What is the clinical evidence from this study?

Study design: Observational. Population: Dyslipidemia / Lipid and lipoprotein subclasses (n=8372). Intervention: Genetic variants (common, low-frequency, and rare) vs. Reference alleles. Primary outcome: Association of genetic variants with 72 lipid and lipoprotein traits (p=<5x10^-8).

October 30, 2017Open Access

Common, low-frequency, and rare genetic variants associated with lipoprotein subclasses and triglyceride measures in Finnish men from the METSIM study

Q: What are the key findings of this study?

Genome-wide association analysis identified five novel signals near established lipid loci at HIF3A, ADAMTS3, PLTP, LCAT, and LIPG, and uncovered novel associations for rare coding variants at LIPC and LIPG with HDL subclasses.

Key Result

Genome-wide association analysis identified five novel signals near established lipid loci at HIF3A, ADAMTS3, PLTP, LCAT, and LIPG, and uncovered novel associations for rare coding variants at LIPC and LIPG with HDL subclasses.

Study Design

Type

Observational (n=8,372)

Structured PICO

Population

8,372 non-diabetic Finnish men from the METSIM study evaluated for genetic variants associated with 72 lipid and lipoprotein subclass traits.

Outcome

Association of 15.1M genetic variants with 72 lipid and lipoprotein traitssurrogate

The identification of novel genetic variants associated with lipoprotein subclasses provides further insight into the molecular basis of dyslipidemia and potential therapeutic targets.

Main Result

p-value: p=<5x10^-8

Limitations

Study was restricted to non-diabetic Finnish men, requiring replication in women and other ancestry groups.
Further analysis with additional samples may be necessary to elucidate haplotype relationships at complex loci like APOE.
It remains unclear which specific variants included in the gene-based tests for LIPC and LIPG truly affect gene function.

Abstract

Lipid and lipoprotein subclasses are associated with metabolic and cardiovascular diseases, yet the genetic contributions to variability in subclass traits are not fully understood. We conducted single-variant and gene-based association tests between 15.1M variants from genome-wide and exome array and imputed genotypes and 72 lipid and lipoprotein traits in 8,372 Finns. After accounting for 885 variants at 157 previously identified lipid loci, we identified five novel signals near established loci at HIF3A, ADAMTS3, PLTP, LCAT, and LIPG. Four of the signals were identified with a low-frequency (0.005<minor allele frequency MAF<0.05) or rare (MAF<0.005) variant, including Arg123His in LCAT. Gene-based associations (P<10-10) support a role for coding variants in LIPC and LIPG with lipoprotein subclass traits. 30 established lipid-associated loci had a stronger association for a subclass trait than any conventional trait. These novel association signals provide further insight into the molecular basis of dyslipidemia and the etiology of metabolic disorders.

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