Dihydroxy Docosatrienoic Acid
Introduction
Section titled “Introduction”Dihydroxy docosatrienoic acid is a small molecule metabolite that has been identified as part of a metabolomic profile associated with heart failure (HF). Metabolomics, the comprehensive study of these small molecules within a biological system, provides insights into the end products of gene function and environmental exposures.[1]Research into such metabolites aims to enhance the understanding of complex diseases like heart failure.
Biological Basis
Section titled “Biological Basis”Metabolites serve as downstream indicators of cellular processes, influenced by both genetic makeup and environmental factors.[1]Identifying the genetic variants that influence metabolite levels can help elucidate their biological roles. In a genome-wide association study (GWAS) conducted among African Americans, the single nucleotide polymorphism (SNP)rs4006531 on chromosome 8q24 was found to have the smallest p-value (6.98 × 10−7) for association with dihydroxy docosatrienoic acid levels. This SNP is located approximately 90.48 kilobases from a hypothetical gene,LOC10013023.[1] Although rs4006531 did not individually meet the strict genome-wide significance threshold (p-value < 5×10−8), the study highlighted its association with this metabolite.[1]
Clinical Relevance
Section titled “Clinical Relevance”Dihydroxy docosatrienoic acid has been linked to incident heart failure.[1]Studies have explored its role as a potential risk factor for the development of HF. In a genetic risk score (GRS) model, combining the most significant risk alleles for dihydroxy docosatrienoic acid along with other HF-related metabolites (pyroglutamine and X-11787), an 11% greater risk of HF per allele was observed.[1]This suggests that dihydroxy docosatrienoic acid, and the genetic factors influencing its levels, may mediate the risk of heart failure.[1]Understanding these metabolic pathways and their genetic underpinnings can provide crucial insights into the pathogenesis and progression of heart failure.
Social Importance
Section titled “Social Importance”Heart failure represents a significant public health challenge, being a leading cause of hospitalization, particularly among the elderly and with increasing prevalence in African American populations.[1] By combining metabolomics with GWAS, researchers aim to gain a deeper understanding of how genetic variations interact with environmental factors in the development of HF.[1]The identification of metabolites like dihydroxy docosatrienoic acid and their associated genetic loci contributes to the broader knowledge base of human metabolic profiles and HF physiology. This knowledge is vital for developing targeted prevention strategies, improved diagnostic tools, and more effective treatments for heart failure, especially for at-risk populations.[1]
Generalizability and Replication Challenges
Section titled “Generalizability and Replication Challenges”The findings concerning dihydroxy docosatrienoic acid are derived from a specific cohort of 1,260 African Americans participating in the Atherosclerosis Risk in Communities (ARIC) study.[1]A significant limitation is the current absence of appropriate, independent African-American sample sets equipped with comprehensive metabolomic profiles and a sufficient number of incident heart failure events to facilitate direct replication of these genetic associations.[1]This makes it challenging to confirm the robustness and reproducibility of the identified genetic variants, which could limit the confidence in these initial associations for dihydroxy docosatrienoic acid.
Furthermore, the generalizability of these results beyond the studied African-American population has not been established.[1]While this research provides valuable insights into metabolomic profiles within African Americans, the distinct genetic architecture and environmental exposures characteristic of this specific ancestry group suggest that the identified associations for dihydroxy docosatrienoic acid may not directly translate to other ethnic or racial populations.[1]This specificity restricts the broader applicability of the findings and highlights the ongoing need for more diverse studies to fully understand the spectrum of genetic influences on dihydroxy docosatrienoic acid levels across various human populations.
Methodological and Phenotypic Considerations
Section titled “Methodological and Phenotypic Considerations”The metabolomic profiling for dihydroxy docosatrienoic acid was conducted on fasting serum samples that had been stored at -80°C for an extended period, approximately 23 years, prior to analysis.[1]Although deep freezing is a standard preservation method, such prolonged storage durations could potentially impact the stability or integrity of certain metabolites, including dihydroxy docosatrienoic acid, which might introduce variability or bias into the measurements. The untargeted metabolomics approach, while comprehensive, may also present limitations in the precise quantification of all detected compounds, potentially affecting the accuracy of dihydroxy docosatrienoic acid level assessments.
