The 10 most replicated genes in GWAS studies for hyperruricemia and gout.
Abstract
Gout is a common and complex form of arthritis that is characterized with hyperuricaemia. It is required urate-lowering therapy (ULT) for lifelong management. ULT includes decreasing uric acid product in serum, increasing renal urate excretion and promoting uric acid to allantoin for excretion. Whole genome association studies in gout identified more than 40 genetic loci that influenced the serum uric acid levels. Most associated genes were found to affect renal urate excretion. Pharmacogenetics and pharmacogenomics approaches on ULT had revealed several genes that underlined the effectiveness and the adverse events of medications for gout. Together with the researches on epigenetic factors such as DNA methylations, miRNAs; and the discovery of environmental factors such as microbiota and metabolites, the current progress provides the opportunities for personalized management of ULT for treating hyperuricaemia and gout.
Keywords
- gout
- hyperuricaemia
- pharmacogenetics
- pharmacogenomics
- urate-lowering therapy
1. Introduction
The term “gout” was firstly used around 1200 AD. It means “a drop” of liquid from the Latin word gutta [1]. The first description of gout as a disease was from Egypt in 2600 BC as arthritis of the big toe. Gout is now referred as a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot, and swollen joint [2]. It is one of the most common forms of arthritis and the prevalence is increasing worldwide. The prevalence is various in different regions across the world and is about 1–4%. In westernized countries, the prevalence is about 3–6% in men and about 1–2% in women. Prevalence can increase up to 10% in some countries. For people aged more than 80 years old, it could rise up to 10% in men and 6% in women [3, 4]. In the USA, the prevalence of gout in adults was estimated to be approximately 3.9% [5]. From 1990 to 2015, the number of prevalent gout cases rose by 30% in Nordic region [6]. In China, the pooled prevalence of gout was 1.1% between 2000 and 2016 [7].
Hyperuricaemia is the key biochemical abnormality in gout. Uric acid is a C5H4N4O3 (7,9-dihydro-1H-purine-2,6,8(3H)-trione) heterocyclic organic compound with a molecular weight of 168 Da. Uric acid is the product from the conversion of the two purine nucleic acids, adenine and guanine [8]. Hyperuricaemia is defined as serum urate level more than 0.42 mmol/l. It results in the formation of monosodium urate (MSU) crystals. MSU crystals precipitate within joints and soft tissues to cause an inflammatory response. The prominent clinical features of gout are attacks of tendonitis, formatting collections of MSU crystals as tophi, joint destruction and chronic gouty arthritis. MSU crystals can also deposit in the interstitium of the kidneys to form renal stones. Hyperuricaemia was associated with hypertension and ischemic heart diseases [9, 10]. The causes of hyperuricaemia are either under excretion of uric acid in the kidneys or increase of production of uric acid in serum [11]. Two key enzymes regulate the production of uric acid. One is xanthine oxidase that makes xanthine to uric acid; the other is urate oxidase that transfers uric acid to allantoin. Allantoin is the end product of purine catabolism in all mammals except humans, great apes, and one breed of dog, the Dalmatian. An animal model of hyperuricaemia from Dalmatian dog revealed the importance of
2. Clinical managements of gout
Effective treatment of acute gout attacks and long-term urate lowering therapy are clinical managements of gout. An acute attack should be treated as soon as possible with non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine as first line treatment options. For patients who do not respond NSAIDs or colchicine, systemic corticosteroids generally are applied [13]. Long-term management of gout with ULT is required for patients who are confirmed as diagnosis of gout and tophi. The diagnosis includes more than two times gout attacks per year, renal stones or stage 2 or worse chronic kidney disease. A sustained reduction of serum urate to less than 0.36 mmol/l (6 mg/dl) is generally recommended and a lower target of less than 0.30 mmol/l (5 mg/dl) is recommended in patients with tophi [14, 15]. A xanthine oxidase inhibitor is the recommended as first-line choice for ULT. A uricosuric can be serviced as second-line medication for ULT. It is for patients who do not response xanthine oxidase inhibitors well. Uricases are the third-line treatments for patients who have refractory disease and are intolerant to oral ULTs. Optimizing therapy for improving the outcomes with affordable drugs such as allopurinol, as well as rationalizing the use of new, more expensive agents is an important clinical goal. The roles of pharmacogenetics and pharmacogenomics are becoming more and more important to predict drug response and adverse events of medications. Rationalization and combination of common medications with genetic screening and other environmental factors will revolutionize gout managements in near future.
