Publications by authors named "Tony R Merriman"

203 Publications

Longitudinal development of incident gout from low-normal baseline serum urate concentrations: individual participant data analysis.

BMC Rheumatol 2021 Aug 28;5(1):33. Epub 2021 Aug 28.

Department of Medicine, University of Auckland, Auckland, New Zealand.

Introduction: Elevated serum urate (SU) concentration is the central risk factor for the development of gout. The aim of this study was to examine the incidence of gout in people with low and normal SU levels (< 7.00 mg/dL).

Methods: Longitudinal cohort data from the Atherosclerosis Risk in Communities Study (ARIC), Coronary Artery Risk Development in Young Adults Study (CARDIA), and both the Original and Offspring cohorts of the Framingham Heart Study (FHS) were used to determine incident gout by baseline SU over 3, 5, 10, 12 and 15 year periods. A Cox proportional hazards model with covariables of age, gender, ethnicity, and cohort was calculated to report the hazard ratios (HR) for incident gout.

Results: The incidence of gout at 15 years for a baseline SU < 4.00 mg/dL was 0.59%, 4.00-4.49 mg/dL was 1.28%, 4.50-4.99 mg/dL was 0.86%, 5.00-5.49 mg/dL was 0.94%, 5.50-5.99 mg/dL was 1.52%, 6.00-6.49 mg/dL was 2.91%, 6.50-6.99 mg/dL was 3.2%, and > 7.00 mg/dL was 12.2%. In an adjusted Cox proportional hazards model, compared to the referent baseline SU < 4.00 mg/dL, there was a non-significant increase in incident gout for baseline SU bands between 4.00-5.49 mg/dL, whereas incident gout was significantly increased for SU 5.50-5.99 mg/dL (HR 2.60), 6.00-6.49 mg/dL (HR 3.70), 6.50-6.99 mg/dL (HR 5.24) and > 7.00 mg/dL (HR 18.62).

Conclusion: A baseline SU of 5.50 mg/dL or more is a risk factor for development of gout over 15 years. However, incident gout does occur over time in a small proportion of people with lower baseline SU levels.
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http://dx.doi.org/10.1186/s41927-021-00204-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399746PMC
August 2021

The CREBRF diabetes-protective rs373863828-A allele is associated with enhanced early insulin release in men of Māori and Pacific ancestry.

Diabetologia 2021 Aug 21. Epub 2021 Aug 21.

Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland, New Zealand.

Aims/hypothesis: The minor A allele of rs373863828 (CREBRF p.Arg457Gln) is associated with increased BMI, but reduced risk of type 2 and gestational diabetes in Polynesian (Pacific peoples and Aotearoa New Zealand Māori) populations. This study investigates the effect of the A allele on insulin release and sensitivity in overweight/obese men without diabetes.

Methods: A mixed meal tolerance test was completed by 172 men (56 with the A allele) of Māori or Pacific ancestry, and 44 (24 with the A allele) had a frequently sampled IVGTT and hyperinsulinaemic-euglycaemic clamp. Mixed linear models with covariates age, ancestry and BMI were used to analyse the association between the A allele of rs373863828 and markers of insulin release and blood glucose regulation.

Results: The A allele of rs373863828 is associated with a greater increase in plasma insulin 30 min following a meal challenge without affecting the elevation in plasma glucose or incretins glucagon-like polypeptide-1 or gastric inhibitory polypeptide. Consistent with this point, following an i.v. infusion of a glucose bolus, participants with an A allele had higher early (p < 0.05 at 2 and 4 min) plasma insulin and C-peptide concentrations for a similar elevation in blood glucose as those homozygous for the major (G) allele. Despite increased plasma insulin, rs373863828 genotype was not associated with a significant difference (p > 0.05) in insulin sensitivity index or glucose disposal during hyperinsulinaemic-euglycaemic clamp.

Conclusions/interpretation: rs373863828-A allele associates with increased glucose-stimulated insulin release without affecting insulin sensitivity, suggesting that CREBRF p.Arg457Gln may increase insulin release to reduce the risk of type 2 diabetes.
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http://dx.doi.org/10.1007/s00125-021-05552-xDOI Listing
August 2021

Genetic and Physiological Effects of Insulin on Human Urate Homeostasis.

Front Physiol 2021 2;12:713710. Epub 2021 Aug 2.

Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

Insulin and hyperinsulinemia reduce renal fractional excretion of urate (FeU) and play a key role in the genesis of hyperuricemia and gout, via uncharacterized mechanisms. To explore this association further we studied the effects of genetic variation in insulin-associated pathways on serum urate (SU) levels and the physiological effects of insulin on urate transporters. We found that urate-associated variants in the human insulin (INS), insulin receptor (INSR), and insulin receptor substrate-1 (IRS1) loci associate with the expression of the insulin-like growth factor 2, IRS1, INSR, and ZNF358 genes; additionally, we found genetic interaction between and the three loci, most evident in women. We also found that insulin stimulates the expression of GLUT9 and increases [C]-urate uptake in human proximal tubular cells (PTC-05) and HEK293T cells, transport activity that was effectively abrogated by uricosurics or inhibitors of protein tyrosine kinase (PTK), PI3 kinase, MEK/ERK, or p38 MAPK. Heterologous expression of individual urate transporters in oocytes revealed that the [C]-urate transport activities of GLUT9a, GLUT9b, OAT10, OAT3, OAT1, NPT1 and ABCG2 are directly activated by insulin signaling, through PI3 kinase (PI3K)/Akt, MEK/ERK and/or p38 MAPK. Given that the high-capacity urate transporter GLUT9a is the exclusive basolateral exit pathway for reabsorbed urate from the renal proximal tubule into the blood, that insulin stimulates both GLUT9 expression and urate transport activity more than other urate transporters, and that shows genetic interaction with urate-associated insulin-signaling loci, we postulate that the anti-uricosuric effect of insulin is primarily due to the enhanced expression and activation of GLUT9.
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http://dx.doi.org/10.3389/fphys.2021.713710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366499PMC
August 2021

Higher Serum Urate Levels Are Associated With an Increased Risk for Sudden Cardiac Death.

J Rheumatol 2021 Jun 15. Epub 2021 Jun 15.