A methodological concern also arises from the imputation strategy for missing metabolite values, where these were assigned the lowest observed value for that particular metabolite.[1]If very low or undetectable levels of dihydroxy docosatrienoic acid are genuinely reflective of underlying genetic variation or specific physiological states, this imputation method could potentially obscure or distort true genetic effects, thereby influencing the statistical power and interpretation of the association analyses.[1]Moreover, the most significant SNP associated with dihydroxy docosatrienoic acid,rs4006531 , did not individually achieve genome-wide significance (p-value = 6.98×10−7), indicating that its individual effect size might be modest or that larger cohorts are required to detect such associations with greater statistical confidence.[1]
Complex Etiology and Remaining Knowledge Gaps
Section titled “Complex Etiology and Remaining Knowledge Gaps”The study acknowledges that metabolite levels, including dihydroxy docosatrienoic acid, are complex downstream products resulting from intricate interactions between genetic predispositions and environmental exposures.[1]While genetic variants influencing dihydroxy docosatrienoic acid were identified, the research did not fully account for specific environmental confounders or gene-environment interactions that could significantly modulate its levels and subsequent association with heart failure.[1]This omission represents a critical knowledge gap, as the multifactorial nature of complex traits like heart failure necessitates a more comprehensive understanding of these intricate interplays to fully elucidate the underlying biological pathways.[1]Furthermore, the precise biological function and identity of dihydroxy docosatrienoic acid are not fully established, with its most strongly associated sentinel SNP,rs4006531 , located near a “hypothetical gene” LOC10013023, which indicates a gap in understanding its direct genetic regulation and physiological role.[1]Although a genetic risk score, which incorporated the top SNPs for several metabolites (including dihydroxy docosatrienoic acid), demonstrated an association with heart failure, individual SNPs for dihydroxy docosatrienoic acid were not independently associated with incident heart failure.[1]This suggests that the impact of individual genetic variants on heart failure risk may be indirect, potentially mediated through metabolite levels, and underscores the complexity in attributing direct causation from single genetic loci.
Variants
Section titled “Variants”The genetic variant *rs4006531 *is significantly associated with the levels of dihydroxy docosatrienoic acid, a metabolite identified as a potential risk factor for incident heart failure.[1]This single nucleotide polymorphism (SNP), located on chromosome 8q24, was a notable finding in a genome-wide association study (GWAS) conducted among 1,260 African-Americans.[1]The variant exhibited a minor allele frequency (MAF) of 0.400 and a p-value of 6.98 × 10−7, marking it as the most significant SNP for dihydroxy docosatrienoic acid in that particular analysis.[1] Its genomic position suggests a potential regulatory influence on nearby elements, including the long intergenic non-coding RNA LINC02964.
LINC02964, as a long intergenic non-coding RNA, does not encode proteins but plays vital roles in regulating gene expression, affecting processes such as transcription, mRNA stability, and chromatin remodeling. A variant like *rs4006531 *, situated in an intergenic region, could influence the expression or stability of LINC02964, thereby indirectly impacting genes involved in lipid metabolism. Such regulatory changes could modulate the cellular machinery responsible for the synthesis or breakdown of specific fatty acids, including dihydroxy docosatrienoic acid. The study aimed to identify novel genetic variants associated with metabolites that had been previously linked to heart failure incidence.[1]These genetic insights contribute to understanding the underlying mechanisms of metabolic traits and their connection to cardiovascular health.[1]Dihydroxy docosatrienoic acid is a complex lipid metabolite, typically derived from polyunsaturated fatty acids, which often function as signaling molecules in biological systems. These derivatives are implicated in various physiological processes, including inflammation, lipid metabolism, and the maintenance of cardiovascular health. Genetic factors, such as the variation at*rs4006531 *, that influence the circulating levels of dihydroxy docosatrienoic acid could therefore have broad systemic implications. The broader research context emphasizes the importance of these metabolites as potential biomarkers and risk factors for diseases like heart failure, especially within the African-American population studied.[1] Identifying genetic factors that influence the levels of these novel metabolites may provide insights into their possible identity and function.[1] The study utilized an untargeted metabolomics approach to profile 602 metabolites in fasting serum samples.[1]
