title: Genetic associations with lipoprotein subfractions provide information on their biological nature.
abstract: Adverse levels of lipoproteins are highly heritable and constitute risk factors for cardiovascular outcomes. Hitherto, genome-wide association studies revealed 95 lipid-associated loci. However, due to the small effect sizes of these associations large sample numbers (>100 000 samples) were needed. Here we show that analyzing more refined lipid phenotypes, namely lipoprotein subfractions, can increase the number of significantly associated loci compared with bulk high-density lipoprotein and low-density lipoprotein analysis in a study with identical sample numbers. Moreover, lipoprotein subfractions provide novel insight into the human lipid metabolism. We measured 15 lipoprotein subfractions (L1-L15) in 1791 samples using (1)H-NMR (nuclear magnetic resonance) spectroscopy. Using cluster analyses, we quantified inter-relationships among lipoprotein subfractions. Additionally, we analyzed associations with subfractions at known lipid loci. We identified five distinct groups of subfractions: one (L1) was only marginally captured by serum lipids and therefore extends our knowledge of lipoprotein biochemistry. During a lipid-tolerance test, L1 lost its special position. In the association analysis, we found that eight loci (LIPC, CETP, PLTP, FADS1-2-3, SORT1, GCKR, APOB, APOA1) were associated with the subfractions, whereas only four loci (CETP, SORT1, GCKR, APOA1) were associated with serum lipids. For LIPC, we observed a 10-fold increase in the variance explained by our regression models. In conclusion, NMR-based fine mapping of lipoprotein subfractions provides novel information on their biological nature and strengthens the associations with genetic loci. Future clinical studies are now needed to investigate their biomedical relevance.
authors.affiliation: Institute of Genetic Epidemiology, Helmholtz Zentrum München, Neuherberg 85764, Germany.
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Petersen
authors.forename: Klaus
authors.initials: K
authors.lastname: Stark
authors.forename: Muntaser D
authors.initials: MD
authors.lastname: Musameh
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nelson
authors.forename: Werner
authors.initials: W
authors.lastname: Römisch-Margl
authors.forename: Werner
authors.initials: W
authors.lastname: Kremer
authors.forename: Johannes
authors.initials: J
authors.lastname: Raffler
authors.forename: Susanne
authors.initials: S
authors.lastname: Krug
authors.forename: Thomas
authors.initials: T
authors.lastname: Skurk
authors.forename: Manuela J
authors.initials: MJ
authors.lastname: Rist
authors.forename: Hannelore
authors.initials: H
authors.lastname: Daniel
authors.forename: Hans
authors.initials: H
authors.lastname: Hauner
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.forename: Maciej
authors.initials: M
authors.lastname: Tomaszewski
authors.forename: Angela
authors.initials: A
authors.lastname: Döring
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.forename: H-Erich
authors.initials: HE
authors.lastname: Wichmann
authors.forename: Bernhard M
authors.initials: BM
authors.lastname: Kaess
authors.forename: Hans Robert
authors.initials: HR
authors.lastname: Kalbitzer
authors.forename: Fritz
authors.initials: F
authors.lastname: Huber
authors.forename: Volker
authors.initials: V
authors.lastname: Pfahlert
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Florian
authors.initials: F
authors.lastname: Kronenberg
authors.forename: Hans
authors.initials: H
authors.lastname: Dieplinger
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.forename: Karsten
authors.initials: K
authors.lastname: Suhre
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Gabi
authors.initials: G
authors.lastname: Kastenmüller
mesh_terms: D000328:Adult; D015992:Body Mass Index; D002874:Chromosome Mapping; D000090943:Delta-5 Fatty Acid Desaturase; D005215:Fasting / Q000502:physiology*; D056426:Genetic Loci / Q000235:genetics*; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D006801:Humans; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000032:analysis* / Q000235:genetics*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D055815:Young Adult
chemical_list: D000090943:Delta-5 Fatty Acid Desaturase; D008074:Lipoproteins; C000716847:FADS1 protein, human