Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease

Cadby, Gemma; Giles, Corey; Melton, Phillip E.; Huynh, Kevin; Mellett, Natalie A.; Duong, Thy; Nguyen, Anh Thu; Cinel, Michelle; Smith, Alex; Olshansky, Gavriel; Wang, Tingting; Brożyńska, Marta; Inouye, Mike; McCarthy, Nina S.; Ariff, Amir; Hung, Joe; Hui, Jennie; Beilby, John; Dubé, Marie‐Pierre; Watts, Gerald F.; Shah, Sonia; Wray, Naomi R.; Lim, Wei Ling Florence; Chatterjee, Pratishtha; Martins, Ian James; Laws, Simon M.; Porter, Tenielle; Vacher, Michaël; Bush, Ashley I.; Rowe, Christopher C.; Villemagne, Victor L.; Ames, David; Masters, Colin L.; Taddei, Kevin; Arnold, Matthias; Kastenmüller, Gabi; Nho, Kwangsik; Saykin, Andrew J.; Han, Xianlin; Kaddurah‐Daouk, Rima; Martins, Ralph N.; Blangero, John; Meikle, Peter J.; Moses, Eric K.

doi:10.1038/s41467-022-30875-7

Cited by 40 publications

(54 citation statements)

References 87 publications

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“…We found that known eQTLs of FADS1 gene among five cancer types still remain to be its eQTLs in tumor tissues. These eQTLs are in strong linkage disequilibrium and studies showed that these SNPs can predict FADS1 expression as well as FADS1 activity that is reflected in circulating PUFA levels in humans ( 19 , 58 , 59 ). Change in the level of PUFAs that are due to these genetic variants, are demonstrated to be associated with cancer risk ( 31 , 33 , 60 , 61 ).…”

Section: Discussionmentioning

confidence: 99%

Fatty acid desaturase 1 (FADS1) is a cancer marker for patient survival and a potential novel target for precision cancer treatment

et al. 2022

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Fatty Acid Desaturase-1 (FADS1) or delta 5 desaturase (D5D) is a rate-limiting enzyme involved in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs), i.e., arachidonic acid (ARA) and eicosapentaenoic (EPA). These LC-PUFAs and their metabolites play essential and broad roles in cancer cell proliferation, metastasis, and tumor microenvironment. However, the role of FADS1 in cancers remains incompletely understood. Utilizing The Cancer Genome Atlas (TCGA) database, we explored the role of FADS1 across different cancer types using multiple bioinformatics and statistical tools. Moreover, we studied the impact of a FADS1 inhibitor (D5D-IN-326) on proliferation of multiple cancer cell lines. We identified that FADS1 gene is a predictor for cancer survival in multiple cancer types. Compared to normal tissue, the mRNA expression of FADS1 is significantly increased in primary tumors while even higher in metastatic and recurrent tumors. Mechanistically, pathway analysis demonstrated that FADS1 is associated with cholesterol biosynthesis and cell cycle control genes. Interestingly, FADS1 expression is higher when TP53 is mutated. Tumors with increased FADS1 expression also demonstrated an increased signatures of fibroblasts and macrophages infiltration among most cancer types. Our in vitro assays showed that D5D-IN-326 significantly inhibited cell proliferation of kidney, colon, breast, and lung cancer cell lines in a dose-dependent manner. Lastly, single nucleotide polymorphisms (SNPs) which are well-established expression quantitative trait loci (eQTLs) for FADS1 in normal human tissues are also significantly correlated with FADS1 expression in tumors of multiple tissue types, potentially serving as a marker to stratify cancer patients with high/low FADS1 expression in their tumor tissue. Our study suggests that FADS1 plays multiple roles in cancer biology and is potentially a novel target for precision cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Fatty acid desaturase 1 (FADS1) is a cancer marker for patient survival and a potential novel target for precision cancer treatment

et al. 2022

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“… 12 , 13 , 14 , 15 , 16 Integration of lipidomics with genomics has also provided new insights into genetic regulation of lipid metabolism and ASCVD pathophysiology. 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 Strong influence of genetic variants, such as FADS1‐2‐3 , LDLR , and PCSK9 , in maintenance of lipid homeostasis, calls for a comprehensive evaluation of potential role of genetic mechanisms in sex differences in lipid metabolism. Thus, stronger consideration should be given to understand sex differences in lipidome and their genetic determinants.…”

