Androsterone Glucuronide
Introduction
Androsterone glucuronide (ADG) is a steroid metabolite derived primarily from the androgen androsterone, which itself is a breakdown product of testosterone and dehydroepiandrosterone (DHEA). As a glucuronide conjugate, it is made more water-soluble for excretion from the body, primarily in urine. Its levels in blood serum are often used as a biomarker reflecting overall androgenic activity, particularly originating from the adrenal glands, as DHEA and its sulfated form, DHEAS, are significant precursors.
Biological Basis
Androgens are a group of steroid hormones that play a crucial role in the development and maintenance of male characteristics, but are also present and functionally important in females. DHEA and DHEAS are adrenal androgens, meaning they are produced by the adrenal glands. These precursors are converted into more potent androgens like testosterone, which can then be metabolized into androsterone. The liver is a primary site for the metabolism and conjugation of these steroids, where glucuronic acid is attached to form compounds like androsterone glucuronide. This conjugation process facilitates the elimination of these steroid metabolites from the body.
Clinical Relevance
Measuring levels of androgen metabolites like androsterone glucuronide can be clinically relevant for assessing androgen status. For example, DHEAS concentrations are measured on serum samples via radioimmunoassay, and such measurements are used in studies examining kidney function and endocrine-related traits. [1] Altered levels of androsterone glucuronide may indicate conditions of androgen excess, such as hirsutism, polycystic ovary syndrome (PCOS), or certain adrenal disorders, or androgen deficiency. Research also explores the broader impact of endogenous sex hormones on health, including their association with cardiovascular disease incidence in men [2] and the relationship between hypogonadism, estradiol levels, and bone mineral density in elderly men. [3] These studies highlight the importance of understanding the complete spectrum of sex hormone metabolism and its downstream products.
Social Importance
Understanding androsterone glucuronide levels contributes to public health by aiding in the diagnosis and management of various endocrine and reproductive health conditions. For individuals, it can provide insights into their hormonal balance, particularly concerning androgen-related issues. From a broader perspective, research into androgen metabolites helps to elucidate the complex interplay between hormones, genetics, and chronic diseases, including cardiovascular disease and metabolic syndromes. This knowledge can inform preventative strategies and personalized medical interventions, ultimately improving health outcomes.
Limitations
Research into complex traits like androsterone glucuronide, particularly through genome-wide association studies (GWAS), is subject to several methodological and interpretative limitations. Acknowledging these constraints is crucial for a balanced understanding of reported genetic associations and for guiding future investigations.
Methodological and Statistical Constraints
A primary limitation in genetic association studies of traits such as androsterone glucuronide often stems from the finite sample sizes of cohorts, which can restrict statistical power to detect genetic effects of modest size. [4] While some studies may have sufficient power to identify SNPs explaining 4% or more of phenotypic variation, smaller effects may be missed, leading to false negative findings. [5] Furthermore, the reliance on initial discovery cohorts, with effect sizes sometimes estimated from subsets of samples, can potentially lead to inflation of reported effect sizes, especially for variants with smaller impacts. [6] The challenge of replicating findings across different studies highlights these power issues, with only a fraction of associations consistently validated, possibly due to false positives in initial reports or differing study designs and statistical power across cohorts. [4]
Technical aspects of genotyping and imputation also introduce limitations. For instance, studies employing older genotyping platforms, such as the Affymetrix 100K gene chip, may have incomplete coverage of genetic variation, thereby limiting the ability to replicate previously reported findings or identify novel associations. [5] Imputation quality, which relies on reference panels like HapMap, can vary, and SNPs with low imputation quality (e.g., R-squared < 0.3) are typically excluded, potentially missing true associations or affecting the accuracy of estimated genetic effects. [7] While efforts are made to control for population stratification through methods like genomic control and family-based tests, residual effects, though often small, cannot always be entirely ruled out and may subtly influence association results. [8]