This research project is supported by cooperative agreement U01 NS041588 co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Service. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NINDS or the NIA. Representatives of the NINDS were involved in the review of the manuscript but were not directly involved in the collection, management, analysis or interpretation of the data. Additional funding was provided by grants R01 HL080477 and K24 HL111154 from the National Heart, Lung, and Blood Institute (NHLBI) and grant P50AR060772 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Representatives from the NHLBI or the NIAMS did not have any role in the design and conduct of the study, the collection, management, analysis, and interpretation of the data, or the preparation or approval of the manuscript. L.D. Colantonio, MD, PhD, N.S. Chaudhary, MBBS, MPH, N.D. Armstrong, PhD, P. Muntner, PhD, M.R. Irvin, PhD, Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA; R.J. Reynolds, PhD, K.G. Saag, MD, MSc, Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA; T.R. Merriman, PhD, Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA, and Department of Biochemistry, University of Otago, Dunedin, New Zealand; A. Gaffo, MD, MSPH, Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, and Birmingham Veterans Affairs Medical Center, Birmingham, Alabama, USA; J.A. Singh, MD, MPH, Department of Epidemiology, University of Alabama at Birmingham, Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, and Birmingham Veterans Affairs Medical Center, Birmingham, Alabama, USA; T.B. Plante, MD, MHS, Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, Vermont, USA; E.Z. Soliman, MD, MSc, MS, Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine, Winston-Salem, North Carolina, USA; J.R. Curtis, MD, MS, MPH, Department of Epidemiology, University of Alabama at Birmingham, and Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA; S.L. Bridges Jr., MD, PhD, Department of Medicine, Division of Rheumatology, Hospital for Special Surgery, and Joan and Sanford I. Weill Department of Medicine, Division of Rheumatology, Weill Cornell Medicine, New York, New York, USA; L. Lang, PhD, Department of Medicine, University of Colorado Denver, Denver, Colorado, USA; G. Howard, DrPH, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, USA; M.M. Safford, MD, Department of Medicine, Weill Cornell Medical College, New York, New York, USA. LDC receives research support from Amgen. AG receives research support from Amgen and honoraria from UpToDate. JAS receives consultant fees from Crealta/Horizon, Medisys, Fidia, UBM LLC, Medscape, WebMD, Clinical Care Options, Clearview Healthcare Partners, Putnam Associates, Spherix, Trio Health, Focus Forward, Navigant Consulting, Practice Point Communications, Simply Speaking, the National Institutes of Health, and the American College of Rheumatology; is a member of the Executive Committee of Outcome Measures in Rheumatology (OMERACT), and is a stockholder of Amarin Pharmaceuticals and Viking Therapeutics. MMS receives research support from Amgen. PM receives research support from Amgen and serves as a consultant for Amgen. KGS receives research support from Horizon, Takeda, Sobi, and Shanton; and serves as a consultant/advisor for Arthrosi, Atom Bioscience, LG Pharma, Mallinkrodt, Sobi, Horizon, and Takeda. The remaining authors have no conflicts of interest relevant to this article. Address correspondence to Dr. L.D. Colantonio, 1720 2nd Ave South, RPHB 527C, Birmingham, AL 35294-0013, USA. Email: Accepted for publication June 2, 2021.

Objective: To determine the association of serum urate (SU) levels with sudden cardiac death and incident coronary heart disease (CHD), separately, among adults without a history of CHD.

Methods: We conducted a case-cohort analysis of Black and White participants aged ≥ 45 years enrolled in the REason for Geographic And Racial Differences in Stroke (REGARDS) study without a history of CHD at baseline between 2003 and 2007. Participants were followed for sudden cardiac death or incident CHD (i.e., myocardial infarction [MI] or death from CHD excluding sudden cardiac death) through December 31, 2013. Baseline SU was measured in a random sample of participants (n = 840) and among participants who experienced sudden cardiac death (n = 235) or incident CHD (n = 851) during follow-up.

Results: Participants with higher SU levels were older and more likely to be male or Black. The crude HR (95% CI) per 1 mg/dL higher SU level was 1.26 (1.14-1.40) for sudden cardiac death and 1.17 (1.09-1.26) for incident CHD. After adjustment for age, sex, race, and cardiovascular risk factors, the HR (95% CI) per 1 mg/dL higher SU level was 1.19 (1.03-1.37) for sudden cardiac death and 1.05 (0.96-1.15) for incident CHD. HRs for sudden cardiac death were numerically higher among participants aged 45-64 vs ≥ 65 years, without vs with diabetes, and among those of White vs Black race, although values for effect modification were all ≥ 0.05.

Conclusion: Higher SU levels were associated with an increased risk for sudden cardiac death but not with incident CHD.
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http://dx.doi.org/10.3899/jrheum.210139DOI Listing
June 2021

Factors associated with orthodontic pain.

J Oral Rehabil 2021 Oct 1;48(10):1135-1143. Epub 2021 Aug 1.

Department of Neuroscience, Reproductive Science and Oral Science, University of Naples Federico II, Naples, Italy.

Background: Pain experienced at teeth during orthodontic treatment varies largely over time, with the reasons for its interindividual variability being largely unknown: age, sex, clinical activations, psychosocial factors and genetic polymorphisms of candidate genes are putative factors that may account to explain this variability. We aimed to investigate the effect of clinical, demographic, psychological and genetic factors on pain levels experienced during fixed orthodontic treatment.

Methods: A convenience sample of 183 patients undergoing full-fixed orthodontic treatment were recruited. Participant's pain levels were assessed seven times over a three-day period via a smartphone app. Clinical, demographic and psychological data were collected via questionnaires. This included the Pain Catastrophising Scale (Child version), the Corah Dental Anxiety Scale and the State and Trait Anxiety Inventory. Participants provided a DNA sample either in the form of blood or saliva, which were used for genotyping COMT gene rs6269, rs4680, rs4646310, NR3C1 gene rs2963155 and the HTR2A gene rs9316233.

Results: Bond ups had the greatest influence on perceived levels of pain experienced on teeth during orthodontic treatment, accounting for over 20% of total variance in pain response. High-pain responders had higher scores on pain catastrophising (magnification subscale). Self-reported pain during fixed orthodontic treatment was not influenced by sex, age, time into treatment, anxiety, nor by polymorphisms of COMT, HTR2A or NR3C1 genes.

Conclusions: Pain on teeth resulting from orthodontic fixed appliances is stronger during bonds-up and in patients with high catastrophising scores. Demographics, type of clinical activations and the genetic polymorphisms investigated in this research had little or no impact on perceived pain levels.
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http://dx.doi.org/10.1111/joor.13227DOI Listing
October 2021

Aotearoa New Zealand Māori and Pacific Population-amplified Gout Risk Variants: Is a Separate Risk Gene at the Locus.

J Rheumatol 2021 Jul 1. Epub 2021 Jul 1.