3. Pharmacogenetics and pharmacogenomics in ULT
“Pharmacogenetics” was a term originally to describe clinical observations of inherited differences in drug effects in 1950s [16]. It is now defined as the study of individual DNA variants that are related to drug responses [17, 18]. Genetic variants also underlie the differential susceptibility to diseases and the sensitivity to drug adverse events. Most drug effects are determined by the interplay of several proteins that influence the pharmacokinetics and pharmacodynamics of medications, including inherited differences in drug targets such as receptors, drug disposition such as metabolizing enzymes and transporters, drug metabolism, and drug adverse reaction. In human, about 20–95% of variability in drug disposition and effects are determined by genetic polymorphisms in the genome [18]. For all practical purpose, the terms pharmacogenetics and pharmacogenomics may be synonymous, but pharmacogenomics normally refers genome-wide approaches to investigate all genes in the genome that influence drug responses while pharmacogenetics implies the study of a single gene’s interactions with drugs. The pharmacogenomics approach tends to be applied to identify genes in the search for novel drug targets. This is in contrast to traditional drug design that depends on a prior knowledge of the target and is based on high-throughput screening to identify small-molecule antagonists or agonists.
3.1 Genetic and genomic approaches of hyperuricaemia and gout
Genetic approaches for complicated diseases and associated traits such as gout and hyperuricaemia are to identify genetic variants in genome that underlie the diseases and syndromes. There are many kinds of genetic variants in human genome. Single nuclear polymorphisms (SNPs) are the most frequent variants found in the genome, accounting for 90% of human genetic variation. Total 84.7 million SNPs were found in 26 human populations [19]. SNPs can be found within coding sequences and noncoding regions of genes, as well as within intergenic regions. Insertion and deletion of short segments of DNA (INDEL) is another type of common polymorphism. More than 3.6 million short insertions/deletions are distributed throughout the human genome, with approximately 36% of them being located within promoters, introns, and exons of known genes [19, 20]. They can have a significant impact on gene function not only when present in exonic coding sequence but also when within a gene intron [21]. Variable number of tandem repeats (VNTRs) polymorphisms is widespread in the genome and contain variable numbers of repeated nucleotide sequences that result in alleles of varying lengths. VNTR loci typically have high levels of heterozygosity that make them very informative for genetics research. There are about 60,000 structural variants around human genome [19]. Inversions may involve larger regions of the genome in which a segment of a chromosome is reversed end to end and occur when a chromosome breaks in two places. A copy number variant (CNV) is a segment of DNA for which there are more than two copies in the genome. The genetic segment involved may range from one kilobase to several megabases in size [22]. Many techniques can allow the detection and discovery of CNVs including cytogenetic techniques such as fluorescent in situ hybridization, comparative genomic hybridization, array comparative genomic hybridization, and by large-scale SNP genotyping.
The genetic approaches to hyperuricaemia and gout include candidate gene studies, positional cloning studies and genome-wide association studies (GWASs). Candidate gene study needs to have relatively big case and control groups to increase the power for statistical analysis. Positional cloning is another genetic approach that identifies disease genes by progressive dissection of linkage regions that are consistently co-inherited with the disease. Nowadays, GWASs have been rapidly changing the landscape of the search of the genes that underlie complicated diseases such as hyperuricaemia and gout. It is a powerful approach to overcome the limitations of candidate gene and positional cloning studies. It examines the relationships between allele frequencies and disease status or associated traits with a large number of genetic polymorphism markers covering of whole genome [23]. GWASs provide the opportunity to identify novel mechanisms of disease pathogenesis that are caused by previously unsuspected genes or regulatory regions. About 10,000 strong associations have been reported between genetic variants and one or more complex traits [24].
