Genome-wide association meta-analysis of circulating odd-numbered chain saturated fatty acids: Results from the CHARGE Consortium

Otto, Marcia C. de Oliveira; Lemaître, Rozenn N.; Sun, Qi; King, Irena B.; Wu, Jason; Manichaikul, Ani; Rich, Stephen S.; Tsai, Michael Y.; Chen, Y. D.; Fornage, Myriam; Guan, Weijun; Aslibekyan, Stella; Irvin, Marguerite R.; Kabagambe, Edmond K.; Arnett, Donna K.; Jensen, Majken K.; McKnight, Barbara; Psaty, Bruce M.; Steffen, Lyn M.; Smith, Caren E.; Risérus, Ulf; Lind, Lars; Rimm, Eric B.; Siscovick, David S.; Mozaffarian, Dariush

doi:10.1371/journal.pone.0196951

Cited by 15 publications

(9 citation statements)

References 42 publications

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“…The possible reasons for the presence of circulating C23:0 in rat brain was found to be either the exogenous intake through milk or endogenous production by the elongation of odd carbon chain fatty acid C17:0 37,38 . Recently, a genome-wide association meta-analysis of circulating odd carbon chain fatty acids revealed that C23:0 is predominantly a component of sphingolipids and is associated with a common variation in ceramide synthase CERS4 gene 39 . However, there is no report underlining the role of odd carbon chain SPLs in cancer patients till date.…”

Section: Discussionmentioning

confidence: 99%

LC-HRMS based approach to identify novel sphingolipid biomarkers in breast cancer patients

Bhadwal¹,

Dahiya²,

Shinde³

et al. 2020

Sci Rep

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perturbations in lipid metabolic pathways to meet the bioenergetic and biosynthetic requirements is a principal characteristic of cancer cells. Sphingolipids (SpLs) are the largest class of bioactive lipids associated to various aspects of tumorigenesis and have been extensively studied in cancer cell lines and experimental models. the clinical relevance of SpLs in human malignancies however is still poorly understood and needs further investigation. in the present study, we adopted a UHpLc-High resolution (orbitrap) Mass spectrometry (HRMS) approach to identify various sphingolipid species in breast cancer patients. A total of 49 SPLs falling into 6 subcategories have been identified. Further, integrating the multivariate analysis with metabolomics enabled us to identify an elevation in the levels of ceramide phosphates and sphingosine phosphates in tumor tissues as compared to adjacent normal tissues. the expression of genes involved in the synthesis of reported metabolites was also determined in local as well as TCGA cohort. A significant upregulation in the expression of CERK and SPHK1 was observed in tumor tissues in local and tcGA cohort. Sphingomyelin levels were found to be high in adjacent normal tissues. Consistent with the above findings, expression of SGMS1 in tumor tissues was downregulated in tcGA cohort only. clinical correlations of the selected metabolites and their performance as biomarkers was also evaluated. Significant ROC and positive correlation with Ki67 index highlight the diagnostic potential and clinical relevance of ceramide phosphates in breast cancer.Dysregulation of lipid homeostasis has become an established hallmark of cancer. The cancer cells exploit lipid metabolic pathways in order to fulfil their demand for energy as well as biosynthetic precursors. Aberrations in lipid metabolism thus affects numerous cellular processes such as cell growth, proliferation, differentiation and cell survival 1 . Sphingolipids (SPLs), apart from the inceptive view of being considered as mere structural components, have evolved as crucial regulators of myriads of cellular functions. The primary elements of sphingolipid metabolism such as ceramide, ceramide 1-phosphate and sphingosine 1-phosphate have recently emerged as key regulators in cancer cell growth, proliferation, survival, migration and drug resistance 2-4 . Numerous studies have described the elementary role of ceramide and sphingosine 1-phosphate rheostat in various types of cancers such as lung, breast and colon. However, these studies have provided the mechanistic details of sphingolipid metabolism in cancer cell lines and experimental models 5-7 , while their role in human malignancies is still poorly understood and needs further elucidation.Breast cancer continues to remain the most common malignancy among women worldwide 8 . The diagnosis rate of breast cancer among Indian females is as high as 25.8 per 100,000 women with a mortality rate of 12.7 per 100,000 women 9 . Despite advancement in diagnostic and therapeutic modalities, th...

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Section: Discussionmentioning

confidence: 99%

LC-HRMS based approach to identify novel sphingolipid biomarkers in breast cancer patients

Bhadwal¹,

Dahiya²,

Shinde³

et al. 2020

Sci Rep

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“…To overcome these limitations, fatty acid composition in tissues or the circulation are increasingly being utilised as biomarkers of dietary fat [ 12 ]. Two odd-chain saturated fatty acids, pentadecanoic acid (15:0) and heptadecanoic acid (17:0), and one trans -fatty acid, trans -palmitoleic acid ( t 16:1n-7), are increasingly used as biomarkers of dairy fat intake because they are mainly found in ruminant foods such as milk and are not strongly influenced by genetic variation [ 12 , 13 ]. Thus, their levels correlate with dairy fat consumption assessed through weighed diet records and 24-hour dietary recalls and change in accordance with dairy food intake in randomised controlled trials [ 12 , 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Biomarkers of dairy fat intake, incident cardiovascular disease, and all-cause mortality: A cohort study, systematic review, and meta-analysis