This research was supported by the Health Research Council of New Zealand (Grant 14/527). 1A. Ji, PhD, Research Fellow, C. Li, PhD, Professor, Shandong Provincial Key Laboratory of Metabolic Diseases, the Affiliated Hospital of Qingdao University, Qingdao, China; 2A. Shaukat, MSc, Doctoral Student, M. Bixley, MSc, Assistant Research Fellow, M. Cadzow, PhD, Research Fellow, R.K. Topless, BSc, Assistant Research Fellow, T.J. Major, PhD, Research Fellow, A. Phipps-Green, MSc, Assistant Research Fellow, M.E. Merriman, BSc, Research Assistant, Department of Biochemistry, University of Otago, Dunedin, New Zealand; 3R. Takei, MSc, Scientist, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, USA; 4J. Harré Hindmarsh, PhD, Research Coordinator, Ngāti Porou Hauora Charitable Trust, Te Puia Springs, Tairāwhiti East Coast, New Zealand; 5L.K. Stamp, PhD, Professor, Department of Medicine, University of Otago, Christchurch, New Zealand; 6N. Dalbeth, MD, Professor, Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand; 7T.R. Merriman, BSc, Research Assistant, Shandong Provincial Key Laboratory of Metabolic Diseases, the Affiliated Hospital of Qingdao University, Qingdao, China, Department of Biochemistry, University of Otago, Dunedin, New Zealand, and Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, USA. A. Ji and A. Shaukat contributed equally to this work. The authors declare no conflict of interest relevant to this article. Address correspondence to T.R. Merriman, School of Biomedical Sciences, Department of Biochemistry, 710 Cumberland Street, Dunedin, Otago 9054, New Zealand. Email: Accepted for publication June 11, 2021.

Objective: The Māori and Pacific (Polynesian) population of Aotearoa New Zealand has a high prevalence of gout. Our aim was to identify potentially functional missense genetic variants in candidate inflammatory genes amplified in frequency that may underlie the increased prevalence of gout in Polynesian populations.

Methods: A list of 712 inflammatory disease-related genes was generated. An in silico targeted exome set was extracted from whole genome sequencing data in people with gout of various ancestral groups (Polynesian, European, East Asian; n = 55, 780, 135, respectively) to identify Polynesian-amplified common missense variants (minor allele frequency > 0.05). Candidate functional variants were tested for association with gout by multivariable-adjusted regression analysis in 2528 individuals of Polynesian ancestry.

Results: We identified 26 variants common in the Polynesian population and uncommon in the European and East Asian populations. Three of the 26 population-amplified variants were nominally associated with the risk of gout (1635712 [], OR = 1.28, = 0.03; [], OR = 1.37, = 0.002; [fibrinogen A alpha chain ()], OR = 1.34, = 0.02). The variant, within the established gout locus, was genetically independent of the association signal at SLC2A9.

Conclusion: We provide nominal evidence for the existence of population-amplified genetic variants conferring risk of gout in Polynesian populations. Polymorphisms in have previously been associated with gout in other populations, supporting our evidence for the association of this gene with gout.
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http://dx.doi.org/10.3899/jrheum.201684DOI Listing
July 2021

Mapping pleiotropic loci using a fast-sequential testing algorithm.

Eur J Hum Genet 2021 Jun 18. Epub 2021 Jun 18.

Department of Epidemiology & Biostatistics, IQ - Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.

Pleiotropy (i.e., genes with effects on multiple traits) leads to genetic correlations between traits and contributes to the development of many syndromes. Identifying variants with pleiotropic effects on multiple health-related traits can improve the biological understanding of gene action and disease etiology, and can help to advance disease-risk prediction. Sequential testing is a powerful approach for mapping genes with pleiotropic effects. However, the existing methods and the available software do not scale to analyses involving millions of SNPs and large datasets. This has limited the adoption of sequential testing for pleiotropy mapping at large scale. In this study, we present a sequential test and software that can be used to test pleiotropy in large systems of traits with biobank-sized data. Using simulations, we show that the methods implemented in the software are powerful and have adequate type-I error rate control. To demonstrate the use of the methods and software, we present a whole-genome scan in search of loci with pleiotropic effects on seven traits related to metabolic syndrome (MetS) using UK-Biobank data (n~300 K distantly related white European participants). We found abundant pleiotropy and report 170, 44, and 18 genomic regions harboring SNPs with pleiotropic effects in at least two, three, and four of the seven traits, respectively. We validate our results using previous studies documented in the GWAS-catalog and using data from GTEx. Our results confirm previously reported loci and lead to several novel discoveries that link MetS-related traits through plausible biological pathways.
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http://dx.doi.org/10.1038/s41431-021-00911-zDOI Listing
June 2021

Assessing the Causal Relationships between Insulin Resistance and Hyperuricemia and Gout Using Bidirectional Mendelian Randomization.

Arthritis Rheumatol 2021 May 13. Epub 2021 May 13.

Clinical Epidemiology Program, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital Boston MA, USA.

Objective: Hyperuricemia is closely associated with insulin resistance syndrome (and its many cardiometabolic sequalae); however, whether they are causally related has long been debated. We used bidirectional Mendelian randomization (MR) to investigate the potential causal nature and direction between insulin resistance and hyperuricemia, along with gout.

Methods: We used genome-wide association data (N=288,649 for SU, N=763,813 for gout, N=153,525 for fasting insulin) to select genetic instruments for two-sample MR analyses, using multiple MR methods to address potential pleiotropic associations. We then used individual-level, electronic-medical-record-linked data from UK Biobank (N=360,453 persons of European ancestry) to replicate our analyses via single-sample MR.

Results: Genetically determined SU, whether inferred from a polygenic score or strong individual loci, was not associated with fasting insulin concentrations. In contrast, genetically determined fasting insulin concentrations were positively associated with SU (0.37 mg/dL per log-unit increase in fasting insulin [95% CI, 0.15 to 0.58], P=0.001). This persisted in outlier-corrected (0.56 mg/dL [0.45 to 0.67]) and multivariable MR analyses conditioned on BMI (0.69 mg/dL [0.53 to 0.85]); all P<0.001. Polygenic scores for fasting insulin were also positively associated with SU among individuals in UK Biobank (P<0.001). Findings for gout were consistent with those for SU bidirectionally.

Conclusions: These findings provide evidence to clarify core questions about the close association between hyperuricemia and insulin resistance syndrome: hyperinsulinemia leads to hyperuricemia, but not the other way around. Reducing insulin resistance could lower SU and gout risk, whereas lowering SU (e.g., allopurinol) is unlikely to mitigate insulin resistance and its cardiovascular-metabolic sequalae.
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http://dx.doi.org/10.1002/art.41779DOI Listing
May 2021

Association of low-level environmental exposure to cadmium and lead with gout flare using a cohort study design.

Chemosphere 2021 Oct 27;280:130648. Epub 2021 Apr 27.