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs4006531 | LINC02964 | dihydroxy docosatrienoic acid |
| rs13395546 | CYCSP8 - ARHGEF4-AS1 | dihydroxy docosatrienoic acid |
| rs9406636 | LINC03041 | dihydroxy docosatrienoic acid |
| rs17691453 | LINC02915 | dihydroxy docosatrienoic acid |
| rs17520351 | SLC44A3 | dihydroxy docosatrienoic acid |
| rs11957368 | MARK2P11 - LINC02227 | dihydroxy docosatrienoic acid |
| rs1826508 | COX6CP3 - LINC00470 | dihydroxy docosatrienoic acid memory performance, sex interaction |
| rs685782 | NUP98 | dihydroxy docosatrienoic acid |
| rs12360000 | ADARB2 - LINC00700 | dihydroxy docosatrienoic acid |
| rs12987661 | AAK1 | dihydroxy docosatrienoic acid gout urate hematocrit erythrocyte count |
Definition and Biological Context
Section titled “Definition and Biological Context”Dihydroxy docosatrienoic acid is precisely defined as a specific small molecule metabolite, representing an end-product of various chemical processes within a biological system.[1]As a metabolite, it serves as a downstream indicator of both genetic function and environmental exposures, offering critical insights into the complex interplay governing physiological states and disease progression.[1]Its identification as part of a metabolomic profile associated with heart failure (HF) incidence underscores its potential role in cardiovascular health.[1]Understanding the genetic determinants that influence the levels of dihydroxy docosatrienoic acid is instrumental for elucidating its exact identity and functional contributions to disease etiology.[1]
Clinical Significance and Classification
Section titled “Clinical Significance and Classification”Dihydroxy docosatrienoic acid is classified among a panel of metabolites that have been identified as risk factors for incident heart failure, particularly within African-American populations.[1]Although individual genetic associations, such as with the single nucleotide polymorphismrs4006531 , did not reach genome-wide significance thresholds for its levels, this metabolite contributes to a broader genetic risk score (GRS).[1]This cumulative GRS was found to be statistically significant in predicting incident HF, suggesting that dihydroxy docosatrienoic acid levels likely mediate genetic effects on heart failure risk.[1]Its inclusion in such a risk assessment highlights its clinical relevance in understanding the complex, multifactorial pathogenesis of heart failure.
Analytical Approaches and Operational Definitions
Section titled “Analytical Approaches and Operational Definitions”The operational definition of dihydroxy docosatrienoic acid levels in research studies is established through rigorous analytical methodologies. Its concentration is quantified from fasting serum samples, which are collected and meticulously stored at -80°C to ensure metabolite stability and integrity.[1] The primary approach involves an untargeted, combined gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS)-based protocol, which allows for comprehensive detection and precise quantification.[1]For statistical analyses, dihydroxy docosatrienoic acid is treated as a continuous variable, with all measured values undergoing natural log-transformation to achieve a normalized distribution; furthermore, any values falling below the assay’s detection limit are consistently assigned the lowest detected value observed across all samples.[1]
Metabolite Identity and Role in Cardiovascular Health
Section titled “Metabolite Identity and Role in Cardiovascular Health”Dihydroxy docosatrienoic acid is a small molecule metabolite identified through untargeted metabolomics profiling, which systematically studies the complete set of small-molecule chemicals found within a biological sample.[1] Metabolites represent the ultimate downstream products of various cellular chemical processes, reflecting the intricate interplay between an individual’s genetic makeup and environmental exposures.[1]In the context of cardiovascular health, understanding the levels and functions of specific metabolites like dihydroxy docosatrienoic acid can provide crucial insights into disease mechanisms and pathways, particularly for complex conditions such as heart failure.[1]Its serves as a window into the metabolic state of an individual, potentially highlighting dysregulations pertinent to disease onset or progression.
