence of T2DM diagnosis on the receipt of such treatment in men with localized PCa.

SUBJECTS AND METHODS: The Prostate Cancer database Sweden (PCBaSe) was used to obtain data on men with T2DM and PCa (n = 2210) for comparison with data on men with PCa only (n = 23 071). All men had intermediate- (T1-2, Gleason score 7 and/or prostate-specific antigen [PSA] 10-20 ng/mL) or high-risk (T3 and/or Gleason score 8-10 and/or PSA 20-50 ng/mL) localized PCa diagnosed between 1 January 2006 and 31 December 2014. Multivariate logistic regression was used to calculate the odds ratios (ORs) for receipt of curative treatment in men with and without T2DM. Overall survival, for up to 8 years of follow-up, was calculated both for men with T2DM only and for men with T2DM and PCa.

RESULTS: Men with T2DM were less likely to receive curative treatment for PCa than men without T2DM (OR 0.78, 95% confidence interval 0.69-0.87). The 8-year overall survival rates were 79% and 33% for men with T2DM and high-risk PCa who did and did not receive curative treatment, respectively.

CONCLUSIONS: Men with T2DM were less likely to receive curative treatment for localized intermediate- and high-risk PCa. Men with T2DM and high-risk PCa who received curative treatment had substantially higher survival times than those who did not. Some of the survival differences represent a selection bias, whereby the healthiest patients received curative treatment. Clinicians should interpret this data carefully and ensure that individual patients with T2DM and PCa are not under- nor overtreated.

Keywords
#PCSM, #ProstateCancer, curative treatment, diabetes, external beam radiotherapy, prostatectomy
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-336246 (URN)10.1111/bju.13880 (DOI)000424029800012 ()28418195 (PubMedID)
Funder
Swedish Research Council, 825-2012-5047Stockholm County CouncilForte, Swedish Research Council for Health, Working Life and WelfareVästerbotten County Council
Available from: 2017-12-13 Created: 2017-12-13 Last updated: 2018-11-16Bibliographically approved
Lind, L., Ingelsson, E., Ärnlöv, J., Sundström, J., Zethelius, B. & Reaven, G. M. (2018). Can the Plasma Concentration Ratio of Triglyceride/High-Density Lipoprotein Cholesterol Identify Individuals at High Risk of Cardiovascular Disease During 40-Year Follow-Up?. Metabolic Syndrome and Related Disorders, 16(8), 433-439
Open this publication in new window or tab >>Can the Plasma Concentration Ratio of Triglyceride/High-Density Lipoprotein Cholesterol Identify Individuals at High Risk of Cardiovascular Disease During 40-Year Follow-Up?
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2018 (English)In: Metabolic Syndrome and Related Disorders, ISSN 1540-4196, E-ISSN 1557-8518, Vol. 16, no 8, p. 433-439Article in journal (Refereed) Published
Abstract [en]

Background: The plasma concentration ratio of triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) is a simple way to estimate insulin resistance. We aimed to evaluate the TG/HDL-C ratio as a simple clinical way to identify apparently healthy individuals with insulin resistance and enhanced risk of future cardiovascular disease (CVD).

Methods: One thousand seven hundred twenty men, aged 50 years, free from diabetes and CVD when evaluated at baseline in 1970-1974 were followed for 40 years regarding incident CVD (myocardial infarction and/or ischemic stroke, n=576).

Results: Participants with a high TG/HDL-C ratio (highest quartile >1.8) at baseline were more insulin resistant, with a significantly more adverse cardiometabolic risk profile (P<0.001) at baseline, compared with those with a lower ratio. This group also showed an increased risk of CVD [hazard ratio, HR 1.47 (95% confidence interval 1.26-1.93) P<0.001]. Fourteen percent of subjects with metabolic syndrome, in whom insulin resistance is increased, were also at enhanced CVD risk [HR 1.75 (1.42-2.16) P<0.001].

Conclusions: Twenty-five percent of apparently healthy 50-year-old men with the highest TG/HDL-C plasma concentration ratio had a significantly more adverse cardiometabolic profile at baseline, and developed more CVD over the next 40 years, compared with those not meeting this cut point. Determining the TG/HDL-C ratio in middle-aged men provided a simple and potentially clinically useful way to identify increased risk of developing CVD in persons free of diabetes or manifest CVD.

