Circulating plasma proteins and new-onset diabetes in a population-based study: proteomic and genomic insights from the STANISLAS cohort

in European Journal of Endocrinology
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  • 1 Université de Lorraine, INSERM, Centre d’Investigations Cliniques Plurithématique 1433, INSERM 1116, CHRU de Nancy, FCRIN INI-CRCT, Nancy, France
  • 2 Université de Lorraine, CNRS, Inria, LORIA, Nancy, France
  • 3 Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, France
  • 4 Department of Endocrinology, CHRU de Nancy, Nancy, France

Correspondence should be addressed to J P Ferreira; Email: j.ferreira@chru-nancy.fr
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Objective:

Determining the factors associated with new-onset pre-diabetes and type 2 diabetes mellitus (T2D) is important for improving the current prevention strategies and for a better understanding of the disease.

Design:

To study the factors (clinical, circulating protein and genetic) associated with new onset pre-diabetes and T2D in an initially healthy (without diabetes) populational familial cohort with a long follow-up (STANISLAS cohort).

Methods:

A total of 1506 participants attended both the visit 1 and visit 4, separated by ≈20 years. Over 400 proteins, GWAS and genetic associations were studied using models adjusted for potential confounders. Both prospective (V1 to V4) and cross-sectional (V4) analyses were performed.

Results:

People who developed pre-diabetes (n = 555) and/or T2D (n = 73) were older, had higher BMI, blood pressure, glucose, LDL cholesterol, and lower eGFR. After multivariable selection, PAPP-A (pappalysin-1) was the only circulating protein associated with the onset of both pre-diabetes and T2D with associations persisting at visit 4 (i.e. ≈20 years later). FGF-21 (fibroblast growth factor 21) was a strong prognosticator for incident T2D in the longitudinal analysis, but not in the cross-sectional analysis. The heritability of the circulating PAPP-A was estimated at 44%. In GWAS analysis, the SNP rs634737 was associated with PAPP-A both at V1 and V4. External replication also showed lower levels of PAPP-A in patients with T2D.

Conclusions:

The risk of developing pre-diabetes and T2D increases with age and with features of the metabolic syndrome. Circulating PAPP-A, which has an important genetic component, was associated with both the development and presence of pre-diabetes and T2D.

Supplementary Materials

    • Acknowledgements
    • Supplemental addenda. Material and Methods for the Olink® technology
    • Supplemental Table 1. Association of PAPP-A with diabetes in the HOMAGE trial

 

     European Society of Endocrinology

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  • 1

    Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus – present and future perspectives. Nature Reviews: Endocrinology 2011 8 228236. (https://doi.org/10.1038/nrendo.2011.183)

    • Search Google Scholar
    • Export Citation
  • 2

    Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Research and Clinical Practice 2011 94 311321. (https://doi.org/10.1016/j.diabres.2011.10.029)

    • Search Google Scholar
    • Export Citation
  • 3

    NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants. Lancet 2016 387 15131530. (https://doi.org/10.1016/S0140-6736(16)00618-8)

    • Search Google Scholar
    • Export Citation
  • 4

    Zhang P, Zhang X, Brown J, Vistisen D, Sicree R, Shaw J, Nichols G. Global healthcare expenditure on diabetes for 2010 and 2030. Diabetes Research and Clinical Practice 2010 87 293301. (https://doi.org/10.1016/j.diabres.2010.01.026)

    • Search Google Scholar
    • Export Citation
  • 5

    Saha S, Gerdtham UG, Johansson P. Economic evaluation of lifestyle interventions for preventing diabetes and cardiovascular diseases. International Journal of Environmental Research and Public Health 2010 7 31503195. (https://doi.org/10.3390/ijerph7083150)

    • Search Google Scholar
    • Export Citation
  • 6

    Backholer K, Peeters A, Herman WH, Shaw JE, Liew D, Ademi Z, Magliano DJ. Diabetes prevention and treatment strategies: are we doing enough? Diabetes Care 2013 36 27142719. (https://doi.org/10.2337/DC12-2501)

    • Search Google Scholar
    • Export Citation
  • 7

    Ferreira JP, Girerd N, Bozec E, Merckle L, Pizard A, Bouali S, Eby E, Leroy C, Machu JL & Boivin JM Cohort Profile: rationale and design of the fourth visit of the Stanislas cohort: a familial longitudinal population-based cohort from the Nancy region of France. International Journal of Epidemiology 2018 47 395395j. (https://doi.org/10.1093/ije/dyx240)

    • Search Google Scholar
    • Export Citation
  • 8

    Xhaard C, Dandine-Roulland C, Villemereuil P, Floch EL, Bacq-Daian D, Machu JL, Ferreira JP, Deleuze JF, Zannad F & Rossignol P Heritability of a resting heart rate in a 20-year follow-up family cohort with GWAS data: insights from the Stanislas cohort. European Journal of Preventive Cardiology 2019 In press. (https://doi.org/10.1177/2047487319890763)

