Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans
Open accessAbstract
Blood concentrations of lipoproteins and lipids are heritable risk factors for cardiovascular disease. Using genome-wide association data from three studies (n = 8,816 that included 2,758 individuals from the Diabetes Genetics Initiative specific to the current paper as well as 1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables reported in a companion paper in this issue) and targeted replication association analyses in up to 18,554 independent participants, we show that common SNPs at 18 loci are reproducibly associated with concentrations of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and/or triglycerides. Six of these loci are new (P < 5 x 10(-8) for each new locus). Of the six newly identified chromosomal regions, two were associated with LDL cholesterol (1p13 near CELSR2, PSRC1 and SORT1 and 19p13 near CILP2 and PBX4), one with HDL cholesterol (1q42 in GALNT2) and five with triglycerides (7q11 near TBL2 and MLXIPL, 8q24 near TRIB1, 1q42 in GALNT2, 19p13 near CILP2 and PBX4 and 1p31 near ANGPTL3). At 1p13, the LDL-associated SNP was also strongly correlated with CELSR2, PSRC1, and SORT1 transcript levels in human liver, and a proxy for this SNP was recently shown to affect risk for coronary artery disease. Understanding the molecular, cellular and clinical consequences of the newly identified loci may inform therapy and clinical care.
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Several genome-wide association studies have linked the rs4420638 and rs10402271 SNPs of the APOE-APOC cluster with higher serum LDL cholesterol levels and an increased risk of coronary artery disease.
“Indeed, several GWAS have linked the rs4420638 and rs10402271 SNPs of the APOE–APOC cluster with higher serum LDL cholesterol levels and an increased risk of coronary artery disease84,85.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [85]
The paper reports that the APOE–APOC1–APOC4–APOC2 locus is associated with LDL cholesterol (Abstract; page unavailable). It does not identify rs4420638 or rs10402271 in that finding or link those SNPs to coronary artery disease; its coronary artery disease passage concerns a different locus, 1p13. (LLM, conf=0.88)
Experimental — accuracy not yet measuredVariants in loci implicated in Mendelian disorders also contribute to susceptibility to more common forms of disease.
“There are now several examples where variants in loci implicated in Mendelian disorders also contribute to susceptibility to more common forms of disease; these include discoveries related to the genetics of blood lipid levels and coronary artery disease (83, 162), genetics of obesity (100, 163), and the genetics of height (96, 159).”
From Unraveling a Multifactorial Late-Onset Disease: From Genetic Susceptibility to Disease Mechanisms for Age-Related Macular Degeneration (2009) · cites this paper as [83]
A single locus can harbor both common variants of weak effect and rare variants of large effect; of 19 lipid loci, nine were already known to carry rare Mendelian mutations with large effects.
“6) A single locus can harbor both common variants of weak effect and rare variants of large effect. In recent GWASs, studies of common SNPs enabled the identification of 19 loci as influencing low- or high-density lipoprotein (LDL, HDL) or triglycerides (84, 85). Nine of these 19 were already known to carry rare Mendelian mutations with large effects, such as the loci for the LDL receptor (LDLR)”
From Genetic Mapping in Human Disease (2008) · cites this paper as [84]
A subset of associations involve genes previously related to the disease; of 19 loci meeting genome-wide significance in a recent GWAS of LDL, HDL, or triglycerides, 12 contained genes with known functions in lipid biology.
“1) A subset of associations involve genes previously related to the disease. Of 19 loci meeting genome-wide significance in a recent GWAS of LDL, HDL, or triglyceride levels, 12 contained genes with known functions in lipid biology (84, 85).”
From Genetic Mapping in Human Disease (2008) · cites this paper as [84]
GWASs have shown that common genetic variation in LDLR and HMGCR influences LDL levels.
“More recently, GWASs have shown that common genetic variation in LDLR and HMGCR influences LDL levels (84, 85).”
From Genetic Mapping in Human Disease (2008) · cites this paper as [84]
SNPs in HMGCR have only a small effect (~5%) on LDL levels, whereas drugs targeting the encoded protein decrease LDL levels by a much greater extent (~30%).
“Although SNPs in HMGCR have only a small effect (~5%) on LDL levels, drugs targeting the encoded protein decrease LDL levels by a much greater extent (~30%).”
From Genetic Mapping in Human Disease (2008) · cites this paper as [84]
Newly described variants on chromosome 1 near SORT1 are associated both with levels of LDL cholesterol and with risk of myocardial infarction.
“For example, newly described variants on chromosome 1 (near SORTI) are associated both with levels of LDL cholesterol (84, 85) and with risk of myocardial infarction (106);”
From Genetic Mapping in Human Disease (2008) · cites this paper as [84]
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- Authors
- Kathiresan, S., Melander, O., Guiducci, C., Surti, A., Burtt, N. P., Rieder, M. J., Cooper, G. M., Roos, C., Voight, B. F., Havulinna, A. S., Wahlstrand, B., Hedner, T., Corella, D., Tai, E. S., Ordovas, J. M., Berglund, G., Vartiainen, E., Jousilahti, P., Hedblad, B., Taskinen, M.-R., Newton-Cheh, C., Salomaa, V., Peltonen, L., Groop, L., Altshuler, D. M., & Orho-Melander, M.
- Affiliations
- Massachusetts General Hospital (US)
- Lund University (SE)
- Broad Institute (US)
- University of Washington (US)
- Sahlgrenska University Hospital (SE)
- Universitat de València (ES)
- Singapore General Hospital (SG)
- University of Helsinki (FI)
- Corresponding author
- Kathiresan, Sekar
- ORCID
- Venue
- Nature Genetics
- Published
- 2008-01-13
- Volume
- 40
- Issue
- 2
- Pages
- 189-197
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2682493
- OpenAlex
- W2140079333
- Cited by
- 1,386
- References
- 29
- Citations by year
- 2026: 11 · 2025: 20 · 2024: 32 · 2023: 33 · 2022: 46 · 2021: 54 · 2020: 39 · 2019: 57 · 2018: 62 · 2017: 66 · 2016: 66 · 2015: 95 · 2014: 105 · 2013: 95 · 2012: 114
- FWCI
- 93.08
- Type
- journal article
- Language
- en
- Update notices
- erratum (2008-11-01)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- Wellcome Trust (089061)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- LDL cholesterol, HDL cholesterol, triglycerides, genetic loci, single nucleotide polymorphisms, CELSR2, PSRC1, SORT1, GALNT2, MLXIPL, TRIB1, ANGPTL3, coronary artery disease, cardiovascular risk, type 2 diabetes, hepatic gene expression
- MeSH terms
- Aged, Alleles, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 7, Chromosomes, Human, Pair 8, Female, Gene Frequency, Genetic Markers, Humans, Cholesterol, HDL, Cholesterol, LDL, Liver, Male, Middle Aged, Probability, Prospective Studies, RNA, Messenger, Triglycerides, Genetic Variation, Cohort Studies, Linkage Disequilibrium, Genome, Human, Case-Control Studies, Randomized Controlled Trials as Topic, Sequence Analysis, DNA, Polymorphism, Single Nucleotide
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