Generalizability and Phenotype Characterization
The generalizability of findings for androsterone glucuronide is often limited by the demographic characteristics of the study populations. Many large-scale genetic studies are conducted in cohorts that are predominantly of European descent, and often middle-aged to elderly. [4] This demographic homogeneity means that results may not be directly transferable to younger individuals or those of different ethnic or racial backgrounds, where genetic architecture, environmental exposures, and lifestyle factors may vary considerably. [4] Additionally, the timing of sample collection, particularly for traits that may be influenced by age-related processes, can introduce survival bias if DNA is collected from individuals who have lived to a certain age, potentially skewing the genetic landscape observed. [4]
The methods used for phenotype measurement and processing also present limitations. For a steroid metabolite like androsterone glucuronide, similar to how dehydroepiandrosterone sulfate (DHEAS) concentrations are measured, techniques such as radioimmunoassay may be employed. [1] While standardized, these assays have inherent precision and accuracy limitations. Furthermore, the raw phenotypic data often undergoes statistical transformations to achieve normality or adjustments for covariates like age, sex, oral contraceptive use, and pregnancy. [9] While necessary for robust statistical analysis, these adjustments mean that reported genetic effects pertain to the adjusted trait, which may not perfectly reflect the genetic influence on the raw, physiological concentration of androsterone glucuronide. Averaging multiple measurements, or using means from monozygotic twins, can reduce measurement error and increase power but may also mask individual variability or context-specific responses. [10]
Environmental Context and Unexplained Variation
A significant limitation in understanding the genetic basis of traits like androsterone glucuronide is the typically unaddressed complexity of gene-environment interactions. Genetic variants do not operate in isolation; their effects can be modulated by various environmental influences, such as diet, lifestyle, and other contextual factors. [5] Most GWAS, including those on similar endocrine-related traits, do not systematically investigate these complex interactions, meaning that the full picture of how genes influence androsterone glucuronide levels under different environmental conditions remains largely unexplored. [5] This omission can lead to an underestimation of the true genetic contribution and a lack of understanding of the pathways through which genetic predispositions manifest.
Moreover, despite the identification of genetic loci, substantial portions of the phenotypic variation for complex traits often remain unexplained, commonly referred to as "missing heritability." This gap could be attributed to the combined effects of many common variants with very small individual effects, rare variants not captured by standard genotyping arrays, structural variants, or epigenetic factors not assessed in typical GWAS designs. The current understanding of causal variants is also often imprecise; associations are frequently reported for marker SNPs that are in linkage disequilibrium with, rather than being, the true causal variant, and the exact functional consequences of these associated variants on androsterone glucuronide metabolism are not always clear. [11] This leaves considerable knowledge gaps regarding the precise biological mechanisms underlying observed genetic associations and how they integrate within broader physiological systems.
Variants
Genetic variations play a significant role in influencing the levels of androsterone glucuronide, a key steroid metabolite, by affecting the enzymes responsible for its synthesis, metabolism, and transport. The UGT2B17 and UGT2B15 genes, for instance, encode UDP-glucuronosyltransferases, which are crucial enzymes that catalyze the conjugation of steroid hormones, including androsterone, with glucuronic acid, a process vital for their detoxification and excretion. The variant rs4860987, located in the region between these two UGT2B genes, may impact the activity or expression of these enzymes, thereby directly altering androsterone glucuronide levels. Similarly, the SULT2A1 gene encodes a sulfotransferase enzyme involved in the sulfation of various steroids, a pathway that often competes with or precedes glucuronidation, and variants like rs62129966 and rs212100 within SULT2A1, or rs10670440 near the LINC01595-SULT2A1 locus, could modulate the balance of steroid conjugation, affecting the availability of androsterone for glucuronidation. [12] These enzymatic variations can lead to individual differences in steroid hormone profiles and their downstream effects on various endocrine-related traits.