    • Search Google Scholar
    • Export Citation
  • 9

    American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in Diabetes-2019. Diabetes Care 2019 42 (Supplement 1) S13S28. (https://doi.org/10.2337/dc19-S002)

    • Search Google Scholar
    • Export Citation
  • 10

    Lundberg M, Eriksson A, Tran B, Assarsson E, Fredriksson S. Homogeneous antibody-based proximity extension assays provide sensitive and specific detection of low-abundant proteins in human blood. Nucleic Acids Research 2011 39 e102. (https://doi.org/10.1093/nar/gkr424)

    • Search Google Scholar
    • Export Citation
  • 11

    Pellicori P, Ferreira JP, Mariottoni B, Brunner-La Rocca HP, Ahmed FZ, Verdonschot J, Collier T, Cuthbert JJ, Petutschnigg J & Mujaj B Effects of spironolactone on serum markers of fibrosis in people at high risk of developing heart failure: rationale, design and baseline characteristics of a proof-of-concept, randomised, precision-medicine, prevention trial. The Heart OMics in AGing (HOMAGE) trial. European Journal of Heart Failure 2020 In press. (https://doi.org/10.1002/ejhf.1716)

    • Search Google Scholar
    • Export Citation
  • 12

    Kohler S, Carmody L, Vasilevsky N, Jacobsen JOB, Danis D, Gourdine JP, Gargano M, Harris NL, Matentzoglu N & McMurry JA Expansion of the Human Phenotype Ontology (HPO) knowledge base and resources. Nucleic Acids Research 2019 47 D1018D1027. (https://doi.org/10.1093/nar/gky1105)

    • Search Google Scholar
    • Export Citation
  • 13

    Pinero J, Bravo À, Queralt-Rosinach N, Gutierrez-Sacristan A, Deu-Pons J, Centeno E, Garcia-Garcia J, Sanz F, Furlong LI. DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants. Nucleic Acids Research 2017 45 D833D839. (https://doi.org/10.1093/nar/gkw943)

    • Search Google Scholar
    • Export Citation
  • 14

    Franco M, Bilal U, Ordunez P, Benet M, Morejon A, Caballero B, Kennelly JF, Cooper RS. Population-wide weight loss and regain in relation to diabetes burden and cardiovascular mortality in Cuba 1980–2010: repeated cross sectional surveys and ecological comparison of secular trends. BMJ 2013 346 f1515. (https://doi.org/10.1136/bmj.f1515)

    • Search Google Scholar
    • Export Citation
  • 15

    Maple-Brown LJ, Sinha AK, Davis EA. Type 2 diabetes in Indigenous Australian children and adolescents. Journal of Paediatrics and Child Health 2010 46 487490. (https://doi.org/10.1111/j.1440-1754.2010.01844.x)

    • Search Google Scholar
    • Export Citation
  • 16

    Jefferies C, Carter P, Reed PW, Cutfield W, Mouat F, Hofman PL, Gunn AJ. The incidence, clinical features, and treatment of type 2 diabetes in children <15 yr in a population-based cohort from Auckland, New Zealand, 1995–2007. Pediatric Diabetes 2012 13 294300. (https://doi.org/10.1111/j.1399-5448.2012.00851.x)

    • Search Google Scholar
    • Export Citation
  • 17

    Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature 2001 414 782787. (https://doi.org/10.1038/414782a)

    • Search Google Scholar
    • Export Citation
  • 18

    Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK. Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA 1990 263 28932898. (https://doi.org/10.1001/jama.263.21.2893)

    • Search Google Scholar
    • Export Citation
  • 19

    Kahn R, Davidson MB. The reality of type 2 diabetes prevention. Diabetes Care 2014 37 943949. (https://doi.org/10.2337/dc13-1954)

  • 20

    Bouton ME. Why behavior change is difficult to sustain. Preventive Medicine 2014 68 2936. (https://doi.org/10.1016/j.ypmed.2014.06.010)

    • Search Google Scholar
    • Export Citation
  • 21

    Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, Brown-Friday JO, Goldberg R & Venditti E 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009 374 16771686. (https://doi.org/10.1016/S0140-6736(09)61457-4)

    • Search Google Scholar
    • Export Citation
  • 22

    Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM & Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England Journal of Medicine 2002 346 393403. (https://doi.org/10.1056/NEJMoa012512)