Place, publisher, year, edition, pages
MARY ANN LIEBERT, INC, 2018
Keywords
HDL-cholesterol, triglycerides, metabolic syndrome, cardiovascular disease, prospective
National Category
Endocrinology and Diabetes Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-368757 (URN)10.1089/met.2018.0058 (DOI)000446027200007 ()30183521 (PubMedID)
Available from: 2018-12-07 Created: 2018-12-07 Last updated: 2018-12-07Bibliographically approved
Crawley, D., Garmo, H., Rudman, S., Stattin, P., Zethelius, B., Armes, J., . . . Van Hemelrijck, M. (2018). Does a prostate cancer diagnosis affect management of pre-existing diabetes? Results from PCBaSe Sweden: a nationwide cohort study. BMJ Open, 8(3), Article ID e020787.
Open this publication in new window or tab >>Does a prostate cancer diagnosis affect management of pre-existing diabetes? Results from PCBaSe Sweden: a nationwide cohort study
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2018 (English)In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 8, no 3, article id e020787Article in journal (Refereed) Published
Abstract [en]

Objectives Both prostate cancer (PCa) and type 2 diabetes mellitus (T2DM) are increasingly prevalent conditions, which frequently coexist in men. Here, we set out to specifically examine the impact of a PCa diagnosis and its treatment on T2DM treatment. Setting This study uses observational data from Prostate Cancer database Sweden Traject. Participants The study was undertaken in a cohort of 16778 men with T2DM, of whom 962 were diagnosed with PCa during mean follow-up of 2.5 years. Primary and secondary outcome measures We investigated the association between PCa diagnosis and escalation in T2DM treatment in this cohort. A treatment escalation was defined as a new or change in anti-T2DM prescription, as recorded in the prescribed drug register (ie, change from diet to meforrnin or sulphonylurea or insulin). We also investigated how PCa diagnosis was associated with two treatment escalations. Multivariate Cox proportional hazards regression with age as a time scale was used while adjusting for educational level and initial T2DM treatment. Results We found no association between PCa diagnosis and risk of a single treatment escalation (HR 0.99, 95% Cl 0.87 to 1.13). However, PCa diagnosis was associated with an increased risk of receiving two consecutive T2DM treatment escalations (HR 1.75, 95% CI 1.38 to 2.22). This increase was strongest for men on gonadotropin-releasing hormone (GnRH) agonists (HR 3.08, 95% Cl 2.14 to 4.40). The corresponding HR for men with PCa not on hormonal treatment was 1.40 (95% CI 1.03 to 1.92) and for men with PCa on antiandrogens 0.91 (95% Cl 0.29 to 2.82). Conclusions Men with T2DM who are diagnosed with PCa, particularly those treated with GnRH agonists, were more likely to have two consecutive escalations in T2DM treatment. This suggests a need for closer monitoring of men with both PCa and T2DM, as coexistence of PCa and its subsequent treatments could potentially worsen T2DM control.

Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP, 2018
National Category
Endocrinology and Diabetes Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-358574 (URN)10.1136/bmjopen-2017-020787 (DOI)000433881200242 ()29549214 (PubMedID)
Funder
Swedish Research Council, 825-2012-5047Forte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2018-09-17 Created: 2018-09-17 Last updated: 2018-09-17Bibliographically approved
Rawshani, A., Rawshani, A., Franzen, S., Sattar, N., Eliasson, B., Svensson, A.-M., . . . Gudbjornsdottir, S. (2018). Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes. New England Journal of Medicine, 379(7), 633-644
Open this publication in new window or tab >>Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes
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2018 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 379, no 7, p. 633-644Article in journal (Refereed) Published
Abstract [en]

