Biological, Clinical and Population Relevance of 95 Loci for Blood Lipids

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Citing Articles

Sex differences in predicting dyslipidemia using polygenic risk score with fatty liver index and fibrotic nonalcoholic steatohepatitis index.

Kim S, Yoo H Sci Rep. 2025; 15(1):7849.

PMID: 40050666 PMC: 11885555. DOI: 10.1038/s41598-025-92766-3.

A Comprehensive Review of the Genetics of Dyslipidemias and Risk of Atherosclerotic Cardiovascular Disease.

Kalwick M, Roth M Nutrients. 2025; 17(4).

PMID: 40004987 PMC: 11858766. DOI: 10.3390/nu17040659.

To explore the causal association between the serum lipid profile and inflammatory bowel disease using bidirectional Mendelian randomisation analysis.

Pang X, Yang H, Li M, Suarez-Farinas M, Tian S eGastroenterology. 2025; 2(2):e100034.

PMID: 39944468 PMC: 11770443. DOI: 10.1136/egastro-2023-100034.

An overview of persistent chylomicronemia: much more than meets the eye.

Larouche M, Watts G, Ballantyne C, Gaudet D Curr Opin Endocrinol Diabetes Obes. 2025; 32(2):75-88.

PMID: 39927417 PMC: 11872273. DOI: 10.1097/MED.0000000000000903.

Silybin A from reprograms lipid metabolism to induce a cell fate-dependent class switch from triglycerides to phospholipids.

Koeberle S, Thurmer M, Su F, Werner M, Grander J, Hofer L Theranostics. 2025; 15(5):2006-2034.

PMID: 39897559 PMC: 11780512. DOI: 10.7150/thno.99562.

References

Wallace C, Newhouse S, Braund P, Zhang F, Tobin M, Falchi M . Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia. Am J Hum Genet. 2008; 82(1):139-49. PMC: 2253977. DOI: 10.1016/j.ajhg.2007.11.001. View

Barter P, Caulfield M, Eriksson M, Grundy S, Kastelein J, Komajda M . Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007; 357(21):2109-22. DOI: 10.1056/NEJMoa0706628. View

Kathiresan S, Willer C, Peloso G, Demissie S, Musunuru K, Schadt E . Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet. 2008; 41(1):56-65. PMC: 2881676. DOI: 10.1038/ng.291. View

Goldstein D . Common genetic variation and human traits. N Engl J Med. 2009; 360(17):1696-8. DOI: 10.1056/NEJMp0806284. View

Saxena R, Voight B, Lyssenko V, Burtt N, de Bakker P, Chen H . Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007; 316(5829):1331-6. DOI: 10.1126/science.1142358. View

Sabatti C, Service S, Hartikainen A, Pouta A, Ripatti S, Brodsky J . Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat Genet. 2008; 41(1):35-46. PMC: 2687077. DOI: 10.1038/ng.271. View

Hardy J, Singleton A . Genomewide association studies and human disease. N Engl J Med. 2009; 360(17):1759-68. PMC: 3422859. DOI: 10.1056/NEJMra0808700. View

Musunuru K, Strong A, Frank-Kamenetsky M, Lee N, Ahfeldt T, Sachs K . From noncoding variant to phenotype via SORT1 at the 1p13 cholesterol locus. Nature. 2010; 466(7307):714-9. PMC: 3062476. DOI: 10.1038/nature09266. View

Schadt E, Molony C, Chudin E, Hao K, Yang X, Lum P . Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 2008; 6(5):e107. PMC: 2365981. DOI: 10.1371/journal.pbio.0060107. View

10.

Willer C, Sanna S, Jackson A, Scuteri A, Bonnycastle L, Clarke R . Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 2008; 40(2):161-9. PMC: 5206900. DOI: 10.1038/ng.76. View

11.

Kooner J, Chambers J, Aguilar-Salinas C, Hinds D, Hyde C, Warnes G . Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides. Nat Genet. 2008; 40(2):149-51. DOI: 10.1038/ng.2007.61. View

12.

Hirschhorn J . Genomewide association studies--illuminating biologic pathways. N Engl J Med. 2009; 360(17):1699-701. DOI: 10.1056/NEJMp0808934. View

13.

Kathiresan S, Manning A, Demissie S, DAgostino R, Surti A, Guiducci C . A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study. BMC Med Genet. 2007; 8 Suppl 1:S17. PMC: 1995614. DOI: 10.1186/1471-2350-8-S1-S17. View

14.

Chasman D, Pare G, Mora S, Hopewell J, Peloso G, Clarke R . Forty-three loci associated with plasma lipoprotein size, concentration, and cholesterol content in genome-wide analysis. PLoS Genet. 2009; 5(11):e1000730. PMC: 2777390. DOI: 10.1371/journal.pgen.1000730. View

15.

Aulchenko Y, Ripatti S, Lindqvist I, Boomsma D, Heid I, Pramstaller P . Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet. 2008; 41(1):47-55. PMC: 2687074. DOI: 10.1038/ng.269. View

16.

Kraft P, Hunter D . Genetic risk prediction--are we there yet?. N Engl J Med. 2009; 360(17):1701-3. DOI: 10.1056/NEJMp0810107. View

17.

Weiss L, Pan L, Abney M, Ober C . The sex-specific genetic architecture of quantitative traits in humans. Nat Genet. 2006; 38(2):218-22. DOI: 10.1038/ng1726. View

18.

Kathiresan S, Melander O, Guiducci C, Surti A, Burtt N, Rieder M . Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 2008; 40(2):189-97. PMC: 2682493. DOI: 10.1038/ng.75. View

19.

Rung J, Cauchi S, Albrechtsen A, Shen L, Rocheleau G, Cavalcanti-Proenca C . Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet. 2009; 41(10):1110-5. DOI: 10.1038/ng.443. View

20.

Zelcer N, Hong C, Boyadjian R, Tontonoz P . LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science. 2009; 325(5936):100-4. PMC: 2777523. DOI: 10.1126/science.1168974. View