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Cited by 359Genetic Associations and EpidemiologyDiabetes and associated disordersPancreatic function and diabetes

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Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes

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Strawbridge, Rona J., Dupuis, Josée, Prokopenko, Inga, Barker, Adam, Ahlqvist, Emma, Rybin, Denis, Petrie, John R., Travers, Mary E., Bouatia-Naji, Nabila, Dimas, Antigone S., Nica, Alexandra, Wheeler, Eleanor, Chen, Han, Voight, Benjamin F., Taneera, Jalal, Kanoni, Stavroula, Peden, John F., Turrini, Fabiola, Gustafsson, Stefan, Zabena, Carina, Almgren, Peter, Barker, David J.P., Barnes, Daniel, Dennison, Elaine M., Eriksson, Johan G., Eriksson, Per, Eury, Elodie, Folkersen, Lasse, Fox, Caroline S., Frayling, Timothy M., Goel, Anuj, Gu, Harvest F., Horikoshi, Momoko, Isomaa, Bo, Jackson, Anne U., Jameson, Karen A., Kajantie, Eero, Kerr-Conte, Julie, Kuulasmaa, Teemu, Kuusisto, Johanna, Loos, Ruth J.F., Luan, Jian'an, Makrilakis, Konstantinos, Manning, Alisa K., Martínez-Larrad, María Teresa, Narisu, Narisu, Nastase Mannila, Maria, Öhrvik, John, Osmond, Clive, Pascoe, Laura, Payne, Felicity, Sayer, Avan A., Sennblad, Bengt, Silveira, Angela, Stančáková, Alena, Stirrups, Kathy, Swift, Amy J., Syvänen, Ann-Christine, Tuomi, Tiinamaija, van 't Hooft, Ferdinand M., Walker, Mark, Weedon, Michael N., Xie, Weijia, Zethelius, Björn, the DIAGRAM Consortium, the GIANT Consortium, the MuTHER Consortium, the CARDIoGRAM Consortium, the C4D Consortium, Ongen, Halit, Mälarstig, Anders, Hopewell, Jemma C., Saleheen, Danish, Chambers, John, Parish, Sarah, Danesh, John, Kooner, Jaspal, Östenson, Claes-Göran, Lind, Lars, Cooper, Cyrus C., Serrano-Ríos, Manuel, Ferrannini, Ele, Forsen, Tom J., Clarke, Robert, Franzosi, Maria Grazia, Seedorf, Udo, Watkins, Hugh, Froguel, Philippe, Johnson, Paul, Deloukas, Panos, Collins, Francis S., Laakso, Markku, Dermitzakis, Emmanouil T., Boehnke, Michael, McCarthy, Mark I., Wareham, Nicholas J., Groop, Leif, Pattou, François, Gloyn, Anna L., Dedoussis, George V., Lyssenko, Valeriya, Meigs, James B., Barroso, Inês, Watanabe, Richard M., Ingelsson, Erik, Langenberg, Claudia, Hamsten, Anders, Florez, Jose C.·2011·Diabetes
DOI 10.2337/db11-0415PMC PMC3178302
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Abstract