Another important set of genes influencing androsterone glucuronide levels are the solute carrier family members, SLC22A24 and SLC22A25, which encode organic anion transporters responsible for moving metabolites across cell membranes, particularly in the liver and kidneys for excretion. Variants such as rs1939768 and rs79586456 located in the intergenic region between SLC22A24 and SLC22A25, along with rs147641133 and rs111327720 near SLC22A24, and rs6591778 near SLC22A25, can alter the efficiency of these transporters. Such changes can directly impact the rate at which androsterone glucuronide is cleared from the body, leading to altered circulating levels . Furthermore, the SRD5A2 gene, which encodes the 5-alpha reductase type 2 enzyme, is critical for the conversion of testosterone to dihydrotestosterone and androstanedione to androsterone. The variant rs9282858 in SRD5A2 may affect the enzyme's activity, thereby influencing the production of androsterone and, consequently, the substrate available for glucuronidation.
Beyond direct metabolic enzymes and transporters, genes involved in broader cellular functions can also indirectly affect androsterone glucuronide levels. For instance, YIPF4 (Yip1 Domain Family Member 4), associated with variant rs72798731, is involved in Golgi organization and vesicle trafficking, processes that can influence the localization and function of enzymes and transporters critical for steroid metabolism. Similarly, the DPY30 gene, a component of histone methyltransferase complexes, plays a role in epigenetic regulation of gene expression, while MEMO1 is involved in cell motility and signaling; the variant rs3754835 near these genes could therefore indirectly modulate the expression of metabolic enzymes or transporters . Lastly, TMPRSS11E, a transmembrane serine protease, with variants rs1117816 and rs983745, may influence androsterone glucuronide by affecting protein activation or degradation pathways that indirectly regulate steroid synthesis or conjugation.
Key Variants
| RS ID | Gene | Related Traits |
|---|---|---|
| rs1939768 rs79586456 |
SLC22A24 - SLC22A25 | androsterone glucuronide measurement 17alpha-hydroxypregnanolone glucuronide measurement 11beta-hydroxyandrosterone glucuronide measurement |
| rs147641133 rs111327720 |
SLC22A24 | etiocholanolone glucuronide measurement androsterone glucuronide measurement metabolite measurement |
| rs10670440 | LINC01595 - SULT2A1 | androsterone glucuronide measurement glycochenodeoxycholate 3-sulfate measurement glycodeoxycholate 3-sulfate measurement X-21471 measurement metabolonic lactone sulfate measurement |
| rs4860987 | UGT2B17 - UGT2B15 | alkaline phosphatase measurement total cholesterol measurement low density lipoprotein cholesterol measurement cholesteryl esters:total lipids ratio, high density lipoprotein cholesterol measurement triglycerides in medium HDL measurement |
| rs6591778 | SLC22A25 | androsterone glucuronide measurement |
| rs62129966 rs212100 |
SULT2A1 | estradiol measurement blood protein amount level of tetraspanin-8 in blood Glycochenodeoxycholate sulfate measurement X-12063 measurement |
| rs9282858 | SRD5A2 | androgenetic alopecia balding measurement etiocholanolone glucuronide measurement X-11444 measurement X-11470 measurement |
| rs72798731 | YIPF4 | sex hormone-binding globulin measurement androsterone glucuronide measurement X-11470 measurement |
| rs3754835 | DPY30, MEMO1 | androsterone glucuronide measurement |
| rs1117816 rs983745 |
TMPRSS11E | high density lipoprotein cholesterol measurement androsterone glucuronide measurement phospholipids in medium LDL measurement free cholesterol in small VLDL measurement blood VLDL cholesterol amount |
Laboratory and Biochemical Assays
The assessment of endocrine-related traits often involves precise biochemical assays to quantify hormone and metabolite levels in serum. For instance, dehydroepiandrosterone sulfate (DHEAS), a steroid hormone and precursor to various androgens, has its concentrations measured on serum samples using radioimmunoassay (RIA) techniques. [1] Such assays provide quantitative data on circulating hormone levels, which are critical for evaluating endocrine function and identifying potential imbalances within steroid metabolic pathways. Beyond specific hormone measurements, comprehensive metabolite profiling offers a broader view of an individual's metabolic state. Targeted metabolite profiling, performed using advanced techniques like electrospray ionization (ESI) tandem mass spectrometry (MS/MS), allows for the quantitative assessment of numerous metabolites in biological samples. [12] This approach, which includes objective quality control measures, can identify and quantify a wide array of compounds, providing detailed insights into various metabolic processes and their potential alterations.