et al. 2021

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Background We aimed to investigate the association of serum pentadecanoic acid (15:0), a biomarker of dairy fat intake, with incident cardiovascular disease (CVD) and all-cause mortality in a Swedish cohort study. We also systematically reviewed studies of the association of dairy fat biomarkers (circulating or adipose tissue levels of 15:0, heptadecanoic acid [17:0], and trans-palmitoleic acid [t16:1n-7]) with CVD outcomes or all-cause mortality. Methods and findings We measured 15:0 in serum cholesterol esters at baseline in 4,150 Swedish adults (51% female, median age 60.5 years). During a median follow-up of 16.6 years, 578 incident CVD events and 676 deaths were identified using Swedish registers. In multivariable-adjusted models, higher 15:0 was associated with lower incident CVD risk in a linear dose–response manner (hazard ratio 0.75 per interquintile range; 95% confidence interval 0.61, 0.93, P = 0.009) and nonlinearly with all-cause mortality (P for nonlinearity = 0.03), with a nadir of mortality risk around median 15:0. In meta-analyses including our Swedish cohort and 17 cohort, case–cohort, or nested case–control studies, higher 15:0 and 17:0 but not t16:1n-7 were inversely associated with total CVD, with the relative risk of highest versus lowest tertile being 0.88 (0.78, 0.99), 0.86 (0.79, 0.93), and 1.01 (0.91, 1.12), respectively. Dairy fat biomarkers were not associated with all-cause mortality in meta-analyses, although there were ≤3 studies for each biomarker. Study limitations include the inability of the biomarkers to distinguish different types of dairy foods and that most studies in the meta-analyses (including our novel cohort study) only assessed biomarkers at baseline, which may increase the risk of misclassification of exposure levels. Conclusions In a meta-analysis of 18 observational studies including our new cohort study, higher levels of 15:0 and 17:0 were associated with lower CVD risk. Our findings support the need for clinical and experimental studies to elucidate the causality of these relationships and relevant biological mechanisms.

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“…The median sample size per analysis was 7,811 (min=284; max=17,267), including analyses of 10 monounsaturated fatty acids (MUFAs), 15 saturated fatty acids, 6 omega 3 PUFAs, 11 omega six PUFAs and 11 other characteristics (Supplementary table 1). The 15 GWAS analyses corresponded to seven independent studies or consortia and 15 separate publications [35][36][37][38][39][43][44][45][46][47][48][49][50][51][52] . An interaction study was the only fatty acid GWAS excluded 53 .…”

Section: Fatty Acid Datasetsmentioning

confidence: 99%

“…The vast majority of the GWAS analyses were conducted in European ancestry populations (11/15), two were conducted in populations of East Asian ancestry, one in a population of South Asian ancestry and one in a trans-ethnic GWAS of Europeans and East Asians. We collated full summary data from 13 of 15 publications, corresponding to six independent consortia or cohort studies: CHARGE 34,[43][44][45]48,49,51,52 , SCHS 35 , the Framingham study (FHS) 37 , the TwinsUK/KORA study 39 , the NHAPC/MESA-CHI study 36,48 and Kettunen et al 38 .…”

Section: Fatty Acid Datasetsmentioning

confidence: 99%

Design and quality control of large-scale two-sample Mendelian randomisation studies

Haycock¹,

Borges²,

Burrows³

et al. 2021

Preprint

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Background: Mendelian randomization studies are susceptible to meta-data errors (e.g. incorrect specification of the effect allele column) and other analytical issues that can introduce substantial bias into analyses. We developed a quality control pipeline for the Fatty Acids in Cancer Mendelian Randomization Collaboration (FAMRC) that can be used to identify and correct for such errors. Methods: We invited cancer GWAS to share summary association statistics with the FAMRC and subjected the collated data to a comprehensive QC pipeline. We identified meta data errors through comparison of study-specific statistics to external reference datasets (the NHGRI-EBI GWAS catalog and 1000 genome super populations) and other analytical issues through comparison of reported to expected genetic effect sizes. Comparisons were based on three sets of genetic variants: 1) GWAS hits for fatty acids, 2) GWAS hits for cancer and 3) a 1000 genomes reference set. Results: We collated summary data from six fatty acid and 49 cancer GWAS. Meta data errors and analytical issues with the potential to introduce substantial bias were identified in seven studies (13%). After resolving analytical issues and excluding unreliable data, we created a dataset of 219,842 genetic associations with 87 cancer types. Conclusion: In this large MR collaboration, 13% of included studies were affected by a substantial meta data error or other analytical issue. By increasing the integrity of collated summary data prior to their analysis, our protocol can be used to increase the reliability of post-GWAS analyses. Our pipeline is available to other researchers via the CheckSumStats package (https://github.com/MRCIEU/CheckSumStats).

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Genome-wide association meta-analysis of circulating odd-numbered chain saturated fatty acids: Results from the CHARGE Consortium

Cited by 15 publications

References 42 publications

LC-HRMS based approach to identify novel sphingolipid biomarkers in breast cancer patients

LC-HRMS based approach to identify novel sphingolipid biomarkers in breast cancer patients

Biomarkers of dairy fat intake, incident cardiovascular disease, and all-cause mortality: A cohort study, systematic review, and meta-analysis

Design and quality control of large-scale two-sample Mendelian randomisation studies

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