    • Search Google Scholar
    • Export Citation
  • 23

    Hamman RF, Wing RR, Edelstein SL, Lachin JM, Bray GA, Delahanty L, Hoskin M, Kriska AM, Mayer-Davis EJ & Pi-Sunyer X Effect of weight loss with lifestyle intervention on risk of diabetes. Diabetes Care 2006 29 21022107. (https://doi.org/10.2337/dc06-0560)

    • Search Google Scholar
    • Export Citation
  • 24

    Lindstrom J, Ilanne-Parikka P, Peltonen M, Aunola S, Eriksson JG, Hemio K, Hamalainen H, Harkonen P, Keinanen-Kiukaanniemi S & Laakso M Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet 2006 368 16731679. (https://doi.org/10.1016/S0140-6736(06)69701-8)

    • Search Google Scholar
    • Export Citation
  • 25

    Diabetes Prevention Program Research Group. The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention: an intent-to-treat analysis of the DPP/DPPOS. Diabetes Care 2012 35 723730. (https://doi.org/10.2337/dc11-1468)

    • Search Google Scholar
    • Export Citation
  • 26

    Hjortebjerg R. IGFBP-4 and PAPP-A in normal physiology and disease. Growth Hormone and IGF Research 2018 41 722. (https://doi.org/10.1016/j.ghir.2018.05.002)

    • Search Google Scholar
    • Export Citation
  • 27

    Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocrine Reviews 1995 16 334. (https://doi.org/10.1210/edrv-16-1-3)

    • Search Google Scholar
    • Export Citation
  • 28

    Conover CA, Mason MA, Bale LK, Harrington SC, Nyegaard M, Oxvig C, Overgaard MT. Transgenic overexpression of pregnancy-associated plasma protein-A in murine arterial smooth muscle accelerates atherosclerotic lesion development. American Journal of Physiology: Heart and Circulatory Physiology 2010 299 H284H291. (https://doi.org/10.1152/ajpheart.00904.2009)

    • Search Google Scholar
    • Export Citation
  • 29

    Mazerbourg S, Overgaard MT, Oxvig C, Christiansen M, Conover CA, Laurendeau I, Vidaud M, Tosser-Klopp G, Zapf J, Monget P. Pregnancy-associated plasma protein-A (PAPP-A) in ovine, bovine, porcine, and equine ovarian follicles: involvement in IGF binding protein-4 proteolytic degradation and mRNA expression during follicular development. Endocrinology 2001 142 52435253. (https://doi.org/10.1210/endo.142.12.8517)

    • Search Google Scholar
    • Export Citation
  • 30

    Byun D, Mohan S, Yoo M, Sexton C, Baylink DJ, Qin X. Pregnancy-associated plasma protein-A accounts for the insulin-like growth factor (IGF)-binding protein-4 (IGFBP-4) proteolytic activity in human pregnancy serum and enhances the mitogenic activity of IGF by degrading IGFBP-4 in vitro. Journal of Clinical Endocrinology and Metabolism 2001 86 847854. (https://doi.org/10.1210/jcem.86.2.7223)

    • Search Google Scholar
    • Export Citation
  • 31

    Beaudeux JL, Burc L, Imbert-Bismut F, Giral P, Bernard M, Bruckert E, Chapman MJ. Serum plasma pregnancy-associated protein A: a potential marker of echogenic carotid atherosclerotic plaques in asymptomatic hyperlipidemic subjects at high cardiovascular risk. Arteriosclerosis, Thrombosis, and Vascular Biology 2003 23 e7e10. (https://doi.org/10.1161/01.atv.0000047448.76485.b8)

    • Search Google Scholar
    • Export Citation
  • 32

    Panagiotou G, Anastasilakis AD, Kynigopoulos G, Skouvaklidou EC, Saridakis ZG, Upadhyay J, Pagkalidou E, Apostolou A & Karagiozoglou-Lampoudi T Physiological parameters regulating circulating levels of the IGFBP-4/Stanniocalcin-2/PAPP-A axis. Metabolism: Clinical and Experimental 2017 75 1624. (https://doi.org/10.1016/j.metabol.2017.07.003)

    • Search Google Scholar
    • Export Citation
  • 33

    Hjortebjerg R, Laugesen E, Hoyem P, Oxvig C, Stausbol-Gron B, Knudsen ST, Kim WY, Poulsen PL, Hansen TK & Bjerre M The IGF system in patients with type 2 diabetes: associations with markers of cardiovascular target organ damage. European Journal of Endocrinology 2017 176 521531. (https://doi.org/10.1530/EJE-16-0940)

    • Search Google Scholar
    • Export Citation
  • 34

    Pellitero S, Reverter JL, Pizarro E, Pastor MC, Granada ML, Tassies D, Reverter JC, Salinas I, Sanmarti A. Pregnancy-associated plasma protein-a levels are related to glycemic control but not to lipid profile or hemostatic parameters in type 2 diabetes. Diabetes Care 2007 30 30833085. (https://doi.org/10.2337/dc07-1092)