3.2 GWASs for hyperuricaemia and gout
More than 30 GWASs papers on hyperuricaemia and gout have been published so far. The first GWAS study identified the associations of three genetic loci with uric acid concentration and risk of gout [25]. The three loci were
Genes | Encoded protein | Chr. | Ref. | Populations | Possible function roles |
---|---|---|---|---|---|
Solute carrier family 2 member 9: GLUT9 | 4p16 | [25, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37] | African, Asian, European | Regulating renal and gut excretion of uric acid | |
ATP binding cassette subfamily G member 2 | 4q22 | [25, 29, 30, 33, 35, 36, 45] | Asian, European | Regulating extra-renal uric acid under-excretion | |
Sodium phosphate transporters | 6p22 | [25, 33, 35, 45] | Asian, European | Regulating renal and excretion of uric acid | |
SIS (Sugar ISomerase) family protein | 2p23 | [33, 35, 45] | Asian, European | Regulating glucokinase in cells | |
Integral membrane proteins | 11q12 | [28, 29, 30, 33, 35, 45] | African, Asian, European | Preventing potentially harmful organic anions | |
PDZ domain-containing scaffolding protein | 1q21 | [33, 35, 36] | Asian, European | Regulating the high-density lipoproteins | |
TGF-beta superfamily of proteins | 12q13 | [33, 45] | Asian, European | Regulating numerous cellular processes | |
APOBEC1 complementation factor | 10q11 | [33, 35] | Asian, European | Regulating RNA-binding subunit | |
Leucine zipper-containing transcription factor | 16q23 | [30, 33] | Asian, European | Regulating several cellular processes | |
Solute carrier family 16 member 9 | 10q21 | [33, 35] | Asian, European | Regulating monocarboxylic acid transporter |
3.2.1 SLC2A9
3.2.2 ABCG2
3.2.3 SCL17A gene cluster
3.2.4 GCKR
3.2.5 SLC22A cluster
3.2.6 PDZK1
3.2.7 INHBC and INHBE
The INHBC and INHBE genes are located on human chromosome 12q13. The genes encode members of the TGF-beta (transforming growth factor-beta) superfamily of proteins. These proteins were implicated in regulating numerous cellular processes including cell proliferation, apoptosis, immune response and hormone secretion. They may be upregulated under conditions of endoplasmic reticulum stress, and may inhibit cellular proliferation and growth in pancreas and liver. The GWAS investigation found the genes had associations with gout and hyperuricaemia in some populations [33, 45].
3.2.8 A1CF
The
3.2.9 MAF
The
3.2.10 SLC16A9
The
GWASs also discovered other genes in some populations. These genes were
3.3 Pharmacogenetics and pharmacogenomics of LUT for gout
The current pharmacogenetics and pharmacogenomics majorly focus on the medications on the three paths that balance the uric acid levels in the serum. Together with treating acute gout, there are about 10 genetic loci that modify the common medications’ effectiveness or adverse events in gout management.
3.3.1 The genes that influence xanthine oxidase inhibitors (XOIs)
XOIs are the first line medications in the long-term treatment of hyperuricaemia and gout. Allopurinol and febuxostat are two important XOIs. Allopurinol is transformed into its active metabolite oxypurinol that reversibly blocks xanthine oxidase while febuxostat is a non-purine-selective inhibitor of xanthine oxidase [56]. Allopurinol is a common efficacious ULT but it associates with rare serious adverse drug reactions of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) [57]. The human leukocyte antigen B allele
3.3.2 The genes that influence uricosurics
Uricosurics are the second line of choice to treat hyperuricaemia and gout clinically. Currently three medications are working as uricosurics for renal excretion of uric acid. They are probenecid, benzbromarone (BBR) and lesinurad. BBR and its metabolite 6-hydroxybenzbromarone block the renal reabsorption of uric acid by inhibiting URAT1 in proximal renal tubular cells [11]. BBR undergoes hepatic hydroxylation to 1′-hydroxy BBR and 6-hydroxy BBR. The BBR elimination in serum was affected by genetic polymorphism in drug metabolism [71]. It was demonstrated that CYP2C9 was the main enzyme responsible for the 6-hydroxylation of BBR [72, 73].
3.3.3 The genes that influence uricase
Rasburicase is an urate oxidase. It is a peroxisomal liver enzyme to catalyze the oxidation of uric acid into the more water-soluble substrates. Urate oxidase is an endogenous enzyme can be found in most mammals but not in humans. The inactivation of the hominoid urate oxidase gene was caused by independent nonsense or frame-shift mutations during evolution [79] . Two nonsense mutations were found in the human urate oxidase gene that makes it non-functional in human [80, 81]. Pegloticase is a recombinant uricase for the treatment of severe, treatment-refractory, chronic gout. It is a third-line treatment for patients who do not tolerate to other treatments [56, 82]. Pegloticase also catalyze uric acid to allantoin which is 5–10 times more soluble than uric acid. Pegloticase is in pegylated form so it can increase its elimination half-life from about 8 hours to 10 or 12 days, and this can decrease the immunogenicity of the foreign uricase protein. Among patients with chronic gout, the use of pegloticase 8 mg either every 2 weeks or every 4 weeks for 6 months resulted in lower uric acid levels compared with placebo [56]. A case of pegloticase-related methemoglobinemia and haemolytic anaemia was reported as it was cause by two mutations in glucose-6-phosphate dehydrogenase (
3.4 The genes that influence medications for acute gout
Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to quickly relieve the pain and swelling of an acute gout episode and can shorten the attack, but NSAIDs may not be suitable for patients with other comorbidities. A proton pump inhibitor should be offered to people at high risk of NSAID-related gastrointestinal complications [85]. Cyclooxygenase-2 (COX-2) is encoded by prostaglandin-endoperoxide synthase 2 (
The potential pharmacological loci for hyperuricaemia and gout were listed in Table 2.
