Srage

Introduction

Soluble Receptor for Advanced Glycation End-products (sRAGE) is a circulating protein that plays a significant role in modulating biological responses to Advanced Glycation End-products (AGEs) and other inflammatory ligands. AGEs are harmful compounds that accumulate in the body and are implicated in the pathogenesis of various chronic diseases. The primary receptor for AGEs on cell surfaces is the Receptor for Advanced Glycation End-products (RAGE), encoded by the AGERgene. sRAGE acts as a “decoy receptor,” binding to AGEs in the bloodstream and preventing them from activating cell-surfaceRAGE, thereby potentially mitigating inflammation and oxidative stress.^[1]of sRAGE levels in plasma, typically performed using ELISA, has emerged as a topic of considerable interest in medical research. These levels have been observed to remain relatively stable within individuals over several years.^[1]Genetic factors are known to be strong determinants of an individual’s sRAGE levels. Genome-wide association studies (GWAS) have identified specific single nucleotide polymorphisms (SNPs) within or near theAGER gene, such as the missense variant rs2070600 , that significantly influence plasma sRAGE concentrations.^[1] Another intronic SNP, rs2071288 , has also been identified as a determinant of sRAGE, particularly in certain populations.^[1]These genetic variants can explain a substantial proportion of the variation in sRAGE levels among individuals.^[1]The clinical relevance of sRAGE lies in its potential as a biomarker for various health conditions, particularly those associated with inflammation, oxidative stress, and AGE accumulation. Researchers have investigated associations between sRAGE levels and clinical outcomes such as coronary heart disease (CHD), heart failure, diabetes mellitus, chronic kidney disease (CKD), and overall mortality.^[1]While sRAGE levels are often correlated with these conditions, genetic studies using sRAGE-associated SNPs have indicated that these strong genetic determinants of sRAGE do not consistently show robust associations with these major clinical outcomes, suggesting a complex interplay that may not be fully captured by current sRAGE measurements alone or that the relationship is not directly causal.^[1]Furthermore, significant racial differences in median plasma sRAGE levels have been observed, with lower levels reported in Black individuals compared to White individuals.^[1]Understanding the genetic architecture and biological function of sRAGE holds significant social importance. It contributes to a deeper comprehension of chronic disease mechanisms and may help in identifying individuals at higher genetic risk for altered sRAGE levels. This knowledge could inform future diagnostic strategies, personalized risk assessments, and the development of novel therapeutic interventions targeting theRAGE-AGE axis. The ongoing research into sRAGE and its genetic underpinnings continues to shed light on its complex role in human health and disease.

Methodological and Statistical Considerations

The genetic evaluation of sRAGE levels was conducted on cohorts with varying sample sizes, notably 581 black and 1,737 white participants for the genome-wide association study (GWAS).^[1]These numbers, particularly for the black cohort, limited the statistical power to detect associations with several clinical outcomes. For instance, the power to identify associations with chronic kidney disease (CKD) was less than 20% in whites, and for coronary heart disease (CHD) in blacks, it was only 52%.^[1]Consequently, the research acknowledges that it cannot definitively exclude the possibility of modest yet clinically significant effects of sRAGE genetic determinants on outcomes such as CKD and CHD, suggesting that a lack of observed significance might be due to insufficient power rather than a true absence of a relationship.^[1]Furthermore, the Mendelian randomization approach, employed to assess the causal role of sRAGE, relies on the fundamental assumption that the genetic variant, such asrs2070600 , influences outcomes exclusively through its effect on sRAGE levels.^[1] While the close proximity of rs2070600 to the AGERgene, which encodes sRAGE, lends confidence to this assumption, its absolute proof remains challenging.^[1]The studies also suggest that Mendelian randomization might be more effective at ruling out causality rather than establishing it, which influences the interpretation of non-significant findings regarding sRAGE’s causal role in the studied clinical outcomes.^[1]

