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A genome-wide association study identifies 41 loci associated with eicosanoid levels.

ABSTRACT: Eicosanoids are biologically active derivatives of polyunsaturated fatty acids with broad relevance to health and disease. We report a genome-wide association study in 8406 participants of the Atherosclerosis Risk in Communities Study, identifying 41 loci associated with 92 eicosanoids and related metabolites. These findings highlight loci required for eicosanoid biosynthesis, including FADS1-3, ELOVL2, and numerous CYP450 loci. In addition, significant associations implicate a range of non-oxidative lipid metabolic processes in eicosanoid regulation, including at PKD2L1/SCD and several loci involved in fatty acyl-CoA metabolism. Further, our findings highlight select clearance mechanisms, for example, through the hepatic transporter encoded by SLCO1B1. Finally, we identify eicosanoids associated with aspirin and non-steroidal anti-inflammatory drug use and demonstrate the substantial impact of genetic variants even for medication-associated eicosanoids. These findings shed light on both known and unknown aspects of eicosanoid metabolism and motivate interest in several gene-eicosanoid associations as potential functional participants in human disease.

SUBMITTER: Rhee EP

PROVIDER: S-EPMC10390489 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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A genome-wide association study identifies 41 loci associated with eicosanoid levels.

Rhee Eugene P EP Surapaneni Aditya L AL Schlosser Pascal P Alotaibi Mona M Yang Yueh-Ning YN Coresh Josef J Jain Mohit M Cheng Susan S Yu Bing B Grams Morgan E ME

Communications biology 20230731 1

Eicosanoids are biologically active derivatives of polyunsaturated fatty acids with broad relevance to health and disease. We report a genome-wide association study in 8406 participants of the Atherosclerosis Risk in Communities Study, identifying 41 loci associated with 92 eicosanoids and related metabolites. These findings highlight loci required for eicosanoid biosynthesis, including FADS1-3, ELOVL2, and numerous CYP450 loci. In addition, significant associations implicate a range of non-oxid ...[more]

PMID: 37524825

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Project description:BACKGROUND:Plasma neurofilament light (NFL) is a promising biomarker for Alzheimer disease (AD), which increases in the early stage of AD and is associated with the progression of AD. We performed a genome-wide association study (GWAS) of plasma NFL in Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) cohort to identify novel variants associated with AD. METHODS:This study included 179 cognitively healthy controls (HC), 176 patients with mild cognitive impairment (MCI), and 172 patients with AD. All subjects were restricted to non-Hispanic Caucasian derived from the ADNI cohort and met all quality control (QC) criteria. Association of plasma NFL with the genetic variants was assessed using PLINK with an additive genetic model, i.e.dose-dependent effect of the minor alleles. The influence of a genetic variant associated with plasma NFL (rs7943454) on brain structure was further assessed using PLINK with a linear regression model. RESULTS:The minor allele (T) of rs7943454 in leucine zipper protein 2 gene (LUZP2) was associated with higher plasma NFL at suggestive levels (P = 1.39 × 10- 6) in a dose-dependent fashion. In contrast, the minor allele (G) of rs640476 near GABRB2 was associated with lower plasma NFL at suggestive levels (P = 6.71 × 10- 6) in a dose-dependent effect in all diagnostic groups except the MCI group. Furthermore, the minor allele (T) of rs7943454 within LUZP2 increased the onset risk of AD (odds ratio = 1.547, confidence interval 95% = 1.018-2.351) and was associated with atrophy of right middle temporal gyrus in the whole cohort in the longitudinal study (P = 0.0234). CONCLUSION:GWAS found the associations of two single nucleotide polymorphisms (rs7943454 and rs640476) with plasma NFL at suggestive levels. Rs7943454 in LUZP2 was associated with the onset risk of AD and atrophy of right middle temporal gyrusin the whole cohort. Using an endophenotype-based approach, we identified rs7943454 as a new AD risk locus.

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A genome-wide association study identifies 41 loci associated with eicosanoid levels.

Publications

A genome-wide association study identifies 41 loci associated with eicosanoid levels.

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