Genetic and Molecular Markers
Genetic factors play a significant role in influencing various endocrine and metabolic traits. Genome-wide association studies utilize genotyping platforms, such as the 100K Affymetrix GeneChip or the Affymetrix 500K Mapping array set, to identify genetic variants across the genome. [1] These molecular markers can be analyzed to understand genetic predispositions or associations with specific biochemical profiles, offering insights into the underlying genetic architecture of endocrine-related conditions and metabolite regulation. Such genotyping efforts involve extracting genomic DNA from blood samples and performing quantitative real-time PCR for specific gene expression studies, ensuring accurate amplification and detection of targeted sequences. [13]
Androgen Metabolism and Endocrine Regulation
Androsterone glucuronide is a key metabolite within the complex network of steroid hormone biosynthesis and breakdown, serving as an endocrine-related trait reflective of androgenic activity. [1] Its levels are typically measured in serum, offering insights into systemic endocrine status. [1] This conjugate is derived from androsterone, which itself originates from precursor androgens like dehydroepiandrosterone sulfate (DHEAS), a hormone measured in serum via radioimmunoassay. [1] The production and metabolism of these endogenous sex hormones are tightly regulated processes involving various endocrine glands, including the adrenal glands and gonads, and are intricately linked to other hormonal axes, such as those involving thyroid-stimulating hormone (TSH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). [1]
The broader endocrine system plays a crucial role in maintaining physiological balance, with sex hormones like testosterone and estradiol exerting wide-ranging effects throughout the body. For instance, endogenous sex hormones have been associated with cardiovascular disease incidence in men [2] and imbalances such as hypogonadism can impact bone mineral density in elderly men. [3] Beyond direct hormonal action, these steroids also influence the production and activity of other key biomolecules, such as adiponectin, with testosterone observed to decrease adiponectin levels by inhibiting its secretion from adipocytes. [14] This highlights the interconnectedness of steroid metabolism with broader metabolic functions and systemic health.
Genetic Determinants of Steroid and Metabolic Pathways
Genetic variations significantly influence the intricate pathways governing steroid hormone metabolism and related physiological traits. Genome-wide association studies (GWAS) are instrumental in identifying genetic loci associated with endocrine-related traits, including androsterone glucuronide. [1] Single nucleotide polymorphisms (SNPs) can impact gene function and expression, thereby modulating the efficiency of metabolic enzymes or receptor activity. For example, common SNPs in the HMGCR gene, which encodes 3-hydroxy-3-methylglutaryl coenzyme A reductase—a rate-limiting enzyme in cholesterol synthesis—have been shown to affect alternative splicing of exon 13, influencing LDL-cholesterol levels. [15] This alternative splicing is a critical post-transcriptional regulatory mechanism that can alter protein function and expression patterns. [16]
Beyond steroid and cholesterol synthesis, genetic mechanisms also govern other metabolic processes with systemic consequences. The SLC2A9 gene, for instance, encodes a urate transporter, and its genetic variants influence serum urate concentration and excretion, thereby affecting conditions like gout. [17] Similarly, common genetic variation near the MC4R gene, which encodes the melanocortin 4 receptor, is associated with waist circumference and insulin resistance, linking genetic predisposition to metabolic health. [18] These examples illustrate how specific genetic alterations can fine-tune or disrupt complex biological pathways, contributing to individual differences in endocrine and metabolic profiles.
