Whole-exome sequencing identifies novel protein-altering variants associated with serum apolipoprotein and lipid concentrations

Niina Sandholm; Ronja Hotakainen; Jani K Haukka; Fanny Jansson Sigfrids; Emma H Dahlström; Anni A Antikainen; Erkka Valo; Anna Syreeni; Elina Kilpeläinen; Anastasia Kytölä; Aarno Palotie; Valma Harjutsalo; Carol Forsblom; Per-Henrik Groop; FinnDiane Study Group

doi:10.1186/s13073-022-01135-6

Whole-exome sequencing identifies novel protein-altering variants associated with serum apolipoprotein and lipid concentrations

Genome Med. 2022 Nov 23;14(1):132. doi: 10.1186/s13073-022-01135-6.

Authors

Niina Sandholm^#^{1

2

3}, Ronja Hotakainen^#^{4

5

6}, Jani K Haukka^{4

5

6}, Fanny Jansson Sigfrids^{4

5

6}, Emma H Dahlström^{4

5

6}, Anni A Antikainen^{4

5

6}, Erkka Valo^{4

5

6}, Anna Syreeni^{4

5

6}, Elina Kilpeläinen⁷, Anastasia Kytölä⁷, Aarno Palotie^{7

8

9}, Valma Harjutsalo^{4

5

6}, Carol Forsblom^{4

5

6}, Per-Henrik Groop^{10

11

12

13}; FinnDiane Study Group

Affiliations

¹ Folkhälsan Research Center, Biomedicum Helsinki, Haartmaninkatu 8, Helsinki, 00290, Finland. niina.sandholm@helsinki.fi.
² Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. niina.sandholm@helsinki.fi.
³ Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland. niina.sandholm@helsinki.fi.
⁴ Folkhälsan Research Center, Biomedicum Helsinki, Haartmaninkatu 8, Helsinki, 00290, Finland.
⁵ Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
⁶ Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
⁷ Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
⁸ Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
⁹ The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁰ Folkhälsan Research Center, Biomedicum Helsinki, Haartmaninkatu 8, Helsinki, 00290, Finland. per-henrik.groop@helsinki.fi.
¹¹ Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. per-henrik.groop@helsinki.fi.
¹² Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland. per-henrik.groop@helsinki.fi.
¹³ Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria, Australia. per-henrik.groop@helsinki.fi.

^# Contributed equally.

Abstract

Background: Dyslipidemia is a major risk factor for cardiovascular disease, and diabetes impacts the lipid metabolism through multiple pathways. In addition to the standard lipid measurements, apolipoprotein concentrations provide added awareness of the burden of circulating lipoproteins. While common genetic variants modestly affect the serum lipid concentrations, rare genetic mutations can cause monogenic forms of hypercholesterolemia and other genetic disorders of lipid metabolism. We aimed to identify low-frequency protein-altering variants (PAVs) affecting lipoprotein and lipid traits.

Methods: We analyzed whole-exome (WES) and whole-genome sequencing (WGS) data of 481 and 474 individuals with type 1 diabetes, respectively. The phenotypic data consisted of 79 serum lipid and apolipoprotein phenotypes obtained with clinical laboratory measurements and nuclear magnetic resonance spectroscopy.

Results: The single-variant analysis identified an association between the LIPC p.Thr405Met (rs113298164) and serum apolipoprotein A1 concentrations (p=7.8×10^-8). The burden of PAVs was significantly associated with lipid phenotypes in LIPC, RBM47, TRMT5, GTF3C5, MARCHF10, and RYR3 (p<2.9×10^-6). The RBM47 gene is required for apolipoprotein B post-translational modifications, and in our data, the association between RBM47 and apolipoprotein C-III concentrations was due to a rare 21 base pair p.Ala496-Ala502 deletion; in replication, the burden of rare deleterious variants in RBM47 was associated with lower triglyceride concentrations in WES of >170,000 individuals from multiple ancestries (p=0.0013). Two PAVs in GTF3C5 were highly enriched in the Finnish population and associated with cardiovascular phenotypes in the general population. In the previously known APOB gene, we identified novel associations at two protein-truncating variants resulting in lower serum non-HDL cholesterol (p=4.8×10^-4), apolipoprotein B (p=5.6×10^-4), and LDL cholesterol (p=9.5×10^-4) concentrations.

Conclusions: We identified lipid and apolipoprotein-associated variants in the previously known LIPC and APOB genes, as well as PAVs in GTF3C5 associated with LDLC, and in RBM47 associated with apolipoprotein C-III concentrations, implicated as an independent CVD risk factor. Identification of rare loss-of-function variants has previously revealed genes that can be targeted to prevent CVD, such as the LDL cholesterol-lowering loss-of-function variants in the PCSK9 gene. Thus, this study suggests novel putative therapeutic targets for the prevention of CVD.

Keywords: APOB; Apolipoprotein A1; Apolipoprotein C-III; GTF3C5; LIPC; Lipidomics; MARCHF10; RBM47; RYR3; Whole-exome sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apolipoprotein C-III / genetics
Apolipoproteins / genetics
Apolipoproteins B / genetics
Cardiovascular Diseases*
Cholesterol, LDL / genetics
Exome Sequencing
Humans
Proprotein Convertase 9* / genetics
RNA-Binding Proteins / genetics

Substances

PCSK9 protein, human
Proprotein Convertase 9
Cholesterol, LDL
Apolipoprotein C-III
Apolipoproteins
Apolipoproteins B
RBM47 protein, human
RNA-Binding Proteins