Blood Metabolite Signatures of Metabolic Syndrome in Two Cross-Cultural Older Adult Cohorts

Mahajan, Uma V; Varma, Vijay R.; Huang, Chiung Wei; An, Yang; Tanaka, Toshiko; Ferrucci, Luigi; Takebayashi, Toru; Harada, Sei; Iida, Miho; Legido‐Quigley, Cristina; Thambisetty, Madhav

doi:10.3390/ijms21041324

Cited by 16 publications

(14 citation statements)

References 57 publications

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“…Compared to the untargeted approach, targeted metabolomics allows the measurements of quantified or semi-quantified identified compounds that facilitates comparability with other studies. The metabolites measured in the current study represent key biochemical pathways and have been previously associated with a number of chronic and metabolic diseases, including cardiovascular disease [ 48 ], metabolic syndrome [ 49 ], obesity [ 50 , 51 ], diabetes [ 52 , 53 ] and cancer [ 45 , 54 , 55 ]. Therefore, using this approach, we can target pathways that are potentially dysregulated in obesity and/or diabetes, two established risk factors for endometrial cancer as well as in cancer development.…”

Section: Discussionmentioning

confidence: 99%

Prospective analysis of circulating metabolites and endometrial cancer risk

Dossus

Kouloura

Biessy

et al. 2021

Gynecologic Oncology

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Background. Endometrial cancer is strongly associated with obesity and dysregulation of metabolic factors such as estrogen and insulin signaling are causal risk factors for this malignancy. To identify additional novel metabolic pathways associated with endometrial cancer we performed metabolomic analyses on pre-diagnostic plasma samples from 853 case-control pairs from the European Prospective Investigation into Cancer and Nutrition (EPIC).Methods. A total of 129 metabolites (acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexoses, and sphingolipids) were measured by liquid chromatography-mass spectrometry. Conditional logistic regression estimated the associations of metabolites with endometrial cancer risk. An analysis focusing on clusters of metabolites using the bootstrap lasso method was also employed.Results. After adjustment for body mass index, sphingomyelin [SM] C18:0 was positively (OR 1SD : 1.18, 95% CI: 1.05-1.33), and glycine, serine, and free carnitine (C0) were inversely (OR 1SD : 0.89, 95% CI: 0.80-0.99; OR 1SD : 0.89, 95% CI: 0.79-1.00 and OR 1SD : 0.91, 95% CI: 0.81-1.00, respectively) associated with endometrial cancer risk. Serine, C0 and two sphingomyelins were selected by the lasso method in >90% of the bootstrap samples. The ratio of esterified to free carnitine (OR 1SD : 1.14, 95% CI: 1.02-1.28) and that of short chain to free acylcarnitines (OR 1SD : 1.12, 95% CI: 1.00-1.25) were positively associated with endometrial cancer risk. Further adjustment for C-peptide or other endometrial cancer risk factors only minimally altered the results.Conclusion. These findings suggest that variation in levels of glycine, serine, SM C18:0 and free carnitine may represent specific pathways linked to endometrial cancer development. If causal, these pathways may offer novel targets for endometrial cancer prevention.

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Section: Discussionmentioning

confidence: 99%

Prospective analysis of circulating metabolites and endometrial cancer risk

Dossus

Kouloura

Biessy

et al. 2021

Gynecologic Oncology

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“…For the WT-Met by ultra-high performance liquid chromatography triple quadrupole mass spectrometry (UHPLC–MS/MS) analyses, 2,187 and 2,310 cohort plasma samples (10 μl, each) were prepared using the AbsoluteIDQ ® p180 kit and MxP ® Quant 500 kit (Biocrates Life Sciences AG, Innsbruck, Austria), respectively ( 48 , 49 ). The optimal conditions of UHPLC–MS/MS for the LC mode and FIA mode and the ionization parameters, ion transfer voltages/temperatures, and the detection of m/z pairs of precursor and product ions in multiple reaction monitoring mode by MS were automatically set based on the instructions for each kit.…”

Section: Methodsmentioning

confidence: 99%

jMorp updates in 2020: large enhancement of multi-omics data resources on the general Japanese population

Tadaka

Hishinuma

Komaki

et al. 2020

Nucleic Acids Research

128

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In the Tohoku Medical Megabank project, genome and omics analyses of participants in two cohort studies were performed. A part of the data is available at the Japanese Multi Omics Reference Panel (jMorp; https://jmorp.megabank.tohoku.ac.jp) as a web-based database, as reported in our previous manuscript published in Nucleic Acid Research in 2018. At that time, jMorp mainly consisted of metabolome data; however, now genome, methylome, and transcriptome data have been integrated in addition to the enhancement of the number of samples for the metabolome data. For genomic data, jMorp provides a Japanese reference sequence obtained using de novo assembly of sequences from three Japanese individuals and allele frequencies obtained using whole-genome sequencing of 8,380 Japanese individuals. In addition, the omics data include methylome and transcriptome data from ∼300 samples and distribution of concentrations of more than 755 metabolites obtained using high-throughput nuclear magnetic resonance and high-sensitivity mass spectrometry. In summary, jMorp now provides four different kinds of omics data (genome, methylome, transcriptome, and metabolome), with a user-friendly web interface. This will be a useful scientific data resource on the general population for the discovery of disease biomarkers and personalized disease prevention and early diagnosis.

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“…Quantitative metabolomics assays were performed on brain tissue samples to measure concentrations of the primary BAs, including CA and CDCA, using the Biocrates Bile Acids kit (Biocrates Life Sciences AG, Austria). Details on both assay kits, as well as calibration steps, have been published previously [25]. Additional details regarding the use of internal standards are included in S1 Text.…”

Section: Quantitative Brain Metabolomics Assaysmentioning

confidence: 99%

Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study

Varma

Wang

et al. 2021

PLoS Med

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Background While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis. Methods and findings We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = <0.001–0.013) in males in BLSA. In ADNI, we found a modest sex-specific effect indicating that lower serum concentrations of CA and CDCA were associated with faster brain atrophy (FDR p = 0.049) in males. Step 2: In the Clinical Practice Research Datalink (CPRD) dataset, covering >4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72–1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose–response relationship between BAS use and risk of VaD (p-trend = 0.045) in males. Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings. Conclusions We combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.

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Blood Metabolite Signatures of Metabolic Syndrome in Two Cross-Cultural Older Adult Cohorts

Cited by 16 publications

References 57 publications

Prospective analysis of circulating metabolites and endometrial cancer risk

Prospective analysis of circulating metabolites and endometrial cancer risk

jMorp updates in 2020: large enhancement of multi-omics data resources on the general Japanese population

Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study

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