Interaction Between GAD65 Antibodies and Dietary Fish Intake or Plasma Phospholipid n-3 Polyunsaturated Fatty Acids on Incident Adult-Onset Diabetes

The EPIC-InterAct Study

  • Löfvenborg, Josefin E.
  • Carlsson, Sofia
  • Andersson, Tomas
  • Hampe, Christiane S.
  • Koulman, Albert
  • Chirlaque Lopez, María Dolores
  • Jakszyn, Paula
  • Katzke, Verena A.
  • Kühn, Tilman
  • Kyrø, Cecilie
  • Masala, Giovanna
  • Nilsson, Peter M.
  • Overvad, Kim
  • Panico, Salvatore
  • Sánchez, Maria-Jose
  • van der Schouw, Yvonne
  • Schulze, Matthias B.
  • Tjønneland, Anne
  • Weiderpass, Elisabete
  • Riboli, Elio
  • Forouhi, Nita G.
  • Sharp, Stephen J.
  • Rolandsson, Olov
  • Wareham, Nicholas J.

  • 1Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

    2Center for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden

    3Department of Medicine, University of Washington School of Medicine, Seattle, WA

    4Medical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, U.K.

    5National Institute for Health Research Biomedical Research Centre Core Nutritional Biomarker Laboratory, University of Cambridge School of Clinical Medicine, Cambridge, U.K.

    6Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia, Spain

    7Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Madrid, Spain

    8Department of Health and Social Sciences, University of Murcia, Murcia, Spain

    9Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain

    10Facultat Ciències Salut Blanquerna, Universitat Ramon Llull, Barcelona, Spain

    11Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany

    12Danish Cancer Society Research Center, Copenhagen, Denmark

    13Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network, Florence, Italy

    14Department of Clinical Sciences, Lund University, Malmö, Sweden

    15Department of Public Health, Aarhus University, Aarhus, Denmark

    16Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark

    17Dipartimento di Medicina Clinica e Chrurgia, Federico II University, Naples, Italy

    18Escuela Andaluza de Salud Pública, Granada, Spain

    19Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain

    20Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain

    21University Medical Center Utrecht, Utrecht, the Netherlands

    22Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany

    23German Center for Diabetes Research, München-Neuherberg, Germany

    24Institute of Nutrition Science, University of Potsdam, Nuthetal, Germany

    25Department of Public Health, University of Copenhagen, Copenhagen, Denmark

    26International Agency for Research on Cancer, World Health Organization, Lyon, France

    27Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, U.K.

    28Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden

Corresponding author: Josefin E. Löfvenborg, [email protected]

Received June 15, 2020

Accepted November 14, 2020

Diabetes Care 44(2):p 416-424, February 2021. | DOI: 10.2337/dc20-1463

OBJECTIVE

Islet autoimmunity is associated with diabetes incidence. We investigated whether there was an interaction between dietary fish intake or plasma phospholipid n-3 polyunsaturated fatty acid (PUFA) concentration with the 65-kDa isoform of GAD (GAD65) antibody positivity on the risk of developing adult-onset diabetes.

RESEARCH DESIGN AND METHODS

We used prospective data on 11,247 incident cases of adult-onset diabetes and 14,288 noncases from the EPIC-InterAct case-cohort study conducted in eight European countries. Baseline plasma samples were analyzed for GAD65 antibodies and phospholipid n-3 PUFAs. Adjusted hazard ratios (HRs) for incident diabetes in relation to GAD65 antibody status and tertiles of plasma phospholipid n-3 PUFA or fish intake were estimated using Prentice-weighted Cox regression. Additive (proportion attributable to interaction [AP]) and multiplicative interactions between GAD65 antibody positivity (≥65 units/mL) and low fish/n-3 PUFA were assessed.

RESULTS

The hazard of diabetes in antibody-positive individuals with low intake of total and fatty fish, respectively, was significantly elevated (HR 2.52 [95% CI 1.76–3.63] and 2.48 [1.79–3.45]) compared with people who were GAD65 antibody negative and had high fish intake, with evidence of additive (AP 0.44 [95% CI 0.16–0.72] and 0.48 [0.24–0.72]) and multiplicative (P = 0.0465 and 0.0103) interactions. Individuals with high GAD65 antibody levels (≥167.5 units/mL) and low total plasma phospholipid n-3 PUFAs had a more than fourfold higher hazard of diabetes (HR 4.26 [2.70–6.72]) and an AP of 0.46 (0.12–0.80) compared with antibody-negative individuals with high n-3 PUFAs.

CONCLUSIONS

High fish intake or relative plasma phospholipid n-3 PUFA concentrations may partially counteract the increased diabetes risk conferred by GAD65 antibody positivity.

Copyright © 2021 by the American Diabetes Association, Inc.