    • Search Google Scholar
    • Export Citation
  • 35

    Aso Y, Okumura K, Wakabayashi S, Takebayashi K, Taki S, Inukai T. Elevated pregnancy-associated plasma protein-a in sera from type 2 diabetic patients with hypercholesterolemia: associations with carotid atherosclerosis and toe-brachial index. Journal of Clinical Endocrinology and Metabolism 2004 89 57135717. (https://doi.org/10.1210/jc.2004-0787)

    • Search Google Scholar
    • Export Citation
  • 36

    Mader JR, Resch ZT, McLean GR, Mikkelsen JH, Oxvig C, Marler RJ, Conover CA. Mice deficient in PAPP-A show resistance to the development of diabetic nephropathy. Journal of Endocrinology 2013 219 5158. (https://doi.org/10.1530/JOE-13-0167)

    • Search Google Scholar
    • Export Citation
  • 37

    Conover CA, Bale LK, Mader JR, Mason MA, Keenan KP, Marler RJ. Longevity and age-related pathology of mice deficient in pregnancy-associated plasma protein-A. Journals of Gerontology: Series A, Biological Sciences and Medical Sciences 2010 65 590599. (https://doi.org/10.1093/gerona/glq032)

    • Search Google Scholar
    • Export Citation
  • 38

    Junnila RK, List EO, Berryman DE, Murrey JW, Kopchick JJ. The GH/IGF-1 axis in ageing and longevity. Nature Reviews: Endocrinology 2013 9 366376. (https://doi.org/10.1038/nrendo.2013.67)

    • Search Google Scholar
    • Export Citation
  • 39

    Silahtaroglu AN, Tumer Z, Kristensen T, Sottrup-Jensen L, Tommerup N. Assignment of the human gene for pregnancy-associated plasma protein A (PAPPA) to 9q33.1 by fluorescence in situ hybridization to mitotic and meiotic chromosomes. Cytogenetics and Cell Genetics 1993 62 214216. (https://doi.org/10.1159/000133479)

    • Search Google Scholar
    • Export Citation
  • 40

    Sagar V, Vatapalli R, Lysy B, Pamarthy S, Anker JF, Rodriguez Y, Han H, Unno K, Stadler WM & Catalona WJ EPHB4 inhibition activates ER stress to promote immunogenic cell death of prostate cancer cells. Cell Death and Disease 2019 10 801. (https://doi.org/10.1038/s41419-019-2042-y)

    • Search Google Scholar
    • Export Citation
  • 41

    Ruby MA, Massart J, Hunerdosse DM, Schonke M, Correia JC, Louie SM, Ruas JL, Naslund E, Nomura DK, Zierath JR. Human carboxylesterase 2 reverses obesity-induced diacylglycerol accumulation and glucose intolerance. Cell Reports 2017 18 636646. (https://doi.org/10.1016/j.celrep.2016.12.070)

    • Search Google Scholar
    • Export Citation
  • 42

    Ware CF. The TNF superfamily-2008. Cytokine and Growth Factor Reviews 2008 19 183186. (https://doi.org/10.1016/j.cytogfr.2008.05.001)

  • 43

    Kong DH, Kim YK, Kim MR, Jang JH, Lee S. Emerging roles of vascular cell adhesion molecule-1 (VCAM-1) in immunological disorders and cancer. International Journal of Molecular Sciences 2018 19 1057. (https://doi.org/10.3390/ijms19041057)

    • Search Google Scholar
    • Export Citation
  • 44

    BonDurant LD, Ameka M, Naber MC, Markan KR, Idiga SO, Acevedo MR, Walsh SA, Ornitz DM, Potthoff MJ. FGF21 regulates metabolism through adipose-dependent and -independent mechanisms. Cell Metabolism 2017 25 935944.e4. (https://doi.org/10.1016/j.cmet.2017.03.005)

    • Search Google Scholar
    • Export Citation
  • 45

    Wang YS, Ye J, Cao YH, Zhang R, Liu Y, Zhang SW, Dai W, Zhang Q. Increased serum/plasma fibroblast growth factor 21 in type 2 diabetes mellitus: a systematic review and meta-analysis. Postgraduate Medical Journal 2019 95 134139. (https://doi.org/10.1136/postgradmedj-2018-136002)

    • Search Google Scholar
    • Export Citation
  • 46

    Davis GR, Deville T, Guillory J, Bellar D, Nelson AG. Relationship between family history of type 2 diabetes and serum FGF21. European Journal of Clinical Investigation 2017 47 853859. (https://doi.org/10.1111/eci.12835)

    • Search Google Scholar
    • Export Citation