Loci | Chr | Affecting drug | Uric acid path or gout | Key reference | Pharmaceutical effects |
---|---|---|---|---|---|
6p21 | Allopurinol | Uric acid formation, XO inhibitors | [58] | Adverse effect: drug allergic response | |
6p21 | Allopurinol | Uric acid formation, XO inhibitors | [69] | Adverse effect: inducing hematologic malignancy | |
6p21 | Allopurinol | Uric acid formation, XO inhibitors | [69] | Adverse effect: inducing hematologic malignancy | |
Allopurinol | Uric acid formation, XO inhibitors | [70] | Dose and change in serum urate | ||
Allopurinol | Uric acid formation, XO inhibitors | [50] | Reducing dose response | ||
10q23 | Benzbromarone | Uric acid renal excretion | [71] | Reducing drug clearance and hepatic failure | |
Xq28 | Pelgoticase | Uric acid transforming | [83] | Adverse effects: inducing haemolytic anaemia | |
1q31 | NSAID | Acute gout | [86] | Drug response: Aspirin insensitivity | |
5q11 | NSAID | Acute gout | [88] | Drug response: Aspirin insensitivity | |
7q21 | Colchicine | Acute gout | [90] | Drug response |
4. Epigenetic factors and environmental factors for hyperuricaemia and gout
4.1 DNA methylation
GAWs have identified dozens of loci associated with gout, but for most cases, the risk genes and the underlying molecular mechanisms contributing to these associations are unknown. Epigenetics studies investigate heritable change in gene expression caused by molecules that bind to DNA without change the actual DNA sequence. There are three main classes of epigenetic marks as DNA methylation, modification of histone tails and noncoding RNAs. DNA methylation has been found to associate with many complicated diseases. Hypomethylation at the promoter region of the gout-risk gene
4.2 miRNA
MicroRNAs (miRNAs) are non-coding RNA species that are highly evolutionarily conserved in human. Up to 5000 miRNAs were identified in human cells. miRNAs are key regulators of the expression of numerous targets at the post-transcriptional level [95]. They are implicated in various cell processes including cell differentiation, metabolism, and inflammation. Experimental evidence suggests that metabolic deregulation is a commonality between these different pathological entities, and that miRNAs are key players in the modulation of metabolic routes [96]. Recent studies have shown that interleukin (IL)-1β is a key inflammatory mediator in acute gouty arthritis (GA), and its level is regulated by miRNAs. Five miRNAs (hsa-miR-30c-1-3p, hsa-miR-488-3p, hsa-miR-550a-3p, hsa-miR-663a, and hsa-miR-920) were found to possibly target IL-1β. MSU crystals in GA patient could inhibit expression of miR-488 and miR-920 and the two miRNAs could directly target the 3′-UTR of IL-1β [97]. MSU crystal-induced IL-1 secretion can be targeted for the new therapeutic strategies in the treatment of acute gout [98].
4.3 Exosomes
Exosomes are best defined as extracellular vesicles that are released from cells upon fusion of an intermediate endocytic compartment, the multivesicular body (MVB), with the plasma membrane. Exosomes can be produced by most cell types. Exosomes derived from immunosuppressive dendritic cells (DCs) have been found to confer potent and lasting immunosuppressive effects, similar to their parental DC [99, 100]. Their protein content largely reflects that of the parental cells and is enriched in certain molecules including adhesion molecules, membrane trafficking molecules, cytoskeleton molecules, heat-shock proteins, cytoplasmic enzymes, signal transduction proteins, and cell-specific antigens [101, 102, 103]. Exosomes also contain functional mRNA and microRNAs molecules [104]. Certain types of exosomes have been shown to confer immunosuppressive effects in different disease models including RA and gout. It is likely that exosomes represent a novel effective and safe therapeutic approach for treating arthritis [105]. In a neutrophil-derived microvesicles (PMN-Ecto) studied for a murine model of MSU-induced. PMN-Ecto from joint aspirates of patients with gouty arthritis had similar anti-inflammatory properties [106]. In a study for investigating the effects of MSU on synovial fibroblasts to elucidate the process of MSU-mediated synovial inflammation, human synovial fibroblasts were stimulated with MSU in the presence or absence of serum amyloid A [107]. MSU stimulation resulted in the activation of caspase-1 and production of active IL-1β and IL-1α. These findings provide insight into the molecular processes underlying the synovial inflammatory condition of gout [108].
