Murphy, Aoife MSmith, Caren EMurphy, Leanne MFollis, Jack LTanaka, ToshikoRichardson, KrisNoordam, RaymondLemaitre, Rozenn NKähönen, MikaDupuis, JoséeVoortman, TrudyMarouli, EiriniMook-Kanamori, Dennis ORaitakari, Olli THong, JaeyoungDehghan, AbbasDedoussis, Georgede Mutsert, RenéeLehtimäki, TerhoLiu, Ching-TiRivadeneira, FernandoDeloukas, PanagiotisMikkilä, VeraMeigs, James BUitterlinden, AndreIkram, Mohammad AFranco, Oscar HHughes, MariaO' Gaora, PeadarOrdovas, Jose MRoche, Helen M2019-10-172019-10-172019-08-20Mol Nutr Food Res. 2019: e19002261613-4125http://hdl.handle.net/20.500.12105/8505SCOPE: 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.engVoRhttp://creativecommons.org/licenses/by-nc/4.0/Cohorts for Heart and Ageing Research in Genomic Epidemiology consortiumNLRP3 inflammasomesGenome-wide interaction studiesInsulin resistanceMeta-analysesSaturated fatsAtribución-NoComercial 4.0 Internacional31432628e190022610.1002/mnfr.2019002261613-4133Molecular nutrition & food researchopen access