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

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FIG. 1. Manhattan plot of the association P values for fasting proinsulin adjusted for fasting insulin. Directly genotyped and imputed SNPs are plotted with their meta-analysis P values (as −log10 values) as a function of genomic position (NCBI Build 36). The SNPs that achieved genome-wide significance (P < 5 × 10−8) on follow-up are shown in red. Insert: Quantile-quantile (Q-Q) plot for fasting proinsulin adjusted for fasting insulin. The expected null distribution is plotted along the diagonal, the entire distribution of observed P values is plotted in blue, and a distribution that excludes the nine novel findings is plotted in red.
FIG. 1. Manhattan plot of the association P values for fasting proinsulin adjusted for fasting insulin. Directly genotyped and imputed SNPs are plotted with their meta-analysis P values (as −log10 values) as a function of genomic position (NCBI Build 36). The SNPs that achieved genome-wide significance (P < 5 × 10−8) on follow-up are shown in red. Insert: Quantile-quantile (Q-Q) plot for fasting proinsulin adjusted for fasting insulin. The expected null distribution is plotted along the diagonal, the entire distribution of observed P values is plotted in blue, and a distribution that excludes the nine novel findings is plotted in red.CC BY-NC-ND · PubMed Central
FIG. 2. Regional plots of eight genomic regions containing novel genome-wide significant associations. For each region, directly genotyped and imputed SNPs are plotted with their meta-analysis P values (as −log10 values) as a function of genomic position (NCBI Build 36). In each panel, the stage 1 discovery SNP taken forward to stage 2 follow-up is represented by a purple diamond (with global meta-analysis P value), with its stage 1 discovery P value denoted by a red diamond with bolded borders. Estimated recombination rates (taken from HapMap) are plotted to reflect the local LD structure around the associated SNPs and their correlated proxies (according to a white to red scale from r2 = 0 to 1, based on pairwise r2 values from HapMap CEU). Gene annotations were taken from the University of California Santa Cruz genome browser. A: ARAP1 region; B: MADD region; C: PCSK1 region; D: TCF7L2 region; E: VPS13C/C2CD4A/B region; F: SLC30A8 region; G: LARP6 region; H: SGSM2 region.
FIG. 2. Regional plots of eight genomic regions containing novel genome-wide significant associations. For each region, directly genotyped and imputed SNPs are plotted with their meta-analysis P values (as −log10 values) as a function of genomic position (NCBI Build 36). In each panel, the stage 1 discovery SNP taken forward to stage 2 follow-up is represented by a purple diamond (with global meta-analysis P value), with its stage 1 discovery P value denoted by a red diamond with bolded borders. Estimated recombination rates (taken from HapMap) are plotted to reflect the local LD structure around the associated SNPs and their correlated proxies (according to a white to red scale from r2 = 0 to 1, based on pairwise r2 values from HapMap CEU). Gene annotations were taken from the University of California Santa Cruz genome browser. A: ARAP1 region; B: MADD region; C: PCSK1 region; D: TCF7L2 region; E: VPS13C/C2CD4A/B region; F: SLC30A8 region; G: LARP6 region; H: SGSM2 region.CC BY-NC-ND · PubMed Central
FIG. 3. Expression profiles of biologically plausible genes within each associated locus across a range of human tissue types, including islet preparations from three donors. Expression levels determined with respect to the geometric mean of three endogenous control assays. A: ARAP1 region; B: MADD region; C: VPS13C/C2CD4A/B region; D: LARP6 region; E: SGSM2 region. F: Expression levels of genes near the proinsulin-associated variants in human FAC-sorted β-cells. Data are expression means ± SD of the relative expression measured by quantitative PCR obtained from three human nondiabetic donors.
FIG. 3. Expression profiles of biologically plausible genes within each associated locus across a range of human tissue types, including islet preparations from three donors. Expression levels determined with respect to the geometric mean of three endogenous control assays. A: ARAP1 region; B: MADD region; C: VPS13C/C2CD4A/B region; D: LARP6 region; E: SGSM2 region. F: Expression levels of genes near the proinsulin-associated variants in human FAC-sorted β-cells. Data are expression means ± SD of the relative expression measured by quantitative PCR obtained from three human nondiabetic donors.CC BY-NC-ND · PubMed Central

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  1. StataCorp, 2007, Stata Statistical Software: Release 10
  2. Li, 2006, Am J Hum Genet, S79, 2290