Phenotypic Complexity and Limitations

The generalizability of the findings is primarily constrained by the study population, which consisted of self-identified white and black participants within a community-based cohort.^[1] While this allowed for the identification of ancestry-specific genetic determinants, such as rs2070600 in whites and rs2071288 in blacks, it limits the direct applicability of these results to other diverse ancestral groups.^[1]Moreover, the lack of a clear genetic explanation for the observed differences in sRAGE levels between black and white participants, combined with the absence of an association between principal components and sRAGE in blacks, suggests that other, non-genetic factors may significantly contribute to these racial disparities.^[1]The of sRAGE itself presents a limitation, as the current ELISA-based assays may not fully capture the complex biological interactions of theRAGE-ligand axis.^[1] The RAGEreceptor is known for its multi-ligand nature and the existence of multiple isoforms, including sRAGE, whose specific roles and concentrations can vary significantly in different physiological and pathological contexts.^[1]Therefore, the measured sRAGE levels, especially when presented in arbitrary units.^[2] might not fully reflect the dynamic and intricate RAGE-ligand system, potentially obscuring its true causal involvement in disease processes.^[1]Additionally, for some participants, sRAGE levels were predicted from earlier measurements, which could introduce estimation errors and impact the precision of the genetic associations.^[1]

Unaccounted Genetic and Environmental Influences

A notable limitation is the study’s focus on common genetic variants, with an initial exclusion of single-nucleotide polymorphisms (SNPs) having a minor allele frequency (MAF) below 5%, and subsequent analyses extending to MAF above 1%.^[1]This strategy inherently overlooks the potential contribution of rare genetic variants, which, despite their low individual frequencies, could collectively account for a portion of the unexplained variability in sRAGE levels and clinical outcomes, contributing to the ‘missing heritability’.^[1]The research also did not explore gene-environment or gene-gene interactions, which are crucial for a comprehensive understanding of sRAGE variability and its impact on health outcomes.^[1]The studies acknowledge that environmental factors likely play a significant role in influencing sRAGE levels and racial disparities in cardiovascular disease, especially given the lack of a clear genetic explanation for black-white differences in sRAGE.^[1]Proximal environmental factors such as lower socioeconomic status, stress, and racial discrimination are suggested to underlie increased inflammation observed in some populations, which can impact theRAGE-ligand axis.^[1]Although adjustments were made for several covariates like age, gender, and diabetes status, the potential for residual confounding from unmeasured or incompletely characterized environmental and lifestyle factors remains, highlighting a gap in fully understanding the complex interplay between genetics, environment, and sRAGE levels.^[1]

Variants

Genetic variations play a significant role in determining circulating levels of soluble Receptor for Advanced Glycation End-products (sRAGE), a key biomarker in inflammatory and metabolic processes. TheAGERgene, which encodes the Receptor for Advanced Glycation End-products (RAGE), is central to these associations, as sRAGE is a truncated, soluble form of this receptor that acts as a decoy to bind advanced glycation end-products (AGEs), thus mitigating inflammatory responses. Among its variants,rs2070600 is a missense mutation (Glycine to Serine) inAGERthat is strongly associated with reduced sRAGE levels.^[1] Specifically, the minor T allele of rs2070600 is linked to approximately 50% lower sRAGE in white populations and 47% lower in black populations, explaining a substantial portion of sRAGE variation in these groups.^[1]This variant exhibits a high CADD score, indicating a strong predicted impact on protein function, which aligns with its observed effect on sRAGE levels.^[2] Another crucial variant within the AGER gene is rs2071288 , an intronic single nucleotide polymorphism that significantly influences sRAGE levels, particularly in black individuals.^[1] The T allele of rs2071288 is associated with a 43% reduction in sRAGE and accounts for 26% of the variability in sRAGE levels within this population.^[1]This variant is notably less frequent in white populations, where it does not show a significant association with sRAGE levels.^[1]Despite their profound effects on sRAGE concentrations, bothrs2070600 and rs2071288 have not been consistently linked to major clinical outcomes such as incident coronary heart disease, heart failure, or diabetes in long-term studies, though a marginal association between the sRAGE-lowering T allele ofrs2071288 and increased CHD risk was observed in black individuals.^[1] The rs204993 variant, located in the PBX2gene, also demonstrates relevance to sRAGE biology. ThePBX2 gene encodes a pre-B-cell leukemia transcription factor, which plays a role in regulating gene expression vital for developmental processes and cellular differentiation.^[1] While rs204993 shows a weak linkage disequilibrium with the AGER variant rs2070600 , suggesting some independent or distantly related genetic influence, studies have not identified a significant genetic interaction between these two single nucleotide polymorphisms regarding their effects on circulating sRAGE levels.^[2]This indicates that their contributions to sRAGE regulation are largely additive rather than synergistic.^[2] Beyond the directly implicated AGER and PBX2variants, other genes and their polymorphisms may indirectly modulate sRAGE levels and related inflammatory pathways. TheRNF5 gene, for example, encodes an E3 ubiquitin ligase, an enzyme critical for targeted protein degradation and the regulation of immune and inflammatory signaling.^[1] Although the specific functional impact of the rs41268928 variant in RNF5on sRAGE is not fully characterized, variations in ubiquitin ligases can alter protein stability and cellular signaling, thereby influencing overall inflammatory status and potentially sRAGE.^[1] Similarly, the B4GALNT3gene is involved in synthesizing complex carbohydrate structures on cell surfaces that are crucial for cell recognition and immune responses; thers7306778 variant could alter these structures, impacting cellular interactions and inflammatory pathways.^[1] Furthermore, the rs116653040 variant, found in the genomic region containing POLR2LP1 and CCHCR1, is situated in an area known for its involvement in immune regulation, with CCHCR1 being linked to autoimmune conditions.^[1]Variations in this complex region can influence gene expression and immune responses, potentially having an indirect effect on systemic inflammation and sRAGE levels.^[1]