Genetic Regulation of Dihydroxy Docosatrienoic Acid Levels
Section titled “Genetic Regulation of Dihydroxy Docosatrienoic Acid Levels”Genetic variations play a significant role in influencing the circulating levels of various metabolites, including dihydroxy docosatrienoic acid.[1]A genome-wide association study identified a notable association between the single nucleotide polymorphism (SNP)rs4006531 on chromosome 8q24 and dihydroxy docosatrienoic acid levels.[1] This particular genetic variant is located approximately 90.48 kilobases from a hypothetical gene, LOC10013023, suggesting a potential regulatory influence on its expression or function, which in turn could impact the metabolic pathways involving dihydroxy docosatrienoic acid.[1] While rs4006531 did not individually reach genome-wide significance for dihydroxy docosatrienoic acid levels, its association underscores the complex genetic architecture underlying metabolite concentrations.
Molecular Pathways and Heart Failure Association
Section titled “Molecular Pathways and Heart Failure Association”The association of dihydroxy docosatrienoic acid with heart failure (HF) suggests its involvement in molecular and cellular pathways critical to cardiac function and disease pathogenesis.[1] Metabolites are direct downstream products of gene function, and their dysregulation can reflect underlying cellular stress, metabolic imbalances, or altered signaling pathways that contribute to HF.[1]The observation that a genetic risk score (GRS), which includes the genetic variant associated with dihydroxy docosatrienoic acid, mediates its effect on HF incidence through the metabolite levels, highlights a plausible mechanism where genetic predispositions manifest metabolically before clinical disease presentation.[1]This suggests dihydroxy docosatrienoic acid could be an integral component of a metabolic pathway contributing to heart failure.
Systemic Relevance and Clinical Implications
Section titled “Systemic Relevance and Clinical Implications”At a systemic level, the observed association between dihydroxy docosatrienoic acid and incident heart failure underscores its potential as a biomarker for cardiovascular risk.[1]The collective impact of genetic variants, as demonstrated by the genetic risk score, indicates that even associations not reaching individual genome-wide significance can contribute cumulatively to disease susceptibility.[1]Identifying such metabolites and their genetic determinants provides a more comprehensive understanding of the multifactorial nature of heart failure, potentially informing strategies for early detection, risk stratification, and targeted interventions.[1]Further research into the specific metabolic roles of dihydroxy docosatrienoic acid at the tissue and organ level, particularly within the heart and related systems, could elucidate its precise involvement in maintaining cardiac homeostasis or contributing to its disruption.
Genetic Modulators of Dihydroxy Docosatrienoic Acid Levels
Section titled “Genetic Modulators of Dihydroxy Docosatrienoic Acid Levels”The levels of dihydroxy docosatrienoic acid are influenced by genetic factors, as evidenced by genome-wide association studies. A significant genetic locus on chromosome 8q24, marked by the single nucleotide polymorphism (SNP)rs4006531 , has been identified to associate with variations in this metabolite’s abundance.[1] This SNP, possessing a minor allele frequency (MAF) of 0.400, is located approximately 90.48 kilobases from a hypothetical gene, LOC10013023.[1] While the precise regulatory mechanisms linking rs4006531 to dihydroxy docosatrienoic acid levels are not fully elucidated, such genetic associations suggest that variants in this genomic region, potentially impactingLOC10013023 or other regulatory elements, can modulate the production, degradation, or transport of this specific metabolite, thereby affecting its circulating concentrations.[1]
Metabolic Classification and Regulation
Section titled “Metabolic Classification and Regulation”Dihydroxy docosatrienoic acid is categorized as a small molecule metabolite within the broader metabolome, representing one of the many end products of various chemical processes occurring within biological systems.[1] Metabolites serve as crucial indicators of physiological state, as their levels reflect the intricate interplay between gene function and environmental exposures.[1]Although the specific metabolic pathways governing the biosynthesis or catabolism of dihydroxy docosatrienoic acid are not detailed in the available research, its identification as a metabolite implies its involvement in biochemical reactions and its levels are subject to endogenous metabolic regulation.[1] Understanding the enzymes and transporters involved in its flux control would provide deeper insights into its precise metabolic role.
