Risk Of Gout Research Articles

Drug Treatment of Hypercholesterolemia in Older Adults: Focus on Newer Agents.

There is increasing research interest in cholesterol-lowering therapy in older patients. The newer lipid-lowering agents (the proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitors evolocumab and alirocumab; the PCSK9 synthesis inhibitor inclisiran, and the adenosine triphosphate–citrate lyase inhibitor bempedoic acid) might also provide more options for the future treatment of older patients. Data analyses of the phase III outcome trials of the PCSK9 inhibitors suggest that their clinical benefits are maintained at older ages and that there is no increased relative risk of adverse events in older patients; however, data from patients aged ≥ 75 years and particularly aged ≥ 85 years are limited, and the trials did not collect information on the frailty status of patients. Frailty is a predictor of adverse outcomes, including mortality, and might help guide therapy decisions. To date, no outcome data are available for cardiovascular endpoints for the low-density lipoprotein cholesterol-lowering drugs inclisiran and bempedoic acid. Except for the risk of gout and tendon rupture with bempedoic acid, which remains to be further characterized in larger populations, the safety profile of the novel lipid-lowering agents in older patients seems favorable. The newer lipid-lowering agents could be added to other lipid-lowering medication or used as an alternative treatment in older patients with documented statin intolerance (as is already recommended in guidelines for the PCSK9 inhibitors), such as myopathy. Especially in older patients needing high-intensity therapy despite polypharmacy or certain comedications, the absence of clinically relevant drug–drug interactions with the PCSK9 inhibitors and inclisiran might be an advantage.

The Risk of Gout in Patients with Psoriasis: A Population-Based Cohort Study in Taiwan

BackgroundPrevious research has pointed to the relationship between psoriasis and the development of gout. However, most previous studies had either small sample sizes or short study durations. Therefore, in this nationwide cohort study, we investigated the effect of psoriasis on the risk of gout development.MethodsThe study group included one million patients from Taiwan, whom we followed for 14 years. The participants were divided into two cohorts designated as psoriasis and non-psoriasis. A 1:4 propensity score matching test was used to compare age, sex, and index year between the two cohorts. Cox proportional hazard regression was used to determine the hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of gout. Sensitivity analyses were conducted to evaluate the HR for gout after the occurrence of psoriasis.ResultsThe incidence densities of gout in the psoriasis and non-psoriasis cohorts were 6.96 and 5.09 per 1000 person-years, respectively. After adjusting for age, sex, urbanization, comorbidities, and nonsteroidal anti-inflammatory drug (NSAID) use, the adjusted hazard ratio (aHR) with 95% CI for incidental gout in the psoriasis group was 1.38 (1.2–1.6). Moreover, the aHR (95% CI) values for gout risk in patients with psoriasis using NSAIDs and those who did not were 1.21 (1.0–1.47) and 1.65 (1.33–2.05), respectively.ConclusionThis study demonstrated an association between psoriasis and risk of developing gout. Clinically, patients with psoriasis should be evaluated for incidental gout.

Effects of fructose from apple and honey on serum uric acid in young Chinese: Randomized crossover trials.

Overconsumption of drinks containing fructose increases the risk for hyperuricemia and gout. Comparative analysis evaluating the indicators of serum uric acid (SUA) load caused by natural food-derived fructose and pure fructose in sweeteners is lacking. We aimed to uncover the effect of fructose from apple and honey and pure fructose powder on the SUA concentration of healthy young Chinese individuals. Two randomized crossover trials were performed. The participants were randomly assigned to consume apple or honey (test food) or pure fructose powder (reference food); one week later, the groups' dietary intervention was switched. Blood samples were collected at 0, 30, 60, and 120 min after meal to measure the SUA and blood glucose concentrations. At 30 and 60 min, the SUA concentration in participants consuming apple or honey was lower than in those consuming fructose powder. At 120 min, the SUA concentration of participants consuming apple returned to baseline. The areas under the curve (AUC) within 2 h (2h- AUCs) of SUA exhibited the trend of fructose >honey >apple. The 2h-AUC ratio between test food and reference food was determined using the uric acid index to assess the efficiency of food-derived fructose in increasing the SUA concentration. The uric acid index of honey was higher than that of apple. Men had higher postprandial SUA concentration than women. Food-derived fructose caused a lighter load on uric acid metabolism than pure fructose. Uric acid index can be useful for distinguishing fructose-containing foods.

Association between perinatal factors and future risk for gout\u2014a nested case-control study

BackgroundIncreased level of urate is the strongest risk factor for gout development but since only a minority of hyperuricemics are affected by gout, other pathogenic factors must be considered. Low birth weight is associated with future morbidities causing hyperuricemia, such as diabetes and renal disease. The purpose of this study was to investigate if, and to what extent, maternal and perinatal factors, including birth weight, are associated with future risk of being diagnosed with gout.MethodsA population-based retrospective nested case-control registry study based on regional and national health care registers in Sweden. All incident cases of gout born in 1973 and onward who had received ≥1 diagnosis of gout from 2000 through 2019 in the region of western Sweden were included. Up to 5 non-gout controls were matched to each case by age, sex, and county at the year of first gout diagnosis. A range of maternal, gestational, and perinatal factors were analyzed for their potential association to future gout development. This included the health of the mother, gestational length, birth weight, number of siblings, and congenital malformations.ResultsMaternal diabetes, any congenital malformation, and being small for gestational age were factors that significantly increased the risk for future gout development, odds ratio (95% CI) 3.1 (1.3 to 7.4) (p=0.01), 1.33 (1.04 to 1.7) (p=0.02), and 1.75 (1.3 to 2.3) (p<.0001), respectively.ConclusionsIn this study, maternal diabetes and being small for gestational age increased the risk for future gout development in young adults. As of today, these conditions are becoming more prevalent and may contribute to the ongoing gout epidemic. These results require both confirmation and further delineation of underlying mechanisms.

Modifiable Factors and Incident Gout Across Ethnicity Within a Large Multiethnic Cohort of Older Adults.

Gout disproportionately affects older Pacific Islander and Black populations relative to White populations. However, the ethnic-specific determinants remain understudied within these groups, as well as within other ethnicities. We examined gout incidence and associations with behavioral factors, including diet, alcohol, and smoking, within a large multiethnic population of older adults from the Multiethnic Cohort Study, which linked prospective cohort data to Medicare gout claims between 1999-2016. Using samples of Black (n = 12,370), Native Hawaiian (n = 6459), Japanese (n = 29,830), Latino (n = 17,538), and White (n = 26,067) participants, we conducted multiple Cox regressions, producing hazard ratios (HRs) and 95% CIs. Relative to White individuals, Native Hawaiians had the highest risk of gout (HR 2.21, 95% CI 2.06-2.38), followed successively by Black and Japanese participants, whereas Latino individuals had a lower risk of gout (HR 0.78, 95% CI 0.73-0.83). Alcohol use was associated with an increased risk, with significantly greater effects observed among Japanese participants drinking ≥ 3 drinks per day (HR 1.46, 95% CI 1.27-1.66), or > 5 beers per week (HR 1.29, 95% CI 1.17-1.43), compared to White individuals (Pinteraction < 0.001). Former smokers with ≥ 20 pack-years had an increased risk (HR 1.14, 95% CI 1.06-1.22). Higher dietary quality was associated with a decreased gout risk, with the largest effect observed among White participants (HRQ5vsQ1 0.84, 95% CI 0.79-0.90), whereas vitamin C was weakly associated with a decreased risk of gout only among Japanese individuals (HR 0.91, 95% CI 0.85-0.98). Overall, notable ethnic differences were observed in both gout risk and associations with modifiable behavioral factors. Our findings offer crucial insights that may improve precision in preventing and managing gout.

Health effects of high serum calcium levels: Updated phenome-wide Mendelian randomisation investigation and review of Mendelian randomisation studies.