Key Variants

RS ID	Gene	Related Traits
rs41268928	RNF5	srage Behcet’s syndrome mean arterial pressure
rs2070600 rs2071288	AGER	gas trapping emphysema imaging FEV/FVC ratio, pulmonary function FEV/FVC ratio, pulmonary function , smoking behavior trait FEV/FVC ratio
rs204993	PBX2	asthma advanced glycosylation end product-specific receptor amount atrophic macular degeneration, age-related macular degeneration, wet macular degeneration hepatocellular carcinoma educational attainment
rs7306778	B4GALNT3	srage stanniocalcin-1 level of phospholipase B1, membrane-associated in blood
rs116653040	POLR2LP1 - CCHCR1	srage

Defining Soluble Receptor for Advanced Glycation End-products (sRAGE) and Methodologies

Soluble Receptor for Advanced Glycation End-products (sRAGE) refers to a circulating isoform of the Receptor for Advanced Glycation End-products (RAGE), a multi-ligand cell surface receptor involved in inflammatory and immune responses. Plasma sRAGE levels are considered a biomarker, reflecting aspects of the complex RAGE-ligand axis, though its precise representation of this interaction can be complex due to the multi-ligand nature of RAGE and multiple possible isoforms of RAGE and sRAGE.^[1]The of sRAGE in plasma samples is a key operational definition in research studies, with methodologies including Enzyme-Linked Immunosorbent Assay (ELISA).^[1] and Proximity Extension Assay techniques.^[2]These approaches quantify sRAGE concentrations, often expressed in arbitrary units (au) for consistency across different analytical platforms.^[2]Studies have indicated that plasma sRAGE levels demonstrate fair stability within individuals over several years, supporting its utility as a measurable trait in longitudinal research.^[1]Despite this, the inability of sRAGE as a biomarker to fully represent the intricate RAGE-ligand interaction, particularly in specific disease states where advanced glycation end-products are abundant, underscores an evolving understanding of its biological significance.^[1]Researchers often predict sRAGE levels for participants with missing data using linear regression models based on available measurements and covariates like age, ensuring comprehensive data analysis.^[1]

Genetic Nomenclature and Determinants of sRAGE Levels

The genetic underpinnings of sRAGE levels are explored through the analysis of single-nucleotide polymorphisms (SNPs), which are variations at a single position in a DNA sequence. Key terminology includes ‘rs numbers’ (e.g.,rs2070600 ), which are unique identifiers for SNPs in databases like dbSNP (referencing GRCh37.p10), and 1000 Genomes SNPID identifiers, used for consistency across studies.^[1] Genetic association studies employ concepts such as minor allele frequency (MAF), which is the frequency of the less common allele in a population, and linkage disequilibrium (LD), where alleles at different loci are inherited together more often than expected by chance.^[1] SNPs with an r² value greater than 0.6 are typically considered to be in LD, guiding the selection of lead SNPs for further analysis.^[2]Genome-wide association analyses (GWAS) identify quantitative trait loci (pQTLs) that influence protein levels, such as sRAGE. These can be classified ascis-pQTLs, located within or near the gene encoding the protein (e.g., a SNP in the AGER gene that encodes RAGE), or trans-pQTLs, located on a different chromosome.^[2] For instance, rs2070600 in the AGER gene on chromosome 6 has been identified as a significant cis-pQTL for sRAGE, explaining a portion of its plasma variance.^[2]Standardized genetic criteria for significance, such as a P-value less than 5 × 10⁻⁸, are applied to identify robust associations between SNPs and sRAGE levels.^[1]