Systems-Level Integration in Disease Etiology
Section titled “Systems-Level Integration in Disease Etiology”The presence and concentration of dihydroxy docosatrienoic acid are not isolated biochemical phenomena but integrate into complex physiological networks, particularly in the context of cardiovascular health. Research indicates that dihydroxy docosatrienoic acid is a risk factor for incident heart failure (HF).[1]This suggests a systems-level interaction where alterations in its levels contribute to disease susceptibility or progression. Furthermore, genetic variants influencing dihydroxy docosatrienoic acid, when combined into a genetic risk score (GRS) with other HF-related metabolites, demonstrate a cumulative effect, mediating an increased risk of heart failure.[1]This highlights a mechanism where genetic predispositions translate into altered metabolite profiles, which in turn influence complex disease outcomes, showcasing pathway crosstalk between genetic regulatory networks and metabolic pathways impacting disease risk.
Disease-Relevant Mechanisms and Clinical Significance
Section titled “Disease-Relevant Mechanisms and Clinical Significance”The association of dihydroxy docosatrienoic acid with incident heart failure underscores its potential role in disease-relevant mechanisms. While individual genetic variants associated with its levels may not independently lead to heart failure, the metabolite itself acts as a mediator of genetic effects on disease risk.[1]This implies that dysregulation in the pathways leading to the production or clearance of dihydroxy docosatrienoic acid could contribute to the pathogenesis of heart failure. Monitoring dihydroxy docosatrienoic acid levels could therefore serve as a biomarker for assessing cardiovascular risk or for understanding underlying disease processes, potentially informing future therapeutic strategies aimed at modulating its concentrations or downstream effects to impact heart failure incidence.[1]
Heart Failure Risk and Prognostic Implications
Section titled “Heart Failure Risk and Prognostic Implications”Dihydroxy docosatrienoic acid has been identified as a metabolite associated with the risk of incident heart failure (HF), particularly within African American populations. While individual genetic variants influencing its levels, such asrs4006531 , may not independently predict HF, their collective impact, integrated into a genetic risk score (GRS) alongside other HF-related metabolites, demonstrates significant prognostic value. This GRS was associated with an 11% greater risk of HF per allele after adjusting for traditional risk factors, indicating its potential to predict long-term HF development over follow-up periods extending up to 22 years. The research suggests that dihydroxy docosatrienoic acid, along with related metabolites, likely mediates these genetic effects on HF risk, offering a deeper understanding of HF pathogenesis.[1]
Genetic Predisposition and Risk Stratification
Section titled “Genetic Predisposition and Risk Stratification”of dihydroxy docosatrienoic acid, in conjunction with an individual’s genetic profile, presents a pathway toward enhanced risk stratification and personalized medicine in heart failure prevention. Levels of this metabolite are influenced by genetic factors, withrs4006531 on chromosome 8q24 showing a suggestive, though not genome-wide significant, association. The integration of such genetic markers into a multi-metabolite GRS underscores a complex polygenic contribution to HF risk, enabling the identification of high-risk individuals based on their inherent predisposition to altered metabolic profiles. This advanced risk stratification could theoretically guide targeted prevention strategies or more intensive monitoring, although the generalizability of these findings beyond the studied African American cohort requires further validation.[1]
Potential for Diagnostic and Monitoring Strategies
Section titled “Potential for Diagnostic and Monitoring Strategies”The role of dihydroxy docosatrienoic acid as a mediator in the genetic pathways contributing to heart failure suggests its future utility in diagnostic and monitoring strategies. Alterations in its circulating levels, influenced by specific genetic predispositions, could potentially serve as early biomarkers for subclinical disease processes or indicators of HF progression, even before overt clinical symptoms appear. While current studies highlight a strong genetic link to HF risk mediated by this metabolite, direct clinical applications, such as guiding treatment selection or establishing routine monitoring protocols, necessitate further robust validation in independent cohorts and a more comprehensive understanding of its underlying biological mechanisms.[1]
Frequently Asked Questions About Dihydroxy Docosatrienoic Acid
Section titled “Frequently Asked Questions About Dihydroxy Docosatrienoic Acid”These questions address the most important and specific aspects of dihydroxy docosatrienoic acid based on current genetic research.
1. If my doctor finds this acid, what does it mean for my heart?
Section titled “1. If my doctor finds this acid, what does it mean for my heart?”Finding dihydroxy docosatrienoic acid in your blood indicates you have a metabolite that’s been linked to an increased risk of heart failure. While it’s one piece of the puzzle, higher levels suggest your body’s metabolic profile might contribute to heart health concerns. Understanding this can help your doctor assess your overall risk.