Institute of Metabolic Diseases, Qingdao University, Qingdao, 266071, China; Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University, China; Medical Research Center, The Affiliated Hospital of Qingdao University, China; Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, China. Electronic address:

Cadmium (Cd) and lead (Pb) are toxic heavy metals with endocrine-disrupting properties. We investigated the associations of low-level environmental exposure to Cd/Pb and gout status (intercritical gout, gout flare and combined gout) in a cohort study. We measured by ICP-MS the levels of Cd and Pb in blood (Cd-B and Pb-B) and urine (Cd-U and Pb-U) from 408 participants with blood and 346 participants with urine samples recruited from a hospital gout clinic. The median levels of Cd-B and Pb-B (in μg/L) in the gout flare group were 0.87 (range 0.41-2.49) and 31.54 (25.38-41.46), respectively, and the median levels of Cd-U and Pb-U in the gout flare group were 1.05 (0.69-1.91) and 3.86 (3.49-4.44), respectively. These medians were significantly higher than those in the control or intercritical groups (P < 0.05). For Cd-B in tertile 2 (T2) and Cd-U in tertile 3, Cd levels were significantly associated with gout flare status compared to the reference tertile 1 (OR = 4.3, P = 0.041 and OR = 25.1, P = 0.002, respectively) after adjustment under Model 3. For Pb-U, the risk of gout flare status was significantly higher in T2 (OR = 51.0, P = 0.002) compared to the T1 under Model 3. Our results show that median levels of Cd-B, Pb-B, Cd-U and Pb-U in the gout flare group were significantly higher than participants without gout or with gout but in the intercritical period. We provide evidence that the risk of gout flare status is associated with increased Cd levels, and that blood and urine levels of Cd are a risk factor for gout flare status.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130648DOI Listing
October 2021

Gout, Rheumatoid Arthritis, and the Risk of Death Related to Coronavirus Disease 2019: An Analysis of the UK Biobank.

ACR Open Rheumatol 2021 May 15;3(5):333-340. Epub 2021 Apr 15.

University of Otago, Dunedin, New Zealand, and University of Alabama at Birmingham.

Objectives: The objectives for this study were to assess whether gout and/or rheumatoid arthritis (RA) are risk factors for coronavirus disease 2019 (COVID-19) diagnosis and to assess whether gout and/or RA are risk factors for death from COVID-19.

Methods: We used data from the UK Biobank. Multivariable-adjusted logistic regression was employed in the following analyses: analysis A, to test for association between gout and/or RA and COVID-19 diagnosis (n = 473,139); analysis B, to test for association between gout and/or RA and death from COVID-19 in a case-control cohort of people who died of or survived COVID-19 (n = 2059); analysis C, to test for association between gout and/or RA and death from COVID-19 in the entire UK Biobank cohort (n = 473,139).

Results: RA, but not gout, was associated with COVID-19 diagnosis in analysis A. Neither RA nor gout was associated with risk of death in the group diagnosed with COVID-19 in analysis B. However, RA was associated with risk of death related to COVID-19 by using the UK Biobank cohort in analysis C, independent of comorbidities and other measured risk factors (odds ratio [OR] 1.9; 95% confidence interval CI 1.2-3.0). Gout was not associated with death related to COVID-19 in the same UK Biobank analysis (OR 1.2; 95% CI 0.8-1.7).

Conclusion: RA is a risk factor for death from COVID-19 by using the UK Biobank cohort. These findings require replication in larger data sets that also allow for inclusion of a wider range of factors.
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http://dx.doi.org/10.1002/acr2.11252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126763PMC
May 2021

Variable expression quantitative trait loci analysis of breast cancer risk variants.

Sci Rep 2021 Mar 30;11(1):7192. Epub 2021 Mar 30.

Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.

Genome wide association studies (GWAS) have identified more than 180 variants associated with breast cancer risk, however the underlying functional mechanisms and biological pathways which confer disease susceptibility remain largely unknown. As gene expression traits are under genetic regulation we hypothesise that differences in gene expression variability may identify causal breast cancer susceptibility genes. We performed variable expression quantitative trait loci (veQTL) analysis using tissue-specific expression data from the Genotype-Tissue Expression (GTEx) Common Fund Project. veQTL analysis identified 70 associations (p < 5 × 10) consisting of 60 genes and 27 breast cancer risk variants, including 55 veQTL that were observed in breast tissue only. Pathway analysis of genes associated with breast-specific veQTL revealed an enrichment of four genes (CYP11B1, CYP17A1 HSD3B2 and STAR) involved in the C21-steroidal biosynthesis pathway that converts cholesterol to breast-related hormones (e.g. oestrogen). Each of these four genes were significantly more variable in individuals homozygous for rs11075995 (A/A) breast cancer risk allele located in the FTO gene, which encodes an RNA demethylase. The A/A allele was also found associated with reduced expression of FTO, suggesting an epi-transcriptomic mechanism may underlie the dysregulation of genes involved in hormonal biosynthesis leading to an increased risk of breast cancer. These findings provide evidence that genetic variants govern high levels of expression variance in breast tissue, thus building a more comprehensive insight into the underlying biology of breast cancer risk loci.
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http://dx.doi.org/10.1038/s41598-021-86690-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009949PMC
March 2021

Serum Metabolomics Identifies Dysregulated Pathways and Potential Metabolic Biomarkers for Hyperuricemia and Gout.

Arthritis Rheumatol 2021 09 6;73(9):1738-1748. Epub 2021 Aug 6.

ShanghaiTech University, Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism, and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China, and University of Chinese Academy of Sciences, Beijing, China.

Objective: To systematically profile metabolic alterations and dysregulated metabolic pathways in hyperuricemia and gout, and to identify potential metabolite biomarkers to discriminate gout from asymptomatic hyperuricemia.

Methods: Serum samples from 330 participants, including 109 with gout, 102 with asymptomatic hyperuricemia, and 119 normouricemic controls, were analyzed by high-resolution mass spectrometry-based metabolomics. Multivariate principal components analysis and orthogonal partial least squares discriminant analysis were performed to explore differential metabolites and pathways. A multivariate methods with Unbiased Variable selection in R (MUVR) algorithm was performed to identify potential biomarkers and build multivariate diagnostic models using 3 machine learning algorithms: random forest, support vector machine, and logistic regression.

Results: Univariate analysis demonstrated that there was a greater difference between the metabolic profiles of patients with gout and normouricemic controls than between the metabolic profiles of individuals with hyperuricemia and normouricemic controls, while gout and hyperuricemia showed clear metabolomic differences. Pathway enrichment analysis found diverse significantly dysregulated pathways in individuals with hyperuricemia and patients with gout compared to normouricemic controls, among which arginine metabolism appeared to play a critical role. The multivariate diagnostic model using MUVR found 13 metabolites as potential biomarkers to differentiate hyperuricemia and gout from normouricemia. Two-thirds of the samples were randomly selected as a training set, and the remainder were used as a validation set. Receiver operating characteristic analysis of 7 metabolites yielded an area under the curve of 0.83-0.87 in the training set and 0.78-0.84 in the validation set for distinguishing gout from asymptomatic hyperuricemia by 3 machine learning algorithms.

Conclusion: Gout and hyperuricemia have distinct serum metabolomic signatures. This diagnostic model has the potential to improve current gout care through early detection or prediction of progression to gout from hyperuricemia.
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http://dx.doi.org/10.1002/art.41733DOI Listing
September 2021

Effects of Fenofibrate Therapy on Renal Function in Primary Gout Patients.

Rheumatology (Oxford) 2021 Mar 11. Epub 2021 Mar 11.

Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, Department of Endocrinology and Metabolism, the Affiliated Hospital of Qingdao University, Qingdao 266003, China.

Objective: To investigate the incidence and potential risk factors for development of fenofibrate-associated nephrotoxicity in gout patients.

Methods: 983 gout patients with fenofibrate treatment were retrospectively enrolled from the electronic record system who visited the dedicated Gout Clinic at the Affiliated Hospital of Qingdao University between September 2016 and June 2020. Fenofibrate-associated nephrotoxicity was defined as an increase in serum creatinine (SCr) ≥0.3 mg/dL within 6 months of fenofibrate initiation. The change trend of SCr and uric acid levels during treatment period were assessed by generalised additive mixed model (GAMM). Multivariate analysis was performed for risk factors affecting elevated SCr.

Results: 100 (10.2%) patients experienced an increase in SCr ≥0.3 mg/dL within 6 months after fenofibrate initiation. The median (quartile) change of SCr in the whole cohort was 0.11 (0.03-0.20) mg/dL, whereas it was 0.36 (0.33-0.45) mg/dL in the fenofibrate-associated nephrotoxicity group. In a multivariable regression model, chronic kidney disease (CKD) (OR, 2.39, 95% CI,1.48-3.86) and tophus (OR, 2.29, 95% CI, 1.39-3.78) were identified to be risk predictors, independent of measured covariates, of fenofibrate-associated nephrotoxicity. During the treatment period, although SCr temporarily elevated, serum urate and triglyceride concentrations decreased resulted from the interaction analysis of GAMM. Of those with fenofibrate withdrawal records, 65% of patients' SCr was reversible after an average of 49 days off the drug.

Conclusions: This observational study implied that fenofibrate-associated nephrotoxicity occurs frequently in gout patients, especially in patients with tophi or CKD. The potential renal risks of fenofibrate usage in gout need additional focus.
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http://dx.doi.org/10.1093/rheumatology/keab231DOI Listing
March 2021

The Shared Genetic Basis of Hyperuricemia, Gout, and Kidney Function.

Semin Nephrol 2020 Nov;40(6):586-599

Department of Biochemistry, University of Otago, Dunedin, New Zealand; Division of Clinical Immunology and Rheumatology, University of Alabama Birmingham, Birmingham, AL. Electronic address:

Increased urate levels and gout correlate with chronic kidney disease with consensus that the primary driver of this relationship is reduced kidney function. However, a comparison of results of genome-wide association studies in serum urate levels and kidney function indicate a more complex situation. Approximately 20% of loci are shared-comprised of those in which the urate-raising allele associates with reduced kidney function, the vice versa situation, and those in which the signals/alleles are different. Although there is very little known regarding the molecular basis of the shared genetic relationship, it is clear that there is no major role for urate transporters and associated transportasome machinery. Some loci, however, do provide clues. The ATXN2 locus, with a shared signal, is one of only a small number of master regulators of expression by chromatin interaction, regulating expression of genes relevant for cholesterol and blood pressure. This suggests a role for systemic metabolic alteration. At HNF4A there is genetic heterogeneity with different genetic variants conferring risk to hyperuricemia and chronic kidney disease, suggesting different pathways. Interestingly, the shared loci congregate in the olfactory receptor pathway. The genome-wide association studies have generated a range of experimentally testable hypotheses that should provide insights into the shared pathogenesis of hyperuricemia/gout and chronic kidney disease.
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http://dx.doi.org/10.1016/j.semnephrol.2020.12.002DOI Listing
November 2020

The comparative effect of exposure to various risk factors on the risk of hyperuricaemia: diet has a weak causal effect.

Arthritis Res Ther 2021 03 4;23(1):75. Epub 2021 Mar 4.

Department of Biochemistry, University of Otago, Dunedin, New Zealand.

Background: Prevention of hyperuricaemia (HU) is critical to the prevention of gout. Understanding causal relationships and relative contributions of various risk factors to hyperuricemia is therefore important in the prevention of gout. Here, we use attributable fraction to compare the relative contribution of genetic, dietary, urate-lowering therapy (ULT) and other exposures to HU. We use Mendelian randomisation to test for the causality of diet in urate levels.

Methods: Four European-ancestry sample sets, three from the general population (n = 419,060) and one of people with gout (n = 6781) were derived from the Database of Genotypes and Phenotypes (ARIC, FHS, CARDIA, CHS) and UK Biobank. Dichotomised exposures to diet, genetic risk variants, BMI, alcohol, diuretic treatment, sex and age were used to calculate adjusted population and average attributable fractions (PAF/AAF) for HU (≥0.42 mmol/L [≥7 mg/dL]). Exposure to ULT was also assessed in the gout cohort. Two sample Mendelian randomisation was done in the UK Biobank using dietary pattern-associated genetic variants as exposure and serum urate levels as outcome.

Results: Adherence to dietary recommendations, BMI (< 25 kg/m), and absence of the SLC2A9 rs12498742 urate-raising allele produced PAFs for HU of 20 to 24%, 59 to 69%, and 57 to 64%, respectively, in the three non-gout cohorts. In the gout cohort, diet, BMI, SLC2A9 rs12498742 and ULT PAFs for HU were 12%, 49%, 48%, and 63%, respectively. Mendelian randomisation demonstrated weak causal effects of four dietary habits on serum urate levels (e.g. preferentially drinking skim milk increased urate, β = 0.047 mmol/L, P = 3.78 × 10). These effects were mediated by BMI, and they were not significant (P ≥ 0.06) in multivariable models assessing the BMI-independent effect of diet on urate.

Conclusions: Diet has a relatively minor role in determining serum urate levels and HU. In gout, the use of ULT was the largest attributable fraction tested for HU.
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http://dx.doi.org/10.1186/s13075-021-02444-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931603PMC
March 2021

Genetic correlations between traits associated with hyperuricemia, gout, and comorbidities.

Eur J Hum Genet 2021 Sep 26;29(9):1438-1445. Epub 2021 Feb 26.

Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA.

Hypertension, obesity, chronic kidney disease and type 2 diabetes are comorbidities that have very high prevalence among persons with hyperuricemia (serum urate > 6.8 mg/dL) and gout. Here we use multivariate genetic models to test the hypothesis that the co-association of traits representing hyperuricemia and its comorbidities is genetically based. Using Bayesian whole-genome regression models, we estimated the genetic marker-based variance and the covariance between serum urate, serum creatinine, systolic blood pressure (SBP), blood glucose and body mass index (BMI) from two independent family-based studies: The Framingham Heart Study-FHS and the Hypertension Genetic Epidemiology Network study-HyperGEN. The main genetic findings that replicated in both FHS and HyperGEN, were (1) creatinine was genetically correlated only with urate and (2) BMI was genetically correlated with urate, SBP, and glucose. The environmental covariance among the traits was generally highest for trait pairs involving BMI. The genetic overlap of traits representing the comorbidities of hyperuricemia and gout appears to cluster in two separate axes of genetic covariance. Because creatinine is genetically correlated with urate but not with metabolic traits, this suggests there is one genetic module of shared loci associated with hyperuricemia and chronic kidney disease. Another module of shared loci may account for the association of hyperuricemia and metabolic syndrome. This study provides a clear quantitative genetic basis for the clustering of comorbidities with hyperuricemia.
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http://dx.doi.org/10.1038/s41431-021-00830-zDOI Listing
September 2021

Elevated Urate Levels Do Not Alter Bone Turnover Markers: Randomized Controlled Trial of Inosine Supplementation in Postmenopausal Women.