Operational Definitions and Diagnostic Criteria for Related Clinical Outcomes

In studies investigating the clinical significance of sRAGE, various associated health conditions are defined using specific diagnostic and criteria. Prevalent diabetes mellitus, for example, is operationally defined by self-reported diabetes, the use of diabetes medications, and/or a fasting glucose level ≥ 6.99 mmol/L (or ≥ 6.0 mmol/L in whole blood, corresponding to ≥ 7.0 mmol/L in plasma).^[1]Incident coronary heart disease (CHD) is adjudicated by an endpoints committee and defined as the first definite or probable myocardial infarction, or fatal CHD or MI by electrocardiogram.^[1]Incident chronic kidney disease (CKD) is characterized by the first occurrence of an estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m².^[1]The eGFR is typically calculated using formulas such as the Modification of Diet in Renal Disease (MDRD) Study Group method, which incorporates measured creatinine, age, sex, and race.^[1]Incident heart failure is defined by death or hospitalization for heart failure.^[1]These precise definitions and thresholds are crucial for classifying disease states and evaluating sRAGE’s potential role as a biomarker or causal factor in the progression of these cardiovascular and metabolic outcomes.

Biological Background of sRAGE

The soluble receptor for advanced glycation end-products (sRAGE) is a circulating protein that serves as a key component of the intricate RAGE-sRAGE axis, playing a significant role in various physiological and pathophysiological processes. sRAGE is measured in plasma and has been observed to maintain relatively stable levels within individuals over time.^[1]Understanding the biological mechanisms underlying sRAGE levels and its interactions is crucial for comprehending its implications for human health, particularly in the context of cardiovascular and metabolic diseases.

The RAGE-sRAGE System and its Molecular Basis

The receptor for advanced glycation end-products (RAGE) is a multi-ligand cell surface receptor encoded by the AGERgene. Its soluble counterpart, sRAGE, functions as a decoy receptor, circulating freely in the bloodstream and binding to various RAGE ligands, thereby preventing them from interacting with cell-bound RAGE.^[1]These ligands include advanced glycation end-products (AGEs), which accumulate during metabolic stress, particularly in conditions like diabetes, and contribute to inflammatory responses. The complex interplay within the RAGE-sRAGE axis, involving multiple isoforms of RAGE and sRAGE, dictates cellular functions and regulatory networks that influence systemic inflammation and tissue homeostasis.^[1]

Genetic Determinants of sRAGE Levels

Genetic variations within the AGERgene are significant determinants of plasma sRAGE levels. A missense variant inAGER, rs2070600 , has been identified as a strong genetic determinant, associated with approximately 50% lower sRAGE levels in both white and black populations.^[1] This variant corresponds to the Gly82Ser polymorphism, which has also been linked to an increased risk for coronary events.^[2]Additionally, an intronic single nucleotide polymorphism (SNP),rs2071288 , also within the AGERgene, is associated with 43% lower sRAGE levels in black individuals and suggests the presence of another independent genetic factor influencing sRAGE levels.^[1] While these AGERSNPs collectively explain a substantial portion of the variation in sRAGE levels (21.5% in blacks and 26% in whites), they do not fully account for observed racial differences in sRAGE concentrations.^[1]

sRAGE, Inflammation, and Metabolic Health

The RAGE-sRAGE axis is intimately linked with inflammation and metabolic processes, as RAGE ligands are inherently pro-inflammatory.^[1]Higher levels of systemic inflammation, often indicated by biomarkers such as C-reactive protein and interleukin-6, are frequently observed in certain populations, notably among black individuals compared to whites.^[1]This heightened inflammatory state is further exacerbated by metabolic factors like elevated body mass index (BMI) and increased fasting glucose, which are prevalent risk factors for inflammatory diseases such as diabetes and coronary heart disease. Environmental factors, including lower socioeconomic status, chronic stress, and racial discrimination, are also implicated in contributing to the observed racial disparities in inflammation and, consequently, may influence the complex RAGE-sRAGE interactions.^[1]

