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Meta‐Analysis of 19,005 Individuals Identifies Interplay Between Dietary Saturated Fats and Genetic Variants of the NLRP3 Inflammasome, to Modulate Insulin Resistance and Diabetes Risk
Author(s) -
Murphy Aoife Marie,
Murphy Leanne,
Smith Caren Elizabeth,
Follis Jack,
Tanaka Toshiko,
Helminen Mika,
Lemaitre Rozenn,
Voortman Trudy,
Dehghan Abbas,
MookKanamori Dennis,
Marouli Eirini,
Richardson Kris,
Dupuis Josee,
Meigs James,
Gaora Peadar O',
Ordovas Jose,
Roche Helen
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.644.19
Subject(s) - insulin resistance , inflammasome , snp , type 2 diabetes , single nucleotide polymorphism , minor allele frequency , pyrin domain , endocrinology , medicine , diabetes mellitus , genetics , allele , biology , receptor , genotype , gene
Type 2 Diabetes (T2D) is a multi‐factorial disease, caused by a complex interaction of environmental and genetic factors. Dietary fats represent an important environmental factor. Our previous research has demonstrated that the ‘nod like receptor pyrin domain containing‐3’ (NLRP3) inflammasome plays a critical role in obesity associated insulin resistance (IR) and has a specific sensitivity to saturated fatty acids (SFA) (*Finucane et al, 2014). We investigated genetic variants related to NLRP3 and potential interactions with SFA, which may modulate T2D risk. Using METAL software, a cross‐sectional meta‐analyses of 6 Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium (n=19,005), tested interactions (linear regression effects) between dietary saturated fats and candidate NLRP3 related SNP's, to determine if these interactions could modulate three glycemic traits, fasting insulin, fasting glucose and Homeostasis Model Assessment of IR (HOMA‐IR). NLRP3 variant rs12143966 interacted with SFA intake (β ± SE = 0.0068 ± 0.002, p= 0.001), suggesting that each 1% increase SFA intake, in the presence of the minor A allele (MAF 0.38), increased fasting insulin by 0.0068 units. Olfactory Receptor Family 2, Subfamily B member 11 ( OR2B11 ) variant rs4925663, minor allele T (MAF 0.4), also interacted with SFA (β ± SE = −0.0068 ± 0.002, p= 0.0001), suggesting a 0.0068 uIU/ml reduction in fasting insulin with each additional 1% SFA intake. Both SNP's are located on Chromosome 1 q44. In Silico functional analysis describes OR2B11 variant rs4925663 as a non‐synonymous missense SNP with highly significant eQTL hits with NLRP3 expression in whole blood and liver tissue. Two inflammatory SNPs show a novel interaction with dietary SFA to modulate fasting insulin. Altering SFA intake may modulate T2D risk depending on the genotype of inflammasome related variants. Support or Funding Information Science Foundation Ireland Principal Investigator Programme awarded to Prof Helen Roche (11/PI/1119)