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confidence: 99%

Lipidome‐ and Genome‐Wide Study to Understand Sex Differences in Circulatory Lipids

Tabassum

Ruotsalainen

Ottensmann

et al. 2022

JAHA

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Background Despite well‐recognized differences in the atherosclerotic cardiovascular disease risk between men and women, sex differences in risk factors and sex‐specific mechanisms in the pathophysiology of atherosclerotic cardiovascular disease remain poorly understood. Lipid metabolism plays a central role in the development of atherosclerotic cardiovascular disease. Understanding sex differences in lipids and their genetic determinants could provide mechanistic insights into sex differences in atherosclerotic cardiovascular disease and aid in precise risk assessment. Herein, we examined sex differences in plasma lipidome and heterogeneity in genetic influences on lipidome in men and women through sex‐stratified genome‐wide association analyses. Methods and Results We used data consisting of 179 lipid species measured by shotgun lipidomics in 7266 individuals from the Finnish GeneRISK cohort and sought for replication using independent data from 2045 participants. Significant sex differences in the levels of 141 lipid species were observed ( P <7.0×10 −4 ). Interestingly, 121 lipid species showed significant age‐sex interactions, with opposite age‐related changes in 39 lipid species. In general, most of the cholesteryl esters, ceramides, lysophospholipids, and glycerides were higher in 45‐ to 50‐year‐old men compared with women of same age, but the sex differences narrowed down or reversed with age. We did not observe any major differences in genetic effect in the sex‐stratified genome‐wide association analyses, which suggests that common genetic variants do not have a major role in sex differences in lipidome. Conclusions Our study provides a comprehensive view of sex differences in circulatory lipids pointing to potential sex differences in lipid metabolism and highlights the need for sex‐ and age‐specific prevention strategies.

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“…Figure 1 shows the general trend of increasing study and experiment (a sub-study examining one phenotype) numbers year-on-year since 2011. Recently, there has been a large increase in the number of experiments reported, caused by individual studies that investigate associations to -omic phenotypes such as the hundreds of experiments reported in lipidome ( 28 ), metabolome ( 29 ) and microbiome ( 30 ) related GWAS.…”

Section: Resultsmentioning

confidence: 99%

GWAS Central: an expanding resource for finding and visualising genotype and phenotype data from genome-wide association studies

Beck

Rowlands

Shorter

et al. 2022

Nucleic Acids Research

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The GWAS Central resource gathers and curates extensive summary-level genome-wide association study (GWAS) data and puts a range of user-friendly but powerful website tools for the comparison and visualisation of GWAS data at the fingertips of researchers. Through our continued efforts to harmonise and import data received from GWAS authors and consortia, and data sets actively collected from public sources, the database now contains over 72.5 million P-values for over 5000 studies testing over 7.4 million unique genetic markers investigating over 1700 unique phenotypes. Here, we describe an update to integrate this extensive data collection with mouse disease model data to support insights into the functional impact of human genetic variation. GWAS Central has expanded to include mouse gene–phenotype associations observed during mouse gene knockout screens. To allow similar cross-species phenotypes to be compared, terms from mammalian and human phenotype ontologies have been mapped. New interactive interfaces to find, correlate and view human and mouse genotype–phenotype associations are included in the website toolkit. Additionally, the integrated browser for interrogating multiple association data sets has been updated and a GA4GH Beacon API endpoint has been added for discovering variants tested in GWAS. The GWAS Central resource is accessible at https://www.gwascentral.org/.

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Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease

Cited by 40 publications

References 87 publications

Fatty acid desaturase 1 (FADS1) is a cancer marker for patient survival and a potential novel target for precision cancer treatment

Fatty acid desaturase 1 (FADS1) is a cancer marker for patient survival and a potential novel target for precision cancer treatment

Lipidome‐ and Genome‐Wide Study to Understand Sex Differences in Circulatory Lipids

GWAS Central: an expanding resource for finding and visualising genotype and phenotype data from genome-wide association studies

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