Systemic Implications and Cardiovascular Outcomes

As a circulating biomarker, sRAGE has been studied for its associations with a range of systemic health outcomes, particularly cardiovascular and metabolic diseases. Research has explored the relationship between sRAGE levels and incident death, coronary heart disease (CHD), diabetes, chronic kidney disease (CKD), and heart failure.^[1]Higher plasma sRAGE levels have been associated with incident cardiovascular events, and serum endogenous secretory RAGE levels are considered an independent risk factor for the progression of carotid atherosclerosis.^[3]Despite these associations, Mendelian randomization analyses suggest that sRAGE, as currently measured, may not be a substantial causal factor for outcomes such as death, heart failure, or diabetes.^[1]This highlights the complexity of the RAGE-ligand interactions and the potential for the current sRAGE measure to not fully capture its multifaceted biological role in disease pathogenesis.^[1]

sRAGE as a Circulating Biomarker and its Epidemiological Associations

Soluble receptor for advanced glycation end-products (sRAGE) has been extensively studied as a circulating biomarker, particularly in relation to cardiovascular disease and all-cause mortality.^[4]Epidemiological research has yielded mixed results regarding its prognostic value; some prospective studies indicate an association between higher sRAGE levels and increased risk of incident cardiovascular disease, cardiovascular mortality, and all-cause mortality.^[4]Conversely, other studies report an inverse relationship, where higher sRAGE levels are associated with a reduced risk of cardiovascular disease, slower progression of carotid atherosclerosis, and lower all-cause mortality.^[5]These variable findings highlight the complexity of sRAGE’s role as a biomarker and suggest that its utility in clinical applications may depend on specific patient populations or disease contexts.^[1]Furthermore, notable differences in sRAGE levels have been observed across various racial and ethnic groups, such as between non-Hispanic blacks and other populations, which may contribute to observed health disparities.^[1]

Genetic Determinants and Their Influence on Outcomes

Genetic studies have identified specific variants within the AGERgene, which encodes RAGE, that significantly influence sRAGE levels. For instance, the coding variantrs2070600 has been identified as a major genetic determinant of sRAGE levels in individuals of white ancestry, while an intronic SNP,rs2071288 , represents an additional determinant in individuals of black ancestry.^[1] The Gly82Ser polymorphism, corresponding to rs2070600 , has been specifically linked to an increased risk for coronary events in the general population.^[2]However, despite these genetic associations with sRAGE levels, Mendelian randomization analyses using these genetic determinants suggest that sRAGE, as currently measured, may not be a substantial causal factor for outcomes such as death, heart failure, or diabetes, in either white or black populations.^[1]While there were no robust associations between these genetic determinants of sRAGE and chronic kidney disease (CKD) or coronary heart disease (CHD), the possibility of modest effects cannot be entirely ruled out due to limitations in statistical power for some outcomes.^[1]

Challenges in Causal Inference and Risk Stratification

The intricate nature of the RAGE-sRAGE axis, involving multiple ligands and isoforms, complicates the interpretation of sRAGE levels as a direct causal factor for disease progression or outcomes.^[1]The current methods of sRAGE may not fully capture the complex interactions within this pathway, suggesting that other highly correlated causal factors might be at play.^[1]Consequently, while sRAGE levels are correlated with important clinical outcomes and racial disparities in cardiovascular disease, a clear genetic explanation for these racial differences remains elusive, pointing towards a significant role for environmental factors.^[1]For example, specific genetic variants influencing sRAGE levels, such as theGly82Ser polymorphism, can contribute to risk stratification for coronary events, yet no significant associations have been found between these genetic variants and carotid intima-media thickness (IMT) progression.^[2]Future research is essential to precisely identify the relevant causal factors within the RAGE-sRAGE axis, which could lead to more effective personalized medicine approaches and prevention strategies by targeting modifiable environmental factors or alternative components of the RAGE pathway.^[1]