Systemic Health and Pathophysiological Implications
Variations in endocrine-related traits like androsterone glucuronide are not isolated events but are often associated with broader systemic health implications and pathophysiological processes. Imbalances in sex hormones, for example, are linked to an increased incidence of cardiovascular disease [2] a condition often characterized by dyslipidemia, which involves abnormal levels of LDL-cholesterol, HDL-cholesterol, and triglycerides. [6] Beyond cardiovascular health, kidney function is another organ-level system where endocrine traits can have significant impact, with glomerulosclerosis observed in animal models of hypertension. [19]
The intricate interplay between endocrine function and systemic health extends to metabolic disorders and bone health. Thyroid dysfunction, for instance, has been associated with altered total cholesterol levels, indicating its role in lipid metabolism. [20] Furthermore, conditions like hypogonadism, characterized by insufficient sex hormone production, are directly linked to reduced bone mineral density, highlighting the crucial role of these hormones in maintaining skeletal integrity. [3] These connections underscore how disruptions in endocrine homeostasis, reflected in metabolites like androsterone glucuronide, can contribute to a spectrum of disease mechanisms across multiple organ systems.
Cellular Processes and Molecular Signaling
At the cellular level, the biological activity of androsterone glucuronide and its related steroids involves a complex interplay of specific biomolecules, metabolic processes, and signaling pathways. Steroid hormones typically exert their effects by binding to intracellular receptors, which then act as transcription factors to regulate gene expression. Metabolic enzymes, such as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), are central to lipid biosynthesis, with its activity influencing mevalonate pathway regulation and cholesterol production. [15] Other key proteins like ANGPTL3 and ANGPTL4 also play roles in regulating lipid metabolism by influencing triglyceride and HDL levels. [21]
Cellular signaling cascades are also intimately involved in mediating the effects of hormones and metabolites. For example, the mitogen-activated protein kinase (MAPK) pathway is activated in response to various stimuli [5] and the phosphorylation of Heat Shock Protein-90 by TSH in thyroid cells illustrates a specific hormonal signaling event. [22] Furthermore, the regulation of cyclic GMP (cGMP) signaling, antagonized by angiotensin II-induced increases in phosphodiesterase 5A expression in vascular smooth muscle cells, demonstrates how molecular interactions can impact cellular functions like vasoregulation. [23] These molecular and cellular mechanisms collectively govern the production, action, and excretion of steroid metabolites, shaping their impact on tissue-specific functions and overall physiological health.
Steroid Metabolism and Conjugation
Androsterone, as an endogenous sex hormone metabolite, participates in complex metabolic pathways that influence systemic physiology. While its specific glucuronidation process is not detailed, the broader metabolism of sex hormones is linked to cardiovascular disease incidence [2] and bone mineral density. [3] These hormones are synthesized through pathways that ultimately derive from cholesterol, a process critically regulated by enzymes like 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). [13] The mevalonate pathway, orchestrated by HMGCR, controls the biosynthesis of isoprenoids and cholesterol, which serve as precursors for steroid hormone synthesis. [24]
Regulation of HMGCR is multifaceted, involving not only its enzymatic activity but also post-transcriptional mechanisms such as alternative splicing. Genetic variants in HMGCR can affect the alternative splicing of exon13, thereby influencing the production of different HMGCR isoforms. [13] This alternative splicing represents a key regulatory mechanism for controlling the flux through the mevalonate pathway, impacting the availability of cholesterol and its downstream metabolites, including steroid precursors. [13] Such intricate control points underscore the metabolic regulation and flux control inherent in steroid biosynthesis pathways.
Hormonal Signaling and Systemic Interactions
Endogenous sex hormones, including androsterone and its conjugates, exert their influence through intricate signaling pathways that modulate various physiological processes. Testosterone, for instance, has been shown to decrease adiponectin levels by inhibiting its secretion from adipocytes. [14] This interaction highlights a feedback loop where hormonal signals directly impact the production and release of other critical metabolic regulators, affecting energy metabolism and systemic health. Such hormonal actions often involve receptor activation followed by intracellular signaling cascades.
Intracellular signaling pathways, such as the mitogen-activated protein kinase (MAPK) cascades, are crucial mediators of cellular responses to various stimuli, including hormones. [25] Activation of these cascades can lead to transcription factor regulation, altering gene expression profiles in target cells. Furthermore, post-translational modifications like phosphorylation, as seen with thyroid-stimulating hormone (TSH) phosphorylating Heat Shock Protein-90 (HSP90) in thyroid cells, represent another layer of regulatory control. [22] These mechanisms collectively integrate hormonal signals into cellular functions, influencing processes like lipid metabolism and immune responses.
