BEVITAL : Targeted profiling of biomarkers related to vitamin status, nutrition, lifestyle
and inflammation
Targeted metabolite profiling (targeted
metabolomics) vs. untargeted metabolomics
Definitions and illusions
• Definition of metabolomics
“To measure the metabolome, which represents the collection of all metabolites in a biological cell, tissue, organ or organism, which are the end products of cellular processes”.
• The Illusion
“An ambitious goal of some of this research is to monitor the level and modification of all proteins and metabolites in a biological sample
such as plasma. --- but the presently available tools are clearly not sufficient for these very difficult tasks” Marvin L. Vestal (J. Am. Soc.
Mass. Spectrom. ).
• Metabolic profiling
To quantify a defined set of metabolites and biomarkers within a biological system (system biology)
Mass spectrometry
Overall activities
• Measurement of direct and functional biomarkers in serum, plasma, CSF and urine
• The biomarkers are related to vitamin status, nutrition,
lifestyle and inflammation
Strategy and internationalization
• An informative web page
• A unique product (profile)
• A stable strategy for decades
• A competent and stable technical staff allocated to platforms
• Publication in high impact journals
• Participation in large multicenter studies
• Rapid adjustments and expansion of instrumental resources
Analytical strategy
• 1. Targeted metabolite profiling
• 2. Complementary biomarkers allocated to dedicated platforms (A – H)
• 3. Analytical methods based on mass spectrometry that are designed to answer specific research questions
• 4. Platform upgrading by ramification
• 5. Biomarker profiles that comprehensively cover defined pathways and metabolite networks
• 6. Analyses of biomarkers of common confounders in epidemiological research
• 7. Unique biomarkers and concepts
Analytical strategy
• 8. Metabolic profiling tailored to large epidemiological studies - Low volume requirement (< 100 µL)
- Multiplexing.
- High sample throughput and analytical capacity.
- Optimized exploitation of the biobank resources (optimizing logistics, no/few thawing-freezing cycles, metabolite ratios across platforms etc)
What is a biomarker?
• Biomarker:
A characteristic that is objectively measured and
evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention.
• Risk factor:
A risk factor is associated with a disease because it is in the causal pathway leading to the disease.
• Risk marker:
A risk marker is associated with the disease (statistically)
but need not be causally linked; it may be a measure of
the disease process itself.
Within-subject reproducibility-
Intraclass correlation coefficient (ICC)
• 0-0.2, poor agreement
• 0.3-0.4, fair agreement
• 0.5-0.6, moderate agreement
• 0.7-0.8, strong agreement
• >0.8, almost perfect agreement
*Variances by a random effects model, with participant ID as the random variable
Pathways and metabolite networks
Pathways and metabolite networks
Common confounders
• Smoking
- Cotinine (D)
- Trans-3'-hydroxycotinine (D)
• Renal function - Creatinine (C)
- Cystatin C and variants (G) - SDMA (C)
• Inflammation - mCRP (G)
- Calprotectin and isoforms (G)
- Serym amyloid A and isoforms (G) - Neopterin (D)
- KTR (kynurenine/tryptophan ratio) (D) - PAr index (D)
• Coffee consumption - Trigonelline (D)
• Meat consumption
- 3-Methylhistidine (C) - 1-Methylhistidine (C)
• Long-term glycaemic control - HbA1c (G)
The kynurenine pathway:
A unique target for
studying multimorbility
Tryptophan (Trp)
Kynurenine (Kyn)
Kynurenic acid (KA) Anthranilic acid (AA)
3-Hydroxykynurenine (HK)
3-Hydroxyanthranilic acid (HAA) Xanthurenic acid (XA) KAT
KYNUB6 KAT B6
B6
KMOB2
Quinolinic acid (QA)
AMO
NAM QPRT
NAD
KYNUB6 IDO TDO
2-Amino-3-carboxymuconate semialdehyde Picolinic acid
HDO
ACSD
ACMS
The kynurenine pathway:
A unique target for
studying multimorbility
Tryptophan (Trp)
Kynurenine (Kyn)
Kynurenic acid (KA) Anthranilic acid (AA)
3-Hydroxykynurenine (HK)
3-Hydroxyanthranilic acid (HAA) Xanthurenic acid (XA) KAT
KYNUB6 KAT B6
B6
KMOB2
Quinolinic acid (QA)
AMO
NAM QPRT
NAD
KYNUB6 IDO TDO
2-Amino-3-carboxymuconate semialdehyde Picolinic acid
HDO
ACSD
INFs, TNFa, IL-1b, IL-6 Corticosteroids
Inflammatory modulation Neuroactive
Endothelial or cardiovascular ef fect Redox properties or modulation Metal modulation
ACMS