4.4 Microbiota
The human microbiota consists of the 10–100 trillion symbiotic microbial cells in each person including primarily bacteria in the gut. The human microbiome refers the genes these cells harbor [109]. Microbiota was found to play the important roles for the development of personalized medicine. Whole microbial genome sequencing revealed the extraordinary diversity of microorganisms and their vast genetic and metabolic repertoire [110]. In a cohort study with 33 healthy and 35 gout patients, the intestinal microbiota of patients were highly distinct from healthy individuals in both organismal and functional structures. In gout, there were more Bacteroides caccae and Bacteroides xylanisolvens, there were less or absence Faecalibacterium prausnitzii and Bifidobacterium pseudocatenulatum. Intestinal microbiota of gout is more similar to those of type-2 diabetes than to liver cirrhosis, whereas depletion of Faecalibacterium prausnitzii and reduced butyrate biosynthesis were shared in each of the metabolic syndromes [111].
4.5 Metabolites
Metabolites are the intermediate products of metabolic reactions catalyzed by various enzymes that naturally occur within cells and play vital roles in cell growth, differentials and proliferations. In a study analyzing 355 metabolites in 1764 individuals and constructed a metabolite network around serum urate. The effect of sex and urate lowering medication on all 38 metabolites assigned to the three network. The three network included the well-known pathway of purine metabolism, as well as several dipeptides, a group of essential amino acids, and a group of steroids. Of the 38 assigned metabolites, 25 showed strong differences between sexes. The findings highlight pathways that are important in the regulation of serum urate and suggest that dipeptides, amino acids, and steroid hormones are playing a role in its regulation [112].
4.6 The relationships between genetic factors and environmental factors for hyperuricaemia and gout
The genetic influence and environmental factors should be considered equally importance for hyperuricaemia and gout. Determining the extent to which environmental versus genetic factors are responsible for particular phenotypes such as gout or hyperuricaemia is a central question in gout or hyperuricaemia research. Elucidating associations between genotype and phenotype has been a central goal in human health research for some time [113]. The complications in cellular process of hyperuricaemia mean many genes may have interactions with each other for the regulation of the products of uric acid in cells; they may not be identifiable even in approaches with GWASs. The environmental factors can also interact with genetic factors that make the process even more complicated. For clinicians, it is important to understand the etiological causes for complicate diseases and always consider both genetic and environmental factors play important roles in hyperuricaemia and gout.
5. Personalized medicine for ULT and gout
The personalized medicine aims to provide the right treatments in the right time for individual patients with hyperuricaemia and gout. The genetics variants that underlie diseases and influence the medications will play great roles for the management of gout in near future. Therapeutics best suited for an individual’s genotype genetic origins of disease and drug response for LUT including adverse events. Precision medicine has made great progress due to the rapid development of pharmacogenomics research. Clinically, patients’ age, race, and gender are all associated with epigenetic status [114]. Together with the developments of miRNA profiling, epigenetics investigation, metabolites screening and microbiota research it will make personalized medicine possible for gout management.
5.1 Intrinsic factor assessment
For intrinsic factor assessment, patients age, gender, geographic residence, social economic status and other conditions for heart, kidney and liver, allergic status are all important factors to be considered for clinical managements of hyperuricaemia and gout. These factors should be considered to decide the medication choice, the dosage of medications. The decision should be managed to benefit for individual patients with hyperuricaemia and gout.
5.2 The life style assessment
In clinical practice, lifestyle changes are frequently urged for prevention and management of gout [115]. It is advocated to promote healthy eating and drinking for gout patients, such as reducing intake of beer, sugar-sweetened drinks, and purine-rich foods such as meat, offal and seafood. Increased intake of cherries, omega-3 fatty acids, low fat milk and coffee are also advocated [116]. There was evidence for a non-additive interaction of sugar-sweetened drinks consumption with a urate-associated variant of
5.3 The genetic inheritance and epigenetic affect
The studies of genetic inheritance of gout and hyperuricaemia provide a lot useful information. More than 40 genetic loci only can explain less than 10% of high uric acid levels in serum. We also need to consider the genetic background in different ethnical populations. The further efforts will be to understand the functional roles of the novel genes in the pathways of uric acid metabolism. The investigation can identify the new pharmacological target for gout and bring new therapeutic tools from preventing to treating gout patients [55]. miRNAs and epigenetic screening are also helpful to identify the regulator elements for potential gout gene’s expression.