Metabolic Interplay and Cardiovascular Health
The metabolic landscape influenced by sex hormones involves extensive pathway crosstalk and network interactions, particularly concerning lipid and uric acid homeostasis. Genes like ANGPTL3 and ANGPTL4 are pivotal in regulating lipid metabolism, with variations in ANGPTL4 affecting triglyceride and HDL levels. [21] These interactions are further modulated by transcription factors such as SREBP-2, which links isoprenoid and adenosylcobalamin metabolism, demonstrating hierarchical regulation within interconnected metabolic networks. [26] The emergent properties of these networks dictate overall lipid profiles and cardiovascular risk.
Beyond lipids, sex hormones can indirectly influence uric acid metabolism, which is a significant factor in cardiovascular disease and metabolic syndrome. [27] The glucose transporter-like protein 9 (GLUT9), also known as SLC2A9, plays a critical role in renal urate transport, and variants in this gene are associated with serum uric acid levels. [28] This exemplifies how diverse metabolic pathways, potentially influenced by hormonal status, converge to impact systemic health outcomes, underscoring the systems-level integration of metabolic processes.
Pathophysiological Implications and Therapeutic Targets
Dysregulation within these interconnected pathways, potentially influenced by altered sex hormone levels or metabolism, contributes significantly to various disease states. For instance, imbalances in endogenous sex hormones are associated with cardiovascular disease incidence [2] and bone mineral density. [3] Similarly, dyslipidemia, characterized by aberrant lipid concentrations, is linked to genetic variants in numerous loci that influence lipid levels. [29] These genetic predispositions, combined with hormonal influences, can lead to pathway dysregulation that manifests as clinical conditions.
Compensatory mechanisms often arise in response to pathway dysregulation, though they may not always restore full physiological function. The intricate regulation of the mevalonate pathway, for example, involves alternative splicing of HMGCR as a means to control cholesterol synthesis, which can be a therapeutic target for dyslipidemia. [13] Furthermore, the Angiotensin II pathway, known to increase phosphodiesterase 5A expression and antagonize cGMP signaling in vascular smooth muscle cells, presents another potential area for therapeutic intervention in cardiovascular diseases. [23] Understanding these mechanistic details is crucial for identifying novel therapeutic targets and developing personalized medicine strategies.
Endocrine Physiology and Cardiovascular Health
Androsterone glucuronide, as a key metabolite of dehydroepiandrosterone sulfate (DHEAS), is implicated in clinical contexts where DHEAS levels are studied. Research has identified DHEAS as an "endocrine-related trait" [1] indicating its involvement in the broader hormonal milieu. Investigations into endogenous sex hormones, which include DHEAS and its metabolic pathways leading to androsterone glucuronide, have shown associations with cardiovascular disease incidence in men. [2] This suggests that variations in androsterone glucuronide levels could reflect underlying endocrine influences on cardiovascular health.
Risk Stratification and Personalized Medicine
Given the established link between endogenous sex hormones and cardiovascular disease outcomes [2] androsterone glucuronide holds potential for contributing to risk stratification. By reflecting aspects of the body's sex hormone profile, its levels could aid in identifying individuals at an elevated risk for cardiovascular events. Integrating such endocrine markers into risk assessment frameworks could facilitate more personalized medicine approaches, allowing for tailored prevention strategies based on an individual's specific hormonal signature.
Diagnostic and Monitoring Applications
The measurement of DHEAS in serum samples via radioimmunoassay has been a standard practice in assessing "endocrine-related traits". [1] Extending this, androsterone glucuronide, as a downstream metabolite, could offer complementary diagnostic utility or serve as a monitoring biomarker. Its levels might provide insights into specific metabolic pathways of DHEAS, reflecting changes in endocrine function or response to therapeutic interventions. Further exploration of its precise measurement and correlation with disease states is warranted to establish its full clinical utility.
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