A lipidome-wide association study of the lipoprotein insulin resistance index

Abstract

Background: The lipoprotein insulin resistance (LPIR) score was shown to predict insulin resistance (IR) and type 2 diabetes (T2D) in healthy adults. However, the molecular basis underlying the LPIR utility for classification remains unclear. Objective: To identify small molecule lipids associated with variation in the LPIR score, a weighted index of lipoproteins measured by nuclear magnetic resonance, in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 980). Methods: Linear mixed effects models were used to test the association between the LPIR score and 413 lipid species and their principal component analysis-derived groups. Significant associations were tested for replication with homeostatic model assessment-IR (HOMA-IR), a phenotype correlated with the LPIR score (r = 0.48, p < 0.001), in the Heredity and Phenotype Intervention (HAPI) Heart Study (n = 590). Results: In GOLDN, 319 lipids were associated with the LPIR score (false discovery rate-adjusted p-values ranging from 4.59 × 10 − 161 to 49.50 × 10 − 3). Factors 1 (triglycerides and diglycerides/storage lipids) and 3 (mixed lipids) were positively (β = 0.025, p = 4.52 × 10 − 71 and β = 0.021, p = 5.84 × 10 − 41 , respectively) and factor 2 (phospholipids/ non-storage lipids) was inversely (β = − 0.013, p = 2.28 × 10 − 18) associated with the LPIR score. These findings were replicated for HOMA-IR in the HAPI Heart Study (β = 0.10, p = 1.21 × 10 − 02 for storage, β = − 0.13, p = 3.14 × 10 − 04 for non-storage, and β = 0.19, p = 8.40 × 10 − 07 for mixed lipids). Conclusions: Non-storage lipidomics species show a significant inverse association with the LPIR metabolic dysfunction score and present a promising focus for future therapeutic and prevention studies.

Nuclear Magnetic Resonance Derived Biomarkers for Evaluating Cardiometabolic Risk in Youth and Young Adults Across the Spectrum of Glucose Tolerance

“…LPIR is a non-insulin dependent fasting test that quantifies one of the earliest manifestations of insulin resistance—dyslipidemia characterized by elevations in triglyceride and lower high-density lipoprotein cholesterol concentrations. LPIR is already an emerging diagnostic and risk stratification tool in adults ( 30 , 31 ) because elevations in LPIR precede the development of abnormal glucose tolerance ( 23 , 32 ). However, its diagnostic and predictive ability in youth is unknown.…”

Leveraging a founder population to identify novel rare-population genetic determinants of lipidome

“…The technical details of the laboratory protocols and methods of the lipodomics experiments are described in our previous paper 5 and reproduced here for completeness.…”

“…Here, we performed a GWAS in 650 individuals from the Old Order Amish founder population (Supp Table 1) using an expanded number of 355 lipid species from 14 classes that included 127 not previously tested for genetic association (Supp Table 2). The population-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study [3][4][5][6] was used for replication and fine mapping, and publicly available association results databases from several large biobanks were used to look up the top results (Supp Table 6). We identified five rare-population but Amish-enriched loci, three of which are novel, and replicated 7 previously known common loci including two loci with novel trait associations.…”

Genomics of Postprandial Lipidomics in the Genetics of Lipid-Lowering Drugs and Diet Network Study

“…Lipid identification was performed by converting the acquired MS/MS spectra to the mascot generic format (MGF) and then conducting a library search using the in-silico MS/MS library LipidBlast [40]. In total, 413 lipids were characterized including CEs, lysophosphatidylcholines (LPCs), phosphatidylcholines (PCs), phosphatidylethanolamines (PEs), lysophosphatidylethanolamines (LPEs), sphingomyelins (SMs), phosphatidlyserines, phosphatidylinositols (PIs), ceramides, and TGs [41].…”

“…Following imputation, variants with imputation quality/INFO < 0.9, minor allele frequency < 0.0001, or deviation from Hardy-Weinberg equilibrium at p < 1.0 × 10 −9 were excluded. Finally, the same lipidomics assays were measured on 639 HAPI Heart participants at the WCMC [41].…”