Longitudinal Cohort Studies and Methodological Rigor

Population studies investigating sRAGE often leverage large-scale, prospective cohorts to understand its role in health and disease over time. The Atherosclerosis Risk in Communities (ARIC) Study, for instance, is a prominent community-based cohort that enrolled 15,792 individuals aged 45 to 64 years across four US communities between 1987 and 1989. This study design facilitated multiple follow-up visits over decades, allowing for the longitudinal ascertainment of various clinical outcomes such as incident coronary heart disease (CHD), diabetes, chronic kidney disease (CKD), and heart failure, as well as mortality.^[1]Similarly, the Malmö Diet and Cancer (MDC) cohort in Sweden, comprising over 30,000 subjects, including a carotid artery disease epidemiology subgroup (MDC-CV) of 6,103 participants, provided a robust framework for studying sRAGE associations with long-term cardiovascular events and mortality over a median follow-up of 21.2 years.^[2]These studies employed rigorous methodologies for both sRAGE phenotyping and genotyping. sRAGE levels were consistently measured using ELISA in stored plasma samples, with one study noting the relative stability of sRAGE within individuals over three years.^[1] Genotyping involved advanced platforms like Affymetrix 6.0 and Illumina GWAS Chips, followed by extensive quality control measures including exclusions for low minor allele frequency (MAF), deviations from Hardy-Weinberg Equilibrium, low call rates, gender mismatch, and genetic outlier status.^[1] Imputation to large reference panels, such as 1000 Genomes Phase I and Haplotype Reference Consortium (HRC r1.1), ensured comprehensive genomic coverage, while principal components analysis was used to account for population substructure, enhancing the representativeness and generalizability of genetic findings across diverse segments of the study populations.^[1]

Genetic Architecture and Cross-Population Variability

Genetic studies have identified specific loci influencing sRAGE levels, revealing important insights into its heritability and population-specific effects. Genome-wide association studies (GWAS) conducted within the ARIC cohort analyzed approximately 9.1 million and 6.5 million single nucleotide polymorphisms (SNPs) in Black and White participants, respectively, with adjustments for demographic and clinical covariates.^[1]This approach allowed for the identification of genetic determinants of sRAGE, with one principal component of population structure being associated with sRAGE in White individuals but none in Black individuals, suggesting differing genetic backgrounds or environmental interactions impacting sRAGE levels between these groups.^[1] Further cross-population comparisons in the MDC cohort, focusing on European subjects, identified 48 genome-wide significant pQTL SNPs, represented by four independent lead SNPs, located in two genomic risk loci on chromosomes 6 and 12.^[2] Notably, a lead cis-pQTL SNP, rs2070600 , mapped to the AGERgene, which encodes RAGE, explaining 1.5% of the plasma sRAGE variance.^[2] Additionally, a trans-pQTL SNP, rs7306778 , was found in the B4GALNT3gene on chromosome 12, explaining 1% of sRAGE variance.^[2] The presence of the Gly82Ser polymorphism in the receptor for advanced glycation endproducts (AGER) has also been shown to increase the risk for coronary events in the general population, highlighting the functional relevance of specific genetic variants within this gene.^[2]

Epidemiological Correlates and Clinical Outcome Associations

Epidemiological investigations have explored the prevalence patterns of sRAGE and its genetic determinants in relation to various demographic factors and clinical outcomes. In the ARIC study, significant differences were observed between Black and White participants across characteristics such as BMI, eGFR, fasting glucose, education level, and prevalent CHD, underscoring the importance of considering socioeconomic and demographic correlates in population health studies.^[1]The MDC cohort also provided baseline epidemiological data, reporting a median BMI of 25 kg/m², with 20% of participants being smokers and 7.5% having diabetes mellitus, establishing a broad context for evaluating sRAGE associations.^[2]Despite identifying genetic determinants of sRAGE, Mendelian randomization studies within the ARIC cohort, designed to assess the causal role of sRAGE in disease, indicated that sRAGE did not appear to be a substantial and significant causal factor for death, heart failure, or diabetes in White participants, with similar findings in Black participants.^[1]Methodological limitations, such as lower statistical power for certain outcomes like CKD and heart failure, particularly in Black populations due to smaller sample sizes, were acknowledged.^[1]Nonetheless, the MDC study further investigated associations between sRAGE-associated SNPs and clinical outcomes, including incident first-time major adverse cardiovascular events (MACE) and mortality, providing a comprehensive view of the long-term epidemiological impact of these genetic variants.^[2]

Frequently Asked Questions About Srage

These questions address the most important and specific aspects of srage based on current genetic research.

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1. Can I change my sRAGE levels by eating healthier?