2. Does my African American heritage change my heart failure risk?
Section titled “2. Does my African American heritage change my heart failure risk?”Yes, research on this specific metabolite, dihydroxy docosatrienoic acid, has primarily been conducted in African American populations. Studies suggest that certain genetic variations, like thers4006531 SNP, might influence your levels of this acid and, consequently, your heart failure risk within this ancestry group. It highlights the importance of tailored health approaches.
3. Can healthy habits really overcome my family’s heart problems?
Section titled “3. Can healthy habits really overcome my family’s heart problems?”While your genetics, including variants near genes like LOC10013023that influence dihydroxy docosatrienoic acid levels, certainly play a role in heart failure risk, lifestyle is also crucial. Heart failure is complex, involving both genetic predispositions and environmental factors. Healthy habits like diet and exercise can significantly mitigate genetic risks, even if you have a family history.
4. Why might my sibling have a healthy heart while I struggle?
Section titled “4. Why might my sibling have a healthy heart while I struggle?”Even within families, genetic variations can differ. You and your sibling might have different versions of genes, like the rs4006531 SNP, that influence your individual levels of dihydroxy docosatrienoic acid and other metabolites linked to heart health. Combined with unique environmental exposures and lifestyle choices, this can lead to different health outcomes, even for siblings.
5. Is it worth getting a genetic test for my heart failure risk?
Section titled “5. Is it worth getting a genetic test for my heart failure risk?”Genetic tests can provide insights into your predispositions, such as how variants near LOC10013023might affect your dihydroxy docosatrienoic acid levels. While individual genetic markers for this specific metabolite don’t independently predict heart failure, a combined genetic risk score including several markers has shown an association. This information can help you and your doctor understand your personalized risk profile.
6. Does what I eat affect my levels of this heart-related acid?
Section titled “6. Does what I eat affect my levels of this heart-related acid?”Metabolite levels, including dihydroxy docosatrienoic acid, are known to be influenced by both your genetic makeup and environmental factors, which definitely include your diet. While the specific dietary impacts on this particular acid aren’t fully detailed, a healthy diet is generally vital for maintaining overall metabolic health and reducing heart failure risk.
7. Why do some people develop heart failure and others don’t?
Section titled “7. Why do some people develop heart failure and others don’t?”Heart failure is a complex condition resulting from many factors. It’s a mix of your unique genetic blueprint, like variations affecting metabolites such as dihydroxy docosatrienoic acid, and your lifetime environmental exposures, diet, and lifestyle choices. This intricate interplay explains why outcomes vary greatly among individuals.
8. Do these acid levels in my blood change much over my lifetime?
Section titled “8. Do these acid levels in my blood change much over my lifetime?”Your metabolite levels, including dihydroxy docosatrienoic acid, are influenced by many factors that change over time, like your age, health status, and environment. While samples can be stable under deep-freeze conditions for years, in your body, these levels are dynamic and can fluctuate, reflecting ongoing cellular processes and exposures throughout your lifetime.
9. Can stress or sleep make my heart failure risk worse?
Section titled “9. Can stress or sleep make my heart failure risk worse?”While the specific impact of stress or sleep on dihydroxy docosatrienoic acid levels isn’t fully detailed, metabolite levels are broadly influenced by environmental factors. We know stress and poor sleep are significant environmental stressors that affect overall health and can contribute to cardiovascular disease risk, including heart failure, through various biological pathways.
10. If I have high levels, what can I actually do?
Section titled “10. If I have high levels, what can I actually do?”If you have higher levels of dihydroxy docosatrienoic acid, understanding this contributes to your overall risk assessment for heart failure. While specific interventions targeting this metabolite aren’t detailed, focusing on established heart-healthy strategies is key. This includes maintaining a balanced diet, regular exercise, managing stress, and working with your doctor to control other risk factors like blood pressure or cholesterol.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] Yu, B. et al. “Genome-wide association study of a heart failure related metabolomic profile among African Americans in the Atherosclerosis Risk in Communities (ARIC) study.”Genet Epidemiol, 2013.