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Metadata

Authors
Strawbridge, R. J., Dupuis, J., Prokopenko, I., Barker, A., Ahlqvist, E., Rybin, D., Petrie, J. R., Travers, M. E., Bouatia-Naji, N., Dimas, A. S., Nica, A., Wheeler, E., Chen, H., Voight, B. F., Taneera, J., Kanoni, S., Peden, J. F., Turrini, F., Gustafsson, S., Zabena, C., Almgren, P., Barker, D. J. P., Barnes, D., Dennison, E. M., Eriksson, J. G., Eriksson, P., Eury, E., Folkersen, L., Fox, C. S., Frayling, T. M., Goel, A., Gu, H. F., Horikoshi, M., Isomaa, B., Jackson, A. U., Jameson, K. A., Kajantie, E., Kerr-Conte, J., Kuulasmaa, T., Kuusisto, J., Loos, R. J. F., Luan, J., Makrilakis, K., Manning, A. K., Martínez-Larrad, M. T., Narisu, N., Nastase Mannila, M., Öhrvik, J., Osmond, C., Pascoe, L., Payne, F., Sayer, A. A., Sennblad, B., Silveira, A., Stančáková, A., Stirrups, K., Swift, A. J., Syvänen, A.-C., Tuomi, T., van 't Hooft, F. M., Walker, M., Weedon, M. N., Xie, W., Zethelius, B., the DIAGRAM Consortium, the GIANT Consortium, the MuTHER Consortium, the CARDIoGRAM Consortium, the C4D Consortium, Ongen, H., Mälarstig, A., Hopewell, J. C., Saleheen, D., Chambers, J., Parish, S., Danesh, J., Kooner, J., Östenson, C.-G., Lind, L., Cooper, C. C., Serrano-Ríos, M., Ferrannini, E., Forsen, T. J., Clarke, R., Franzosi, M. G., Seedorf, U., Watkins, H., Froguel, P., Johnson, P., Deloukas, P., Collins, F. S., Laakso, M., Dermitzakis, E. T., Boehnke, M., McCarthy, M. I., Wareham, N. J., Groop, L., Pattou, F., Gloyn, A. L., Dedoussis, G. V., Lyssenko, V., Meigs, J. B., Barroso, I., Watanabe, R. M., Ingelsson, E., Langenberg, C., Hamsten, A., & Florez, J. C.
Affiliations
  • Karolinska University Hospital (SE)
  • Boston University (US)
  • Centre for Human Genetics (GB)
  • Addenbrooke's Hospital (GB)
  • Lund University (SE)
  • University of Glasgow (GB)
  • University of Oxford (GB)
  • Université Lille-Nord de France, Lille, France
  • University of Geneva (CH)
  • Wellcome Sanger Institute (GB)
  • Broad Institute (US)
  • University of Verona (IT)
  • Karolinska Institutet (SE)
  • CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
  • Oregon Health & Science University (US)
  • Southampton General Hospital (GB)
  • University of Helsinki (FI)
  • Centre National de la Recherche Scientifique (FR)
  • Brigham and Women's Hospital (US)
  • University of Exeter (GB)
  • Folkhälsans Forskningscentrum (FI)
  • University of Michigan (US)
  • Inserm (FR)
  • Kuopio University Hospital (FI)
  • Laiko General Hospital of Athens (GR)
  • Hospital Clínico San Carlos (ES)
  • National Institutes of Health (US)
  • Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
  • Newcastle University (GB)
  • Uppsala University (SE)
  • Folkhälsan Research Centre, Helsinki, Finland
  • University of Cambridge (GB)
  • Ealing Hospital NHS Trust (GB)
  • University of Pisa (IT)
  • Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland
  • Mario Negri Institute for Pharmacological Research (IT)
  • University of Münster (DE)
  • Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, U.K.
  • Harokopio University of Athens (GR)
  • Harvard University (US)
  • University of Southern California (US)
  • Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
Corresponding author
  • Langenberg, Claudia
  • Hamsten, Anders
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2011-09-16
Volume
60
Issue
10
Pages
2624-2634
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db11-0415
PMC
PMC3178302
OpenAlex
W2151600164
Cited by
356
References
50
Citations by year
2026: 7 · 2025: 7 · 2024: 12 · 2023: 16 · 2022: 18 · 2021: 23 · 2020: 23 · 2019: 27 · 2018: 27 · 2017: 36 · 2016: 30 · 2015: 30 · 2014: 39 · 2013: 29 · 2012: 31
FWCI
19.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
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  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • JuSER (Forschungszentrum Jülich) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
  • Scopus (Elsevier) (submittedVersion)
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  • SERVAL (Université de Lausanne) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by-nc-nd)
  • OPUS (Augsburg University) (submittedVersion)
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  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Apollo (cc-by)
  • Newcastle University ePrints (Newcastle Univesity)
Funders
  • Wellcome Trust (083270/Z/07/Z, 077016/Z/05/Z, 090532)
  • National Institute for Health and Care Research (NF-SI-0508-10082)
  • British Heart Foundation (RG/08/014/24067)
  • Novo Nordisk Fonden (#NNF10OC1013354)
  • Medical Research Council (MC_PC_U127592696, MC_PC_U127561128, MRC_MC_UP_A620_1015, G0601966, G0601261, MC_UP_A620_1014, G0700931)
  • National Heart, Lung, and Blood Institute (U01HL054527)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK078616, K24DK080140, DK-062370)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
Keywords
proinsulin, type 2 diabetes, single nucleotide polymorphisms, genetic loci, beta-cell function, fasting blood glucose, insulin resistance, ARAP1, PCSK1, prohormone convertase 1/3, TCF7L2, SLC30A8, VPS13C, MADD, LARP6, coronary artery disease, glucose homeostasis
MeSH terms
Adult, Diabetes Mellitus, Type 2, Fasting, Female, Genotype, Humans, Insulin, Male, Proinsulin, Genetic Variation, Genome, Human, Polymorphism, Single Nucleotide

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