SummaryBackgroundCalcium plays a role in a wide range of biological functions. Here we conducted a phenome-wide Mendelian randomisation (MR-PheWAS) analysis and a systematic review for MR studies to comprehensively investigate the health effects of serum calcium.MethodsOne-hundred and thirty genetic variants strongly associated with serum calcium levels were used as instrumental variables. A phenome-wide association analysis (PheWAS) was conducted to examine the associations of genetically predicted serum calcium with 1473 distinct phenotypes in the UK Biobank including 339,197 individuals. Observed associations in PheWAS were further tested for replication in two-sample MR replication analysis. A systematic review for MR studies on serum calcium was performed to synthesize the published evidence and compare with the current MR-PheWAS findings.FindingsHigher genetically predicted calcium levels were associated with decreased risk of 5 diseases in dermatologic and musculoskeletal systems and increased risk of 17 diseases in circulatory, digestive, endocrine, genitourinary and immune systems. Eight associations were replicated in two-sample MR analysis. These included decreased risk of osteoarthritis and increased risk of coronary artery disease, myocardial infarction, coronary atherosclerosis, hyperparathyroidism, disorder of parathyroid gland, gout, and calculus of kidney and ureter with increased serum calcium. Systematic review of 25 MR studies provided supporting evidence on five out of the eight disease outcomes, while the increased risk of gout, hyperparathyroidism and disorder of parathyroid gland were novel findings.InterpretationThis study found wide-ranged health effects of high serum calcium, which suggests that the benefits and adversities of strategies promoting calcium intake should be assessed.FundingET is supported by a CRUK Career Development Fellowship (C31250/A22804). XL is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province. SCL acknowledges research funding from the Swedish Heart Lung Foundation (Hjärt-Lungfonden, 20210351), the Swedish Research Council (Vetenskapsrådet, 2019-00977), and the Swedish Cancer Society (Cancerfonden).

Clinical efficacy and safety outcomes of bempedoic acid for LDL-C lowering therapy in patients at high cardiovascular risk: a systematic review and meta-analysis

ObjectivesBempedoic acid (BA) is a novel oral low-density lipoprotein cholesterol lowering drug. This systematic review and meta-analysis aims to assess efficacy and safety for clinical outcomes in high cardiovascular (CV)...

Adherence to 2020 to 2025 Dietary Guidelines for Americans and the Risk of New-Onset Female Gout

Female-specific gout data are scarce despite perceived differences from males in its risk factors and disproportionate worsening in disease and comorbidity burden globally. The 2020 to 2025 Dietary Guidelines for Americans recommend multiple healthy eating patterns for prevention of cardiovascular-metabolic outcomes, which may also be relevant to the prevention of female gout. To examine the associations of dietary scores for the latest guideline-based healthy eating patterns with risk of incident female gout. This prospective cohort study included 80 039 US women in the Nurses' Health Study followed up through questionnaires every 2 years starting from 1984. Participants had no history of gout at baseline, and the study used questionnaire responses through 2018. Statistical analyses were performed over September 2020 to August 2021. Four healthy eating patterns: Dietary Approaches to Stop Hypertension (DASH), Alternate Mediterranean Diet Score, Alternative Healthy Eating Index (AHEI), and Prudent, plus Western (unhealthy) for comparison, with scores derived from validated food frequency questionnaires. Incident, physician-diagnosed female-specific gout. During 34 years of follow-up, we documented 3890 cases of incident female gout. Compared with the least-adherent quintile, women most adherent to healthy diets had significantly lower risk of incident gout, with multivariable-adjusted hazard ratios (HRs) 0.68 (95% CI, 0.61-0.76) (DASH), 0.88 (95% CI, 0.80-0.98) (Mediterranean), 0.79 (95% CI, 0.71-0.89) (AHEI), and 0.75 (95% CI, 0.73-0.90) (Prudent); all P for trend ≤.009. Conversely, women with highest-quintile Western diet score had 49% higher risk of gout (HR, 1.49; 95% CI, 1.33-1.68], P <.001). When combined, the most DASH-diet adherent women with normal body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) had a 68% lower risk of gout compared with the least adherent women with overweight or obese BMI; the corresponding risk reduction was 65% combining high DASH diet adherence with no diuretic use. These large-scale, long-term prospective cohort findings extend the pleotropic benefits of the 2020 to 2025 Dietary Guidelines for Americans to female gout prevention, with multiple healthy diets that can be adapted to individual food traditions, preferences, and comorbidities.