Arthritis Rheumatol 2021 09 16;73(9):1758-1764. Epub 2021 Jul 16.

University of Auckland, Auckland, New Zealand.

Objective: Observational studies have consistently demonstrated that serum urate level positively correlates with bone mineral density (BMD). We undertook this study to determine whether moderate hyperuricemia induced by inosine supplements influences bone turnover markers in postmenopausal women over a 6-month period.

Methods: One hundred twenty postmenopausal women were recruited for a 6-month randomized, double-blind, placebo-controlled trial. Key exclusion criteria were osteoporosis, previous fragility fracture, bisphosphonate therapy, gout, kidney stones, and a urine pH level of ≤5.0. Participants were randomized in a 1:1 ratio to receive placebo or inosine. The coprimary end points were change in levels of N-propeptide of type I procollagen (PINP) and change in levels of β-C-telopeptide of type I collagen (β-CTX). Change in BMD, as measured by dual x-ray absorptiometry, was an exploratory end point.

Results: Administration of inosine led to a significant increase in serum urate concentration over the study period (P < 0.0001 for all follow-up time points). At week 26, the mean change in serum urate concentration was +0.13 mmoles/liter (+2.2 mg/dl) in the inosine group and 0.00 mmoles/liter (0 mg/dl) in the placebo group. There was no difference in PINP or β-CTX levels between groups over the 6 months. There were no significant changes in bone density between groups over the 6 months. Adverse events and serious adverse events were similar between the 2 groups.

Conclusion: This clinical trial shows that although inosine supplementation leads to sustained increases in serum urate levels over a 6-month period, it does not alter markers of bone turnover in postmenopausal women. These findings do not support the concept that urate has direct biologic effects on bone turnover.
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http://dx.doi.org/10.1002/art.41691DOI Listing
September 2021

Assessing the Relationship Between Serum Urate and Urolithiasis Using Mendelian Randomization: An Analysis of the UK Biobank.

Am J Kidney Dis 2021 08 2;78(2):210-218. Epub 2021 Jan 2.

Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand. Electronic address:

Rationale & Objective: The association between hyperuricemia and urolithiasis has been previously reported. However, this association is based on observational data, which are prone to residual confounding. The aim of this work was to use Mendelian randomization (MR) to evaluate if this relationship represents a causal effect of hyperuricemia.

Study Design: MR analysis using 2 approaches: 2-stage MR and 2-sample MR.

Setting & Participants: Participants aged 40-69 years from the UK Biobank Resource.

Exposure: Serum urate.

Outcome: Urolithiasis.

Analytical Approach: An observational analysis testing for an association between serum urate level and urolithiasis was performed using logistic regression. For MR analyses, serum urate-associated single-nucleotide polymorphisms, identified from genome-wide association data, were used as instrumental variables for serum urate. In the 2-stage MR analysis, a weighted genetic urate score was calculated from the instrumental variables, and a control function estimation model was fit. In the 2-sample MR analysis, multiple-instrument MR via the inverse-variance weighted method was performed.

Results: Individual-level data were available for 359,827 participants, of whom 6,398 (1.8%) reported urolithiasis. In the observational analysis, serum urate was positively associated with urolithiasis in an unadjusted analysis (odds ratio [OR], 1.47 [95% CI, 1.42-1.51]); however, after adjustment for relevant confounders, no association was observed (OR, 1.03 [95% CI, 0.99-1.08]). In the 2-stage MR analysis, no significant causal effect of serum urate level on urolithiasis was observed in the unadjusted (OR, 0.93 [95% CI, 0.81-1.08]) or adjusted (OR, 0.94 [95% CI, 0.80-1.09]) models. In the 2-sample MR analysis, multiple-instrument MR did not indicate a causal effect of serum urate on urolithiasis.

Limitations: Stone composition and urinalysis data, including urine pH, were not available for this study.

Conclusions: Our analyses do not support a causal effect of serum urate level on urolithiasis. The association between serum urate level and urolithiasis reported in observational studies is likely due to residual confounding.
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http://dx.doi.org/10.1053/j.ajkd.2020.11.018DOI Listing
August 2021

Genetic Polymorphisms on , and in Young Adults: Lack of Association With Alcohol Consumption.

Front Psychiatry 2020 7;11:549429. Epub 2020 Dec 7.

Discipline of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.

Risk behaviors for young adults such as alcohol use are associated with increased risk of morbidity and mortality. Patterns of risk behavior may be genetically determined and vary between genders. Previous studies in both young adults and heavy drinking adult samples have demonstrated that some genotypes, such as A118G, Val158Met and Taq1A and C52IT, may predict addictive behaviors including alcohol consumption and impulsivity, although results have been mixed. This study aimed to investigate the predictive relationship of these four single nucleotide polymorphisms (SNPs) prospectively on student patterns of drinking using a micro-longitudinal daily diary design in a sample of 628 young adults ages 18-25 of predominantly of European ethnicity. Linear mixed models were used to examine the effect of SNPs on the number of drinks per drinking session with gender as a moderating variable. There were no main effects for genotype on alcohol consumption, nor for gender × genotype for any of the SNPs. There was a trend for an effect of the Taq1A on the number of drinks per drinking day and for the interaction of gender and Taq1A on the number of drinks per drinking day. These findings suggest that the Taq1A A118G, C521T, or Val158Met polymorphisms, are not associated with alcohol consumption in young adults, although there may be a relationship between Taq1A and alcohol consumption in young adult males.
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http://dx.doi.org/10.3389/fpsyt.2020.549429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750453PMC
December 2020

The efficacy and safety of citrate mixture vs sodium bicarbonate on urine alkalization in Chinese primary gout patients with benzbromarone: a prospective, randomized controlled study.

Rheumatology (Oxford) 2021 06;60(6):2661-2671

Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, Qingdao, China.

Objectives: To compare the efficacy and safety of citrate mixture and sodium bicarbonate on urine alkalization in gout patients under benzbromarone treatment.

Methods: A prospective, randomized, parallel controlled trial was conducted among 200 gout patients in the dedicated gout clinic of the Affiliated Hospital of Qingdao University. The participants were randomly divided into two groups (1:1), sodium bicarbonate group (3 g/day) and citrate mixture group (7 g/day). All patients were prescribed with 25 mg/day benzbromarone at initiation and maintained at a dose of 50 mg/day. Clinical and biochemical data were collected at each follow-up time point (baseline, weeks 2, 4, 8 and 12).

