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

Rona J Strawbridge¹, Angela Silveira², Marcel den Hoed³, Stefan Gustafsson⁴, Jian'an Luan⁵, Denis Rybin⁶, Josée Dupuis⁷, Ruifang Li-Gao⁸, Maryam Kavousi⁹, Abbas Dehghan¹⁰, Kadri Haljas¹¹, Jari Lahti¹², Jesper R Gådin², Alexandra Bäcklund², Ulf de Faire¹³, Karl Gertow², Phillipe Giral¹⁴, Anuj Goel¹⁵, Steve E Humphries¹⁶, Sudhir Kurl¹⁷, Claudia Langenberg⁵, Lars L Lannfelt¹⁸, Lars Lind¹⁹, Cecilia C M Lindgren²⁰, Elmo Mannarino²¹, Dennis O Mook-Kanamori²², Andrew P Morris²³, Renée de Mutsert⁸, Rainer Rauramaa²⁴, Peter Saliba-Gustafsson², Bengt Sennblad²⁵, Andries J Smit²⁶, Ann-Christine Syvänen²⁷, Elena Tremoli²⁸, Fabrizio Veglia²⁹, Björn Zethelius³⁰, Hanna M Björck², Johan G Eriksson³¹, Albert Hofman³², Oscar H Franco⁹, Hugh Watkins¹⁵, J Wouter Jukema³³, Jose C Florez³⁴, Nicholas J Wareham⁵, James B Meigs³⁵, Erik Ingelsson³⁶, Damiano Baldassarre³⁷, Anders Hamsten²; IMPROVE study group

Affiliations

¹ Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Mental Health and Wellbeing, Institute of Mental Health and Wellbeing, University of Glasgow, Glasgow, UK. Electronic address: Rona.Strawbridge@ki.se.
² Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
³ Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁴ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁵ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
⁶ Boston University Data Coordinating Center, Boston, MA, USA.
⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
⁸ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
⁹ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
¹⁰ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, The Netherlands; MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, UK.
¹¹ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹² Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Folkhälsan Research Centre, Helsinki, Finland.
¹³ Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
¹⁴ Assistance Publique-Hôpitaux de Paris, Service Endocrinologie-Métabolisme, Groupe Hospitalier Pitié-Salpétrière, Unités de Prévention Cardiovasculaire, Paris, France.
¹⁵ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹⁶ Centre for Cardiovascular Genetics, Institute Cardiovascular Science, University College London, UK.
¹⁷ Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Campus, Kuopio, Finland.
¹⁸ Department of Public Health and Caring Sciences, Geriatrics, Molecular Geriatrics, Uppsala University, Uppsala, Sweden.
¹⁹ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK; Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
²⁰ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
²¹ Department of Clinical and Experimental Medicine, Internal Medicine, Angiology and Arteriosclerosis Diseases, University of Perugia, Perugia, Italy.
²² Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
²³ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Biostatistics, University of Liverpool, Liverpool, UK.
²⁴ Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland; Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
²⁵ Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Dept of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Sweden.
²⁶ Department of Medicine, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
²⁷ Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
²⁸ Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy; Centro Cardiologico Monzino, IRCCS, Milan, Italy.
²⁹ Centro Cardiologico Monzino, IRCCS, Milan, Italy.
³⁰ Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden.
³¹ Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; National Institute for Health and Welfare, Finland; Folkhälsan Research Center, Helsinki, Finland.
³² Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, The Netherlands; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³³ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
³⁴ Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Cambridge, MA, USA.
³⁵ Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Cambridge, MA, USA; General Medicine Division, Massachusetts General Hospital, Boston, MA, USA.
³⁶ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
³⁷ Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy; Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Italy.

PMID: 29040868
PMCID: PMC5679136
DOI: 10.1016/j.atherosclerosis.2017.09.031

Meta-Analysis

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

Rona J Strawbridge et al. Atherosclerosis. 2017 Nov.

. 2017 Nov:266:196-204.

doi: 10.1016/j.atherosclerosis.2017.09.031. Epub 2017 Sep 28.

Authors

Affiliations

¹ Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Mental Health and Wellbeing, Institute of Mental Health and Wellbeing, University of Glasgow, Glasgow, UK. Electronic address: Rona.Strawbridge@ki.se.
² Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
³ Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁴ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁵ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
⁶ Boston University Data Coordinating Center, Boston, MA, USA.
⁷ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA; National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, MA, USA.
⁸ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
⁹ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
¹⁰ Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, The Netherlands; MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, UK.
¹¹ Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
¹² Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Folkhälsan Research Centre, Helsinki, Finland.
¹³ Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
¹⁴ Assistance Publique-Hôpitaux de Paris, Service Endocrinologie-Métabolisme, Groupe Hospitalier Pitié-Salpétrière, Unités de Prévention Cardiovasculaire, Paris, France.
¹⁵ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
¹⁶ Centre for Cardiovascular Genetics, Institute Cardiovascular Science, University College London, UK.
¹⁷ Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Campus, Kuopio, Finland.
¹⁸ Department of Public Health and Caring Sciences, Geriatrics, Molecular Geriatrics, Uppsala University, Uppsala, Sweden.
¹⁹ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK; Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
²⁰ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
²¹ Department of Clinical and Experimental Medicine, Internal Medicine, Angiology and Arteriosclerosis Diseases, University of Perugia, Perugia, Italy.
²² Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands.
²³ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Biostatistics, University of Liverpool, Liverpool, UK.
²⁴ Foundation for Research in Health Exercise and Nutrition, Kuopio Research Institute of Exercise Medicine, Kuopio, Finland; Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland.
²⁵ Cardiovascular Medicine Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Dept of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Sweden.
²⁶ Department of Medicine, University Medical Center Groningen, Groningen, The Netherlands; Department of Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
²⁷ Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
²⁸ Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy; Centro Cardiologico Monzino, IRCCS, Milan, Italy.
²⁹ Centro Cardiologico Monzino, IRCCS, Milan, Italy.
³⁰ Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden.
³¹ Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; National Institute for Health and Welfare, Finland; Folkhälsan Research Center, Helsinki, Finland.
³² Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, The Netherlands; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
³³ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
³⁴ Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Cambridge, MA, USA.
³⁵ Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Cambridge, MA, USA; General Medicine Division, Massachusetts General Hospital, Boston, MA, USA.
³⁶ Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA.
³⁷ Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy; Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Italy.

PMID: 29040868
PMCID: PMC5679136
DOI: 10.1016/j.atherosclerosis.2017.09.031

Abstract

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 IMT_mean and IMT_max (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: Atherosclerosis; Genetic variants; Intima-media-thickness; Mendelian randomisation; Proinsulin; Single nucleotide polymorphisms.

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Figures

**Fig. 1**
Manhattan plots of the association between SNPs and proinsulin levels in participants without T2D, adjusted for the glucose model. SNPs within 250 Kb up or downstream of SNPs with p < 1*10⁻⁵ are highlighted in green. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

**Fig. 2**
Regional plots of suggestive loci. (A) Chromosome 11 locus; (B) chromosome 11 locus after conditioning on the previously reported *ARAP1* loci (rs11603334 and rs77756118); (C) chromosome 15 locus; (D) chromosome 15 locus adjusted for the previously reported, nearby loci (*LARP6* rs7163439 and *VPS13C* rs4502156); (E) chromosome 6 locus.

See this image and copyright information in PMC

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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

Affiliations

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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