BACKGROUND Patients with diabetes are at higher risk for death and cardiovascular outcomes than the general population. We investigated whether the excess risk of death and cardiovascular events among patients with type 2 diabetes could be reduced or eliminated. METHODS In a cohort study, we included 271,174 patients with type 2 diabetes who were registered in the Swedish National Diabetes Register and matched them with 1,355,870 controls on the basis of age, sex, and county. We assessed patients with diabetes according to age categories and according to the presence of five risk factors (elevated glycated hemoglobin level, elevated low-density lipoprotein cholesterol level, albuminuria, smoking, and elevated blood pressure). Cox regression was used to study the excess risk of outcomes (death, acute myocardial infarction, stroke, and hospitalization for heart failure) associated with smoking and the number of variables outside target ranges. We also examined the relationship between various risk factors and cardiovascular outcomes. RESULTS The median follow-up among all the study participants was 5.7 years, during which 175,345 deaths occurred. Among patients with type 2 diabetes, the excess risk of outcomes decreased stepwise for each risk-factor variable within the target range. Among patients with diabetes who had all five variables within target ranges, the hazard ratio for death from any cause, as compared with controls, was 1.06 (95% confidence interval [CI], 1.00 to 1.12), the hazard ratio for acute myocardial infarction was 0.84 (95% CI, 0.75 to 0.93), and the hazard ratio for stroke was 0.95 (95% CI, 0.84 to 1.07). The risk of hospitalization for heart failure was consistently higher among patients with diabetes than among controls (hazard ratio, 1.45; 95% CI, 1.34 to 1.57). In patients with type 2 diabetes, a glycated hemoglobin level outside the target range was the strongest predictor of stroke and acute myocardial infarction; smoking was the strongest predictor of death. CONCLUSIONS Patients with type 2 diabetes who had five risk- factor variables within the target ranges appeared to have little or no excess risk of death, myocardial infarction, or stroke, as compared with the general population. (Funded by the Swedish Association of Local Authorities and Regions and others.)

Place, publisher, year, edition, pages
MASSACHUSETTS MEDICAL SOC, 2018
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-362678 (URN)10.1056/NEJMoa1800256 (DOI)000441659100007 ()30110583 (PubMedID)
Funder
Swedish Association of Local Authorities and Regions
Available from: 2018-11-13 Created: 2018-11-13 Last updated: 2018-11-13Bibliographically approved
Rowley, M., Garmo, H., Van Hemelrijck, M., Wulaningsih, W., Grundmark, B., Zethelius, B., . . . Coolen, A. C. (2017). A latent class model for competing risks. Statistics in Medicine, 36(13), 2100-2119
Open this publication in new window or tab >>A latent class model for competing risks
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2017 (English)In: Statistics in Medicine, ISSN 0277-6715, E-ISSN 1097-0258, Vol. 36, no 13, p. 2100-2119Article in journal (Refereed) Published
Abstract [en]

Survival data analysis becomes complex when the proportional hazards assumption is violated at population level or when crude hazard rates are no longer estimators of marginal ones. We develop a Bayesian survival analysis method to deal with these situations, on the basis of assuming that the complexities are induced by latent cohort or disease heterogeneity that is not captured by covariates and that proportional hazards hold at the level of individuals. This leads to a description from which risk-specific marginal hazard rates and survival functions are fully accessible, 'decontaminated' of the effects of informative censoring, and which includes Cox, random effects and latent classmodels as special cases. Simulated data confirm that our approach can map a cohort's substructure and remove heterogeneity-induced informative censoring effects. Application to data from the Uppsala Longitudinal Study of Adult Men cohort leads to plausible alternative explanations for previous counter-intuitive inferences on prostate cancer. The importance of managing cardiovascular disease as a comorbidity in women diagnosed with breast cancer is suggested on application to data from the Swedish Apolipoprotein Mortality Risk Study.

Keywords
survival analysis, heterogeneity, informative censoring, competing risks
National Category
Occupational Health and Environmental Health Probability Theory and Statistics
Identifiers
urn:nbn:se:uu:diva-327367 (URN)10.1002/sim.7246 (DOI)000402797900007 ()28233395 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme
Available from: 2017-08-15 Created: 2017-08-15 Last updated: 2018-01-13Bibliographically approved
Strawbridge, R. J., Silveira, A., den Hoed, M., Gustafsson, S., Luan, J., Rybin, D., . . . Hamsten, A. (2017). Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation. Atherosclerosis, 266, 196-204
Open this publication in new window or tab >>Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation
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2017 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 266, p. 196-204Article in journal (Refereed) Published
Abstract [en]

Background and aims: Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling.

Methods: We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants.

Results: We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures.

Conclusions: We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT.

Keywords
Proinsulin, Atherosclerosis, Intima-media-thickness, Single nucleotide polymorphisms, Genetic variants, Mendelian randomisation
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:uu:diva-341363 (URN)10.1016/j.atherosclerosis.2017.09.031 (DOI)000414069700027 ()29040868 (PubMedID)
Funder
Swedish Research Council, 8691 09533 2012-1397 2015-03657Swedish Heart Lung Foundation, 20120197 20140543EU, European Research CouncilKnut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research Stockholm County Council, 592229EU, FP7, Seventh Framework Programme, IMI/115006Swedish National Infrastructure for Computing (SNIC), b2011036
Available from: 2018-02-08 Created: 2018-02-08 Last updated: 2018-02-08Bibliographically approved
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