Gout and the risk of COVID-19 diagnosis and death in the UK Biobank: a population-based study.

BackgroundThere is a paucity of data on outcomes for people with gout and COVID-19. We aimed to assess whether gout is a risk factor for diagnosis of COVID-19 and COVID-19-related death, and to test for sex- and drug-specific differences in risk.MethodsWe used data from the UK Biobank, which included 15 871 people with gout. We used multivariable-adjusted logistic regression in the following analyses using a case-control study design: to test for an association between gout and COVID-19 diagnosis in the entire UK Biobank cohort (n=459 837); to test for an association between gout and COVID-19-related death in people who were known to have died or survived with COVID-19 (n=15 772); to test for an association between gout and COVID-19-related death in the entire UK Biobank cohort (n=459 837); and to assess risk of COVID-19-related death in a subset of patients from the UK Biobank cohort with prescription data, stratified by prescription of urate-lowering therapy and colchicine (n=341 398). Models 1 and 2 were adjusted for age group, sex, ethnicity, Townsend deprivation index, BMI, and smoking status. Model 2 was also adjusted for diagnosis of 16 other diseases that are established comorbidities of gout or established risk factors for COVID-19-related death.FindingsGout was associated with diagnosis of COVID-19 (odds ratio [OR] 1·20, 95% CI 1·11–1·29) but not with risk of COVID-19-related death in the cohort of patients diagnosed with COVID-19 (1·20, 0·96–1·51). In the entire cohort, gout was associated with COVID-19-related death (1·29, 1·06–1·56); women with gout had an increased risk of COVID-19-related death (1·98, 1·34–2·94), whereas men with gout did not (1·16, 0·93–1·45). We found no significant differences in the risk of COVID-19-related death according to prescription of urate-lowering therapy or colchicine. When patients with gout were stratified by vaccination status, the risk of diagnosis with COVID-19 was significant in the non-vaccinated group (1·21, 1·11–1·30) but not the vaccinated group (1·09, 0·65–1·85).InterpretationGout is a risk factor for COVID-19-related death in the UK Biobank cohort, with an increased risk in women with gout, which was driven by risk factors independent of the metabolic comorbidities of gout.FundingHealth Research Council of New Zealand.

Genetic assessment of hyperuricemia and gout in Asian, Native Hawaiian, and Pacific Islander subgroups of pregnant women: biospecimens repository cross-sectional study

BackgroundGout, an inflammatory condition, is characterized by the precipitation of monosodium urate crystals (MSU) in or around distal joints. The latter is caused by chronic hyperuricemia (HU)—high urate levels in the blood. Genetic variations in urate transporters play a significant role in determining urate levels within the human body, rendering some racial and ethnic groups more or less susceptible to developing either HU or gout. This study aims to estimate the frequencies of HU and gout risk alleles in Asian, Native Hawaiian, and Pacific Islander subgroups, using biorepository DNA samples.MethodsThe biospecimens repository at the University of Hawai’i provided DNA samples of consented post-partum women of Japanese, Filipino, Korean, Native Hawaiian, Samoan, and Marshallese descent. The DNA was previously extracted from maternal blood and genotyped at the Genomics and Bioinformatics Shared Resource, Cancer Center (Honolulu, HI). Nine urate genes: ABCG2, SLC2A9, SLC16A9, GCKR, SLC22A11, SLC22A12, LRR16A, PDZK1, and SLC17A1, were selected due to their significant association with HU and gout risk. Hardy–Weinberg Equilibrium (HWE) for genotype frequencies was assessed, using the Chi-Square test with p < 0.006 for statistical significance. Allele frequencies in our study were then compared to EUR from the 1000 Genomes Project Database Phase III, using Chi-square or Fisher's exact test, when appropriate. Bonferroni correction for multiple comparisons was used, with p < 0.006 for statistical significance.ResultsOur study involved 1059 post-partum women 18-year-old or older who self-reported their respective race and ethnicity, including Asian, Native Hawaiian, and Pacific Islander ancestry. The Asian subgroups included Japanese, Filipino, and Korean. The Pacific Islander subgroups included Marshallese and Samoan. None of the study participants had a history of gout. We excluded the PDZK1 gene from the final analysis due to its deviation from HWE (p < 0.006) across all the population subgroups, with eight loci remaining for cross-subgroup comparisons. Compared to EUR, the genetic polymorphism frequencies were significantly different-8/8 in Japanese, 6/8 in Korean, 6/8 in Filipino, 8/8 in Samoan, 6/8 in Native Hawaiian, and 6/8 in Marshallese. HU and gout risk alleles indices were 8, 6, 5, 5, 4, and 4 in Japanese, Filipino, Korean, Samoan, Marshallese, and Native Hawaiian, respectively. The percentage of cumulative risk alleles was 100% in both Japanese and Filipino, followed by 83.5% in Korean.ConclusionsCompared to EUR, Asian subgroups, particularly Japanese, Filipino, and Korean, had the highest percentage of the cumulative uric acid risk alleles. These results could partly explain the increased risk of developing gout among some Asian ancestral subgroups compared to EUR.

The Risk of Gout in Patients with Psoriasis: A Population-Based Cohort Study in Taiwan.

Previous research has pointed to the relationship between psoriasis and the development of gout. However, most previous studies had either small sample sizes or short study durations. Therefore, in this nationwide cohort study, we investigated the effect of psoriasis on the risk of gout development. The study group included one million patients from Taiwan, whom we followed for 14 years. The participants were divided into two cohorts designated as psoriasis and non-psoriasis. A 1:4 propensity score matching test was used to compare age, sex, and index year between the two cohorts. Cox proportional hazard regression was used to determine the hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of gout. Sensitivity analyses were conducted to evaluate the HR for gout after the occurrence of psoriasis. The incidence densities of gout in the psoriasis and non-psoriasis cohorts were 6.96 and 5.09 per 1000 person-years, respectively. After adjusting for age, sex, urbanization, comorbidities, and nonsteroidal anti-inflammatory drug (NSAID) use, the adjusted hazard ratio (aHR) with 95% CI for incidental gout in the psoriasis group was 1.38 (1.2-1.6). Moreover, the aHR (95% CI) values for gout risk in patients with psoriasis using NSAIDs and those who did not were 1.21 (1.0-1.47) and 1.65 (1.33-2.05), respectively. This study demonstrated an association between psoriasis and risk of developing gout. Clinically, patients with psoriasis should be evaluated for incidental gout.

Sleep Patterns, Genetic Susceptibility, and Risk of Hospital-Diagnosed Gout: A Prospective Study of 403 630 UK Biobank Participants

Sleep Patterns, Genetic Susceptibility, and Risk of Hospital-Diagnosed Gout: A Prospective Study of 403 630 UK Biobank Participants

The burden of low back pain, rheumatoid arthritis, osteoarthritis, and gout and their respective attributable risk factors in Brazil: results of the GBD 2017 study.