Results: A total of 182 patients completed the 12-week urine alkalization study. The urine pH value of both groups increased significantly from the baseline to the final follow-up time point (sodium bicarbonate group, 5.50-6.00, P < 0.05; citrate mixture group, 5.53-5.93, P < 0.05). While the comparisons regarding urine pH between treatment groups showed no significant differences for each time point. The estimated glomerular filtration rate (eGFR) dropped significantly after 12 weeks' trial in the sodium bicarbonate group (P < 0.01), while it was comparable between baseline and the last follow-up (P > 0.05) in the citrate mixture group. Results of urine analysis showed that the incident rate of occult blood in the sodium bicarbonate group was higher than that in the citrate mixture group (38 vs 24%, P < 0.05), accompanied by a similar occurrence of kidney stones. After 12-week follow-up, the frequency of twice gout flare in the citrate mixture group was significantly lower than that in sodium bicarbonate group (4 vs 12%, P = 0.037). No treatment-emergent adverse events occurred.

Conclusion: The efficacy of citrate mixture on urine alkalization is comparable to sodium bicarbonate under benzbromarone treatment without significant adverse events. Citrate mixture is superior to sodium bicarbonate in lowering the incidence of urine occult blood and the frequency of gout attacks.

Trial Registration: Registered with ChiCTR (http://www.chictr.org.cn), No. ChiCTR1800018518.
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http://dx.doi.org/10.1093/rheumatology/keaa668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213434PMC
June 2021

Effect of body mass index on serum urate and renal uric acid handling responses to an oral inosine load: experimental intervention study in healthy volunteers.

Arthritis Res Ther 2020 11 4;22(1):259. Epub 2020 Nov 4.

Department of Biochemistry, University of Otago, Dunedin, New Zealand.

Background: High body mass index (BMI) is strongly associated with hyperuricaemia. It is unknown whether overweight and obesity influences serum urate primarily through increased urate production or reduced renal clearance of uric acid. The aim of this study was to determine the influence of BMI on the response to inosine, a purine nucleoside that functions as an intermediate in the purine salvage and degradation pathways.

Methods: Following an overnight fast, 100 healthy participants without gout attended a study visit. Blood and urine samples were taken prior to and over 180 min after 1.5 g oral inosine. Serum urate and fractional excretion of uric acid (FEUA) were analysed according to high BMI (≥ 25 kg/m) and low/normal BMI (< 25 kg/m) groups, and according to BMI as a continuous variable.

Results: Participants in the high BMI group (n = 52, mean BMI 30.8 kg/m) had higher serum urate concentrations at baseline (P = 0.002) compared to those with low/normal BMI (mean BMI 21.8 kg/m). However, the high BMI group had a smaller increase in serum urate following the inosine load (P = 0.0012). The two BMI groups had a similar FEUA at baseline (P = 0.995), but those in the high BMI group had a smaller increase in FEUA following the inosine (P = 0.0003). Similar findings were observed when analysing BMI as a continuous variable. Those with high BMI had a smaller increase in FEUA per increase in serum urate, compared to those with low BMI (P = 0.005).

Conclusions: In a fasting state, people with high BMI have elevated serum urate levels but similar FEUA values compared with those with low/normal BMI. Following a purine load, those with high BMI have an attenuated renal excretion of uric acid. These data, using an experimental method to dynamically assess human urate handling, suggest that people with high BMI have a higher renal capacity for uric acid reabsorption when fasted and following a dietary purine intake have reduced renal clearance.

Trial Registration: Australia and New Zealand Clinical Trials Registry, ACTRN12615001302549 , date of registration 30 November 2015.
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http://dx.doi.org/10.1186/s13075-020-02357-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641836PMC
November 2020

Urate in fingernail represents the deposition of urate burden in gout patients.

Sci Rep 2020 09 23;10(1):15575. Epub 2020 Sep 23.

Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Pharmaceutical Analysis, College of Pharmacy, Yanbian University, Yanji, 133002, Jilin Province, China.

Urate in the fingernails of gout patients and healthy volunteers was successfully detected by high-performance liquid chromatography (HPLC) with ultraviolet (UV) in our previous research. This study aimed to further investigate whether nail urate could be a proxy for the burden of monosodium urate (MSU) crystals deposits in gout. To this end, we conducted a study in two parts. Firstly, we successfully detected urate in the nail by HPLC-UV and evaluated nail urate concentrations in control subjects and patients with gout. As expected, we found that levels of nail urate were significantly higher in patients with gout than in healthy controls, and the nail urate level was significantly correlated with the volume of MSU crystals deposits measured by dual-energy CT (DECT). Secondly, we found that nail urate can reflect changes in urate levels in the body during urate lowering therapy through a 3-month follow-up study. Our results provide the possibility of quantification of urate in human fingernails as a non-invasive alternative for assessing MSU crystals deposits in gout.
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http://dx.doi.org/10.1038/s41598-020-72505-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511301PMC
September 2020

Trends in the manifestations of 9754 gout patients in a Chinese clinical center: A 10-year observational study.

Joint Bone Spine 2020 Sep 18:105078. Epub 2020 Sep 18.

Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, Department of Endocrinology and Metabolism, the Affiliated Hospital of Qingdao University, 266003 Qingdao, China; Institute of Metabolic Diseases, Qingdao University, 266003 Qingdao, China. Electronic address:

Objective: The prevalence of gout is increasing but studies of its clinical features in large samples are lacking. This study aimed to clarify changes in the clinical manifestations of gout in China over the last decade and investigate the clinical features and risk factors of early-onset gout.

Methods: Clinical manifestations were compared between 9754 gout patients who first presented at our clinic with gout in 2008-2012 (earlier group) or 2013-2018 (later group). Gout onset≤30 years old was defined as early-onset and>30 years as late-onset. Clinical features and risk factors were compared between the groups.

Results: The gout-onset age was 4.14 years younger and the percentage of early-onset gout (3827 patients) was higher in the later 2013-2018 group (5979 patients). The disease duration was significantly shorter (5.72±0.09 vs. 6.01±0.11 years P < 0,05) and the ratio of patients with tophi was correspondingly lower in the later group (22.0% vs. 20.0%, P < 0,05). More patients were obese (32.6% vs. 37.7%, P<0.001) and serum urate levels (465.0±1.9μmol/L vs. 485.5±1.5μmol/L) were significantly higher in the later group. As the age of gout-onset became younger, we did the multivariate logistic regression and identified a positive family history, male sex, obesity, elevated serum urate, and sugar-sweetened soft drinks as independent predictors of early-onset gout.