5.4 Microbiome and metabolite factors
Microbiome and metabolite factors are also need to be considered when managing gout patients clinically. At the present times, not enough reports have been published in the field. It can be useful to exam the intestinal levels of Bacteroides caccae, Bacteroides xylanisolvens, Faecalibacterium prausnitzii, Bifidobacterium pseudocatenulatum in gout patients. Screening key metabolites in serum may also helpful in clinical management of gout and hyperuricaemia patients.
5.5 The pharmacogenetic consideration
Total about 10 genetic loci were identified to influence the medications of gout. These loci can be used to predict the drug’s response and adverse effects. For treating acute gout with NSAIDs
The personalized factors have been summarized in Table 3.
Assessments | Considering factors |
---|---|
Intrinsic factor assessment | Age; gender; geographic residence; other conditions for heart, kidney and liver, allergic history etc |
Life style assessment | Diet and activities; the in-taking of food with rich purines—such as meat, poultry, and seafood; alcohol consumption etc |
Genetic inheritance | Suspected gene screening such as |
Epigenetic factors | miRNA; methylation screening for suspected loci; histone methylation etc |
Environmental factors | Microbiota; metabolites screening |
Pharmacogenetics consideration | For NSAIDs, screening |
6. Summary
Personalized medicine has made great progress due to the development of the technology in genetic and genomic approaches. The ultimate goal for personal medicine of gout management is to provide the best medical advice and best medical treatment according to conditions of individual patients. The patient conditions including age, gender, ethnic group, life styles, genetic variations for common gout associated genes are important factors for clinical managements. Most importantly the pharmacogenetic loci for the common medications for gout provide useful guidance for individual patients. The developments of miRNA profiling, epigenetics investigation, metabolites screening and microbiota research will make personalized medicine even more in great details for management. It will revolutionize medical cares for gout patients in near future.
Acknowledgments
Dewen Yan is supported by National Natural Science Foundation of China. Youming Zhang is supported by Asmarley Foundation in the UK.
Abbreviations
ABC | ATP-binding cassette |
ABCB1 | ATP binding cassette subfamily B member 1 |
ABCG2 | ATP binding cassette, subfamily G, member 2 |
ADRB3 | adrenergic receptor beta-3 |
AHS | allopurinol hypersensitivity syndrome |
BBR | benzbromarone |
CCA4 | congenital cerulean cataract 4 |
COX2 | cyclooxygenase-2 |
CNV | copy number variant |
DCs | dendritic cells |
DNMTs | DNA methyltransferases |
EC | endothelial cell |
GA | gouty arthritis |
GCKR | glucokinase regulator |
GWAS | genome-wide association study |
G6PD | glucose-6-phosphate dehydrogenase |
HDL | high-density lipoproteins |
hnRNPs | heteregeneous ribonucleoproteins |
HNF4G | hepatocyte nuclear factor 4 gamma |
HNF4A | hepatocyte nuclear factor 4 alpha |
HLA | human leukocyte antigen |
INDEL | insertion and deletion of short segments of DNA |
ITGA2 | integrin subunit alpha 2 |
LRP2 | lipoprotein receptor-related protein 2 |
miRNA | micro RNA |
MODY | maturity-onset diabetes of the young |
MSU | monosodium urate |
MVB | multivesicular body |
NSAIDs | nonsteroid anti-inflammatory drugs |
PAK | p21-activated protein kinase |
PTGS2 | prostaglandin-endoperoxide synthase 2 |
SAA | serum amyloid A |
SCAR | serious cutaneous adverse reactions |
SNPs | single nuclear polymorphisms |
siRNA | small interfering RNA |
SJS | Stevens-Johnson syndrome |
SU | serum urate |
SUA | serum uric acid |
TEN | toxic epidermal necrolysis |
TGF | transforming growth factor |
ULT | urate-lowering therapy |
UMOD | uromodolin |
Vmax | maximum velocity |
VNTRs | variable number of tandem repeats |
XOI | xanthine oxidase inhibitor |
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