Your sRAGE levels are quite stable over time and are strongly influenced by your genes. While a healthy diet is crucial for overall health, current research suggests that lifestyle changes like diet don’t significantly alter your sRAGE levels in the long run. Genes like those nearAGER are the primary determinants.

2. Does exercising regularly affect my sRAGE levels?

Similar to diet, regular exercise is excellent for your overall well-being, but it’s unlikely to have a major impact on your sRAGE levels. Your individual sRAGE concentration is largely set by your genetic makeup, with specific variants in theAGER gene playing a key role in determining these stable levels.

3. If my sRAGE levels are high, am I definitely sicker?

Not necessarily. While sRAGE levels are oftencorrelatedwith conditions like heart disease or diabetes, having high sRAGE doesn’t automatically mean you’re sicker. Genetic studies show that the genetic factors influencing sRAGE don’t always directly cause these diseases, suggesting a more complex relationship.

4. Why do my sRAGE levels stay the same year after year?

Your sRAGE levels are remarkably stable within you over several years because they are largely determined by your genetic code. Specific genetic variants, particularly in or near theAGERgene, account for a significant portion of what sets your individual sRAGE concentration.

5. Could my family history explain my sRAGE levels?

Yes, absolutely. Genetic factors are strong determinants of sRAGE levels, meaning that if your parents or close relatives have certain sRAGE levels, you are likely to have similar predispositions. Variants likers2070600 and rs2071288 in the AGER gene are known to be passed down and influence these levels.

6. Does my race or ethnicity impact my sRAGE levels?

Yes, research has shown significant differences in median plasma sRAGE levels across racial groups. For instance, lower levels have been observed in Black individuals compared to White individuals. While some genetic variants are specific to certain ancestries, other non-genetic factors likely contribute to these observed disparities.

7. Can sRAGE levels really predict my risk for heart disease?

While sRAGE levels are oftenassociatedwith conditions like coronary heart disease, the relationship isn’t straightforward for prediction. Genetic studies using sRAGE-associated variants haven’t consistently shown a strong, direct causal link to major clinical outcomes. So, while it’s a biomarker, it’s not a definitive predictor on its own.

8. Is getting my sRAGE measured helpful for my health?

Currently, sRAGE is primarily a tool in medical research to understand disease mechanisms. While it’s a biomarker for inflammation and AGE accumulation, its precise role in predicting individual health risks or guiding treatment is still being investigated. The complexity of the RAGE system means a single might not capture the full picture.

9. If my sRAGE is low, does that make me more prone to inflammation?

Potentially, yes. sRAGE acts as a “decoy receptor” that binds to harmful AGEs in your bloodstream, preventing them from causing inflammation and oxidative stress. If your sRAGE levels are naturally lower, it could mean less protection against these inflammatory triggers, though the exact impact on your health is complex.

10. Why are some people’s sRAGE levels naturally higher than others?

The biggest reason for differences in sRAGE levels between people is genetics. Specific variations in genes, particularly within or near theAGERgene, largely determine an individual’s baseline sRAGE concentration. These genetic differences can explain a substantial amount of the variation you see among individuals.

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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

[1] Maruthur NM, et al. “Genetics of Plasma Soluble Receptor for Advanced Glycation End-Products and Cardiovascular Outcomes in a Community-based Population: Results from the Atherosclerosis Risk in Communities Study.”PLoS One, 2015.

[2] Grauen Larsen, H., et al. “The Gly82Ser polymorphism in the receptor for advanced glycation endproducts increases the risk for coronary events in the general population.” Sci Rep, 2023.

[3] Nin, Jan-Willem, et al. “Higher plasma soluble Receptor for Advanced Glycation End Products (sRAGE) levels are associated with incident cardiovascular events in type 2 diabetic patients.”Journal of Clinical Endocrinology & Metabolism, vol. 95, no. 9, 2010, pp. E186-E192.

[4] Colhoun, Helen M., et al. “Total soluble and endogenous secretory receptor for advanced glycation end products as predictive biomarkers of coronary heart disease risk in patients with type 2 diabetes: an analysis from the CARDS trial.”Diabetes, vol. 58, no. 11, 2009, pp. 2661-2668.

[5] Katakami, Noriaki, et al. “Serum endogenous secretory RAGE level is an independent risk factor for the progression of carotid atherosclerosis in type 2 diabetic patients.”Diabetes Care, vol. 32, no. 10, 2009, pp. 1913-1918.