Potential Interplay between Dietary Saturated Fats and Genetic Variants of the NLRP3 Inflammasome to Modulate Insulin Resistance and Diabetes Risk: Insights from a Meta-Analysis of 19 005 Individuals

Aoife M Murphy; Caren E Smith; Leanne M Murphy; Jack L Follis; Toshiko Tanaka; Kris Richardson; Raymond Noordam; Rozenn N Lemaitre; Mika Kähönen; Josée Dupuis; Trudy Voortman; Eirini Marouli; Dennis O Mook-Kanamori; Olli T Raitakari; Jaeyoung Hong; Abbas Dehghan; George Dedoussis; Renée de Mutsert; Terho Lehtimäki; Ching-Ti Liu; Fernando Rivadeneira; Panagiotis Deloukas; Vera Mikkilä; James B Meigs; Andre Uitterlinden; Mohammad A Ikram; Oscar H Franco; Maria Hughes; Peadar O' Gaora; José M Ordovás; Helen M Roche

doi:10.1002/mnfr.201900226

Potential Interplay between Dietary Saturated Fats and Genetic Variants of the NLRP3 Inflammasome to Modulate Insulin Resistance and Diabetes Risk: Insights from a Meta-Analysis of 19 005 Individuals

Mol Nutr Food Res. 2019 Nov;63(22):e1900226. doi: 10.1002/mnfr.201900226. Epub 2019 Sep 12.

Authors

Aoife M Murphy¹, Caren E Smith², Leanne M Murphy³, Jack L Follis⁴, Toshiko Tanaka⁵, Kris Richardson², Raymond Noordam⁶, Rozenn N Lemaitre⁷, Mika Kähönen⁸, Josée Dupuis⁹, Trudy Voortman¹⁰, Eirini Marouli¹¹, Dennis O Mook-Kanamori¹², Olli T Raitakari¹³, Jaeyoung Hong⁹, Abbas Dehghan¹⁰, George Dedoussis¹⁴, Renée de Mutsert¹², Terho Lehtimäki¹⁵, Ching-Ti Liu⁹, Fernando Rivadeneira¹⁶, Panagiotis Deloukas¹¹, Vera Mikkilä¹⁷, James B Meigs^{18

19

20}, Andre Uitterlinden¹⁶, Mohammad A Ikram¹⁰, Oscar H Franco¹⁰, Maria Hughes¹, Peadar O' Gaora³, José M Ordovás^{2

21

22}, Helen M Roche^{1

23}

Affiliations

¹ Nutrigenomics Research Group, Conway Institute of Biomedical and Biomolecular Sciences, University College Dublin, Belfield, Dublin 4, D04 V1W8, Ireland.
² Jean Mayer USDA Human Nutrition Research Centre on Aging, Tufts University, Boston, MA, 02111, USA.
³ UCD School of Biomolecular and Biomedical Science, Conway Institute of Biomedical and Biomolecular Sciences, University College Dublin, Belfield, Dublin 4, D04 V1W8, Ireland.
⁴ Department of Mathematics, University of St. Thomas, Houston, TX, 77006-4626, USA.
⁵ Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, 21224, USA.
⁶ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, 2333 ZA., The Netherlands.
⁷ Department of Medicine, University of Washington, Seattle, WA, 98195, USA.
⁸ Department of Clinical Physiology, Tampere University Hospital and University of Tampere School of Medicine, 33521, Tampere, Finland.
⁹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02130, USA.
¹⁰ Department of Epidemiology, Erasmus MC-University Medical Center, Postbus 2040, 3000 CA, Rotterdam, The Netherlands.
¹¹ William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, E1 4NS, UK.
¹² Department of Clinical Epidemiology and Department of Public Health and Primary Care, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
¹³ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, and Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, 20521, Turku, Finland.
¹⁴ Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, El. Venizelou 70, 17671, Athens, Greece.
¹⁵ Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, 33520, Finland.
¹⁶ Department of Internal Medicine, Erasmus University Medical Center, Postbus 2040, 3000 CA, Rotterdam, The Netherlands.
¹⁷ Division of Nutrition, Department of Food and Environmental Sciences, 00014, Helsinki, Finland.
¹⁸ Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
¹⁹ Harvard Medical School, Boston, MA, 02115, USA.
²⁰ Broad Institute, Cambridge, MA, 02142, USA.
²¹ Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029, Madrid, Spain.
²² IMDEA Food Institute, CEI UAM + CSIC, E - 28049, Madrid, Spain.
²³ Institute For Global Food Security, Queen's University Belfast, Northern Ireland.

Abstract

Scope: Insulin resistance (IR) and inflammation are hallmarks of type 2 diabetes (T2D). The nod-like receptor pyrin domain containing-3 (NLRP3) inflammasome is a metabolic sensor activated by saturated fatty acids (SFA) initiating IL-1β inflammation and IR. Interactions between SFA intake and NLRP3-related genetic variants may alter T2D risk factors.

Methods: Meta-analyses of six Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 19 005) tested interactions between SFA and NLRP3-related single-nucleotide polymorphisms (SNPs) and modulation of fasting insulin, fasting glucose, and homeostasis model assessment of insulin resistance.

Results: SFA interacted with rs12143966, wherein each 1% increase in SFA intake increased insulin by 0.0063 IU mL^-1 (SE ± 0.002, p = 0.001) per each major (G) allele copy. rs4925663, interacted with SFA (β ± SE = -0.0058 ± 0.002, p = 0.004) to increase insulin by 0.0058 IU mL^-1 , per additional copy of the major (C) allele. Both associations are close to the significance threshold (p < 0.0001). rs4925663 causes a missense mutation affecting NLRP3 expression.

Conclusion: Two NLRP3-related SNPs showed potential interaction with SFA to modulate fasting insulin. Greater dietary SFA intake accentuates T2D risk, which, subject to functional validation, may be further elaborated depending on NLRP3-related genetic variants.

Keywords: Cohorts for Heart and Ageing Research in Genomic Epidemiology consortium; NLRP3 inflammasomes; genome-wide interaction studies; insulin resistance; meta-analyses; saturated fats.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Diabetes Mellitus, Type 2 / etiology*
Dietary Fats / administration & dosage*
Genetic Variation
Humans
Inflammasomes / genetics*
Insulin Resistance*
NLR Family, Pyrin Domain-Containing 3 Protein / genetics*
Polymorphism, Single Nucleotide*

Substances

Dietary Fats
Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding