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Murphy, A.M.; Smith, C.E.; Murphy, L.M.; Follis, J.L.; Tanaka, T.; Richardson, K.; ... ; Roche, H.M. (2019)

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

Article / Letter to editor
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-1 beta 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 (beta +/- SE = -0.0058 +/- 0.002, p = 0.004) to increase insulin by 0.0058 IU mL(-1), per additional copy of the major (C)...Show moreScope 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-1 beta 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 (beta +/- 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.Show less
Cohorts for Heart and Ageing Research in Genomic Epidemiology consortium
genome-wide interaction studies
insulin resistance
meta-analyses
NLRP3 inflammasomes
saturated fats
All authors
Murphy, A.M.; Smith, C.E.; Murphy, L.M.; Follis, J.L.; Tanaka, T.; Richardson, K.; Noordam, R.; Lemaitre, R.N.; Kahonen, M.; Dupuis, J.; Voortman, T.; Marouli, E.; Mook-Kanamori, D.O.; Raitakari, O.T.; Hong, J.; Dehghan, A.; Dedoussis, G.; Mutsert, R. de; Lehtimaki, T.; Liu, C.T.; Rivadeneira, F.; Deloukas, P.; Mikkila, V.; Meigs, J.B.; Uitterlinden, A.; Lkram, M.A.; Franco, O.H.; Hughes, M.; O'Gaorajose, P.; Ordovas, J.M.; Roche, H.M.
Date
2019-09-12
Journal
Molecular Nutrition and Food Research
Volume
63
Issue
22
DOI
doi:10.1002/mnfr.201900226