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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?

SUBMITTER: Bagheri M

PROVIDER: S-EPMC7318473 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Bagheri Minoo M Tiwari Hemant K HK Murillo Anarina L AL Al-Tobasei Rafet R Arnett Donna K DK Kind Tobias T Barupal Dinesh Kumar DK Fan Sili S Fiehn Oliver O O'connell Jeff J Montasser May M Aslibekyan Stella S Irvin Marguerite R MR

Lipids in health and disease 20200625 1

<h4>Background</h4>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.<h4>Objective</h4>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). ...[more]

PMID: 32586392

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Project description:BackgroundAfrican Americans have a high risk for type 2 diabetes (T2D) and insulin resistance. Studies among other population groups have identified DNA methylation loci associated with insulin resistance, but data in African Americans are lacking. Using DNA methylation profiles of blood samples obtained from the Illumina Infinium® HumanMethylation450 BeadChip, we performed an epigenome-wide association study to identify DNA methylation loci associated with insulin resistance among 136 non-diabetic, unrelated African American men (mean age 41.6 years) from the Howard University Family Study.ResultsWe identified three differentially methylated positions (DMPs) for homeostatic model assessment of insulin resistance (HOMA-IR) at 5% FDR. One DMP (cg14013695, HOXA5) is a known locus among Mexican Americans, while the other two DMPs are novel-cg00456326 (OSR1; beta = 0.027) and cg20259981 (ST18; beta = 0.010). Although the cg00456326 DMP is novel, the OSR1 gene has previously been found associated with both insulin resistance and T2D in Europeans. The genes HOXA5 and ST18 have been implicated in biological processes relevant to insulin resistance. Differential methylation at the significant HOXA5 and OSR1 DMPs is associated with differences in gene expression in the iMETHYL database. Analysis of differentially methylated regions (DMRs) did not identify any epigenome-wide DMRs for HOMA-IR. We tested transferability of HOMA-IR associated DMPs from five previous EWAS in Mexican Americans, Indian Asians, Europeans, and European ancestry Americans. Out of the 730 previously reported HOMA-IR DMPs, 47 (6.4%) were associated with HOMA-IR in this cohort of African Americans.ConclusionsThe findings from our study suggest substantial differences in DNA methylation patterns associated with insulin resistance across populations. Two of the DMPs we identified in African Americans have not been reported in other populations, and we found low transferability of HOMA-IR DMPs reported in other populations in African Americans. More work in African-ancestry populations is needed to confirm our findings as well as functional analyses to understand how such DNA methylation alterations contribute to T2D pathology.

Dataset Information

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

Publications

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

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