Online citations, reference lists, and bibliographies.
← Back to Search

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

R. Strawbridge, A. Silveira, M. Hoed, S. Gustafsson, J. Luan, D. Rybin, J. Dupuis, R. Li-Gao, M. Kavousi, A. Dehghan, Kadri Haljas, J. Lahti, J. Gådin, Alexandra Bäcklund, U. de Faire, K. Gertow, P. Giral, A. Goel, S. Humphries, S. Kurl, C. Langenberg, L. Lannfelt, L. Lind, C. Lindgren, E. Mannarino, D. Mook-Kanamori, A. Morris, R. de Mutsert, R. Rauramaa, P. Saliba-Gustafsson, B. Sennblad, A. Smit, A. Syvänen, E. Tremoli, F. Veglia, B. Zethelius, H. Björck, J. Eriksson, A. Hofman, Ò. Franco, H. Watkins, J. Jukema, J. Florez, N. Wareham, J. Meigs, E. Ingelsson, D. Baldassarre, A. Hamsten
Published 2017 · Medicine, Biology

Cite This
Download PDF
Analyze on Scholarcy
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.
This paper references
Association between Serum C-Peptide as a Risk Factor for Cardiovascular Disease and High-Density Lipoprotein Cholesterol Levels in Nondiabetic Individuals
Y. Li (2015)
Cross-sectional analysis of baseline data to identify the major determinants of carotid intima-media thickness in a European population: the IMPROVE study.
D. Baldassarre (2010)
John B. Shoven (1824)
GWAMA: software for genome-wide association meta-analysis
R. Mägi (2009)
Genome-wide mapping of susceptibility to coronary artery disease identifies a novel replicated locus on chromosome
M. Farrall (2006)
High proinsulin concentration precedes acute myocardial infarction in a nondiabetic population.
B. Lindahl (1999)
Structural insight into the UNC-45-myosin complex, Proteins, 2013;81:1212-1221
F Fratev (2013)
The Third Generation Cohort of the National Heart, Lung, and Blood Institute's Framingham Heart Study: design, recruitment, and initial examination.
G. L. Splansky (2007)
Proinsulin Is an Independent Predictor of Coronary Heart Disease: Report From a 27-Year Follow-Up Study
B. Zethelius (2002)
Disproportionately elevated proinsulin levels reflect the degree of impaired B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus.
M. Røder (1998)
Yu-Qin Cao (1824)
J. Lackie (2013)
Relationship of proinsulin and insulin with noninsulin-dependent diabetes mellitus and coronary heart disease in Japanese-American men: impact of obesity--clinical research center study.
S. Kahn (1995)
Proteinuria and progressive renal disease: birth weight and microalbuminuria.
J. Yudkin (1997)
Apolipoprotein E epsilon4 genotype is independently associated with increased intima-media thickness in a recessive pattern, Lipids, 2007;42:451-456
M Wohlin (2007)
Insulin, intact and split proinsulin, and coronary artery disease in young men.
P. Båvenholm (1995)
Apolipoprotein E epsilon 4.
S. Sakoda (1994)
The Framingham Offspring Study. Design and preliminary data.
M. Feinleib (1975)
UCS proteins: chaperones for myosin and co-chaperones for Hsp90.
Weiming Ni (2015)
The Genotype-Tissue Expression (GTEx) project
J. Lonsdale (2013)
Chlorpromazine Thorazine (1824)
Structural insight into the UNC‐45–myosin complex
F. Fratev (2013)
Echogenecity of the carotid intima-media complex is related to cardiovascular risk factors, dyslipidemia, oxidative stress and inflammation: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.
J. Andersson (2009)
Saskia Bonjour (1824)
Assessing L2 Writing in the Absence of Scoring Procedures: Construction of Rating Scales in a Cypriot-greek Efl in Class Context
Olivier Giraud (1824)
Seguin Hen (1824)
Cardiovascular Protection in the Treatment of Type 2 Diabetes: A Review of Clinical Trial Results Across Drug Classes.
F. Paneni (2017)
PLINK: a tool set for whole-genome association and population-based linkage analyses.
S. Purcell (2007)
Epidemiological approaches to heart disease: the Framingham Study.
T. R. Dawber (1951)
Genome - wide association identi fi es nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2
J. Dupuis Strawbridge (2011)
Concentrations of proinsulin like molecules predict coronary heart disease risk independently of insulin: prospective data from the Caerphilly Study
J. Yudkin (2001)
Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease
G. Trynka (2011)
J. Lackie (2013)
Il Liceo (1824)
M. Sankar (1824)
Measurements of carotid intima-media thickness and of interadventitia common carotid diameter improve prediction of cardiovascular events: results of the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study.
D. Baldassarre (2012)
Sex-Specific Effects of Adiponectin on Carotid Intima-Media Thickness and Incident Cardiovascular Disease
J. Persson (2015)
Early growth and coronary heart disease and type 2 diabetes: findings from the Helsinki Birth Cohort Study (HBCS).
J. Eriksson (2011)
Genome-Wide Mapping of Susceptibility to Coronary Artery Disease Identifies a Novel Replicated Locus on Chromosome 17
M. Farrall (2006)
Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes
A. Morris (2012)
? ? ? ? f ? ? ? ? ?
A. ADoefaa (2003)
Martin P. Catherwood (1824)
Alimentary lipemia, postprandial triglyceride-rich lipoproteins, and common carotid intima-media thickness in healthy, middle-aged men.
S. Boquist (1999)
Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes
R. Strawbridge (2011)
UNC45A localizes to centrosomes and regulates cancer cell proliferation through ChK1 activation.
Yasmeen Jilani (2015)
A study of middle-aged men with particular reference to risk factors for cardiovascular disease.
H. Hedstrand (1975)
Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression
J. Bowden (2015)
The Metabochip, a Custom Genotyping Array for Genetic Studies of Metabolic, Cardiovascular, and Anthropometric Traits
B. Voight (2012)
Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes, Diabetes, 2011;60:2624-2634
RJ Strawbridge (2011)
Genome - wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2
D Baldassarre (2011)
D. Davies (1998)
The framingham offspring study: A commentary
H. Swan (2000)
Structural insight into the UNC-45myosin complex
F. Fratev (2013)
Low-grade albuminuria and the incidence of heart failure in a community-based cohort of elderly men.
E. Ingelsson (2007)
Association of Genetic Risk Variants With Expression of Proximal Genes Identifies Novel Susceptibility Genes for Cardiovascular Disease
L. Folkersen (2010)

This paper is referenced by
Semantic Scholar Logo Some data provided by SemanticScholar