Conclusion: The manifestations of gout in China have changed over the last decade, associated with a trend towards younger onset.
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http://dx.doi.org/10.1016/j.jbspin.2020.09.010DOI Listing
September 2020

Advances in our understanding of gout as an auto-inflammatory disease.

Semin Arthritis Rheum 2020 10 30;50(5):1089-1100. Epub 2020 Jun 30.

Division of Rheumatology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States.

Gout, the most common inflammatory arthritis, is the result of hyperuricemia and inflammation induced by monosodium urate (MSU) crystal deposition. However, most people with hyperuricemia will never develop gout, implying a molecular-genetic contribution to the development of gout. Recent genomic studies reveal links between certain genetic variations and gout. We highlight recent advances in our understanding of gout as an auto-inflammatory disease. We review the auto-inflammatory aspects of gout, including the inflammasome and thirteen gout-associated inflammatory-pathway genes and associated comorbidities. This information provides important insights into emerging immune-modulating targets in the management of gout, and future novel therapeutic targets in gout treatment. Cumulatively, this has important implications for treating gout as an auto-inflammatory disease, as opposed to a purely metabolic disease.
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http://dx.doi.org/10.1016/j.semarthrit.2020.06.015DOI Listing
October 2020

Randomised cross-over trial of vildagliptin and pioglitazone as add-on therapy in patients with type 2 diabetes: predicting Which One is Right Here (WORTH) study protocol.

BMJ Open 2020 09 1;10(9):e036518. Epub 2020 Sep 1.

Medicine, The University of Auckland Faculty of Medical and Health Sciences, Auckland, New Zealand

Introduction: There is emerging evidence for stratified glucose-lowering responses to certain oral medications for type 2 diabetes (T2D) by individual characteristics. The objective of this study was to test whether glycaemic response to representative treatments of dipeptidyl peptidase-4 inhibitors (vildagliptin) and thiazolidinediones (pioglitazone) varies according to ethnicity, gender, baseline obesity, triglyceride level or genetic variation.

Methods: This is a multicentre, two-period, two-treatment, open-label, randomised cross-over trial of vildagliptin and pioglitazone as second-line or third-line therapy in patients with T2D who have suboptimal glycaemic control on metformin and/or sulfonylurea therapy. It is conducted in New Zealand with a target of 300 patients (40% with Māori or Pacific ancestry) eligible if aged ≥18 and ≤80 years, with T2D for more than 1 year, on stable doses of metformin and/or sulfonylurea for at least 3 months, with HbA1c between 59 and 110 mmol/mol inclusive. Participants are assigned to complete 4 months of vildagliptin 50 mg per day or pioglitazone 30 mg per day, followed by 4 months of the other medications in randomly allocated sequences. Participant characteristics, including ethnicity, obesity, lipid profile and candidate genotypes are collected at baseline. Primary outcome variable is on treatment HbA1c. Secondary outcomes include weight change, frequency of side effects and patient preference.

Ethics And Dissemination: Ethical approval of the trial has been obtained from the New Zealand Health and Disability Ethics Committee (18/STH/242). The trial commenced in February 2019 and recruitment is expected to be completed by March 2020. Results will be reported in articles submitted to peer-reviewed journals, as well as in presentations at national and international meetings.

Trial Registration Number: ACTRN12618001907235.
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http://dx.doi.org/10.1136/bmjopen-2019-036518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467516PMC
September 2020

Trans-ancestral dissection of urate- and gout-associated major loci SLC2A9 and ABCG2 reveals primate-specific regulatory effects.

J Hum Genet 2021 Feb 10;66(2):161-169. Epub 2020 Aug 10.

Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

Gout is a complex inflammatory arthritis affecting ~20% of people with an elevated serum urate level (hyperuricemia). Gout and hyperuricemia are essentially specific to humans and other higher primates, with varied prevalence across ancestral groups. SLC2A9 and ABCG2 are major loci associated with both urate and gout in multiple ancestral groups. However, fine mapping has been challenging due to extensive linkage disequilibrium underlying the associated regions. We used trans-ancestral fine mapping integrated with primate-specific genomic information to address this challenge. Trans-ancestral meta-analyses of GWAS cohorts of either European (EUR) or East Asian (EAS) ancestry resulted in single-variant resolution mappings for SLC2A9 (rs3775948 for urate and rs4697701 for gout) and ABCG2 (rs2622621 for gout). Tests of colocalization of variants in both urate and gout suggested existence of a shared candidate causal variant for SLC2A9 only in EUR and for ABCG2 only in EAS. The fine-mapped gout variant rs4697701 was within an ancient enhancer, whereas rs2622621 was within a primate-specific transposable element, both supported by functional evidence from the Roadmap Epigenomics project in human primary tissues relevant to urate and gout. Additional primate-specific elements were found near both loci and those adjacent to SLC2A9 overlapped with known statistical epistatic interactions associated with urate as well as multiple super-enhancers identified in urate-relevant tissues. We conclude that by leveraging ancestral differences trans-ancestral fine mapping has identified ancestral and functional variants for SLC2A9 or ABCG2 with primate-specific regulatory effects on urate and gout.
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http://dx.doi.org/10.1038/s10038-020-0821-zDOI Listing
February 2021

Common variants of EDA are associated with non-syndromic hypodontia.

Orthod Craniofac Res 2021 Feb 7;24(1):155-163. Epub 2020 Sep 7.

Faculty of Dentistry, Sir John Walsh Research Institute, University of Otago, Dunedin, New Zealand.

Objective: The aim of this case-control study was to investigate the association between non-syndromic hypodontia and nineteen common variants of candidate genes ectodysplasin A (EDA), paired box 9 (PAX9), msh homeobox 1 (MSX1) and axis inhibition protein 2 (AXIN2).

Settings And Sample Population: Sixty-one hypodontia cases were frequency-matched to 253 controls with no missing teeth (excluding the third molars).

Material And Methods: Self-report data and DNA samples were collected from each participant.

Results: The sample had a mean age of 16.6 years (SD = 7.3), with most participants being female (59.6%), and of New Zealand European origin (75.4%). Using multiple logistic regression analysis, it was found that the T-allele of rs12853659 (EDA) and the G-allele of rs2428151 (EDA) were both associated with a higher risk of hypodontia (odds ratio, OR = 2.79, 95% CI = 1.11-7.01; and OR = 2.87, 95% CI = 1.04-7.94, respectively). The G-allele of rs2520378 (EDA) showed a protective effect with an OR of 0.61 (95% CI = 0.38-0.99). The EDA SNP findings were consistent with previous reports included in a meta-analysis. No associations were found with the PAX9, AXIN2 and MSX1 genes, after adjusting for sex and ethnicity.

Conclusions: Common variants of the EDA genes are associated with specific phenotypes of non-syndromic hypodontia, thus confirming their role in the regulatory pathways of normal tooth development. However, larger samples are needed to investigate the association further.
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http://dx.doi.org/10.1111/ocr.12419DOI Listing
February 2021
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