INTRODUCTION: Musculoskeletal (MSK) disorders are a major cause of disability worldwide. Different modifiable risk factors are associated to these disorders. The objective of this study was to analyze the burden of low back pain (LBP), rheumatoid arthritis (RA), osteoarthritis (OA), and gout, attributable to risk factors, in 2017. METHODS: The burden of LBP, RA, OA, and gout, and attributable risk factors were analyzed using data extracted from the Global Burden of Disease (GBD) Brasil-2017 study. Descriptive analysis was conducted to compare disability-adjusted life years (DALY) rates between sexes and age groups (15-49 and 50-69 years), in 2017. RESULTS: The highest rates of DALY due to LBP were attributed to occupational ergonomic factors in the 15-49-year group, regardless of sex and males aged 50-69 years, whereas smoking was the major contributor in the 50-69-year female group. RA-related DALY rates were attributed to smoking and were higher among women aged 50-69 years. High body mass index (BMI) was the most relevant risk factor for the burden of OA, with higher rates detected in the 50-69-year group, and it was the most significant risk factor for DALY rate attributed to gout, regardless of sex or age group. CONCLUSIONS: Occupational surveillance measures are indicated to prevent LBP. Actions to decrease smoking and overweight, and the surveillance of weight gain are warranted to decrease the burden of LBP, RA and OA, and gout, respectively. These actions will be more effective if age and sex differentials are considered in planning.

NRBP1 modulates uric acid transporter ABCG2 expression by activating the Wnt/β-catenin pathway in HK-2 cells

BackgroundNuclear receptor binding protein 1 (NRBP1) and ATP-binding cassette subfamily G member 2 (ABCG2) was the gout risk gene and high-capacity urate exporter respectively. However, the relationship between NRBP1 and ABCG2 and the underlying molecular mechanism contributing to these associations are unknown. MethodsFirstly, the efficiency of the overexpression and knockdown of NRBP1 was confirmed by western blot. Next, the effect of NRBP1 overexpression and knockdown on the expression of ABCG2, organic anion transporter 1 (OAT1), glucose transporter 9 (GLUT9) and urate transporter 1 (URAT1) was detected by qRT-PCR and western blot. At the same time, the cellular location of ABCG2 and its expression after NRBP1 overexpression and knockdown was tested by immunofluorescence (IF) staining. Then, the mechanism of NRBP1 modulates ABCG2 expression was evaluated by western blot with or without the β-catenin inhibitor (21H7). ResultsThe lentivirus system was used to generate stable NRBP1 overexpression, while the plasmids carrying a NRBP1 siRNA was generated to knockdown NRBP1 expression in HK-2 cells. Meanwhile, the overexpression of NRBP1 significantly decreased the mRNAs and proteins expression of GLUT9 and URAT1, while the knockdown of NRBP1 increased the mRNAs and proteins expression of ABCG2 significantly. In addition, the NRBP1 modulates the expression of ABCG2 was by ctivating the Wnt/β-catenin pathway in HK-2 cells according to the IF and western blot results. ConclusionTaken together, our study demonstrated that NRBP1 inhibition played an essential role in attenuating hyperuricemia and gout by upregulation of ABCG2 via Wnt/β-catenin signaling pathway in HK-2 cells.

Patient characteristics and safety outcomes in new users of ticagrelor and clopidogrel-An observational cohort study in Sweden.

We aimed to describe characteristics of new users of ticagrelor or clopidogrel following a recent coronary event, and to compare incidences of selected safety outcomes. This observational cohort study used data from national Swedish registers. Patients first dispensed ticagrelor or clopidogrel (June 2011-December 2013) were identified from the Prescribed Drug Register and followed until censoring or 31 December 2014. Cohorts were restricted to patients with a recent coronary event-related hospital contact identified in the Patient Register. The study included 45 987 unique, naïve users of ticagrelor (73% men; mean age 66 years) or clopidogrel (69% men; mean age 69 years). Corresponding to indication, diagnoses before initiation were acute coronary syndrome (93%), myocardial infarction (76%), and percutaneous coronary intervention (69%). The most common medications used in the year before initiation of study therapy were antithrombotic agents (clopidogrel 62%, ticagrelor 43%), mainly low-dose acetylsalicylic acid. Ticagrelor users had a higher incidence (per 1000 person-years) of respiratory bleeding (24.6 [95% confidence interval (CI): 22.1-27.3]; vs clopidogrel users: 14.4 [13.1-15.8]) and dyspnea (25.9 [23.3-28.7]; vs clopidogrel users: 16.8 [15.4-18.4]). Epistaxis accounted for 83-93% of respiratory bleeds. Adjusted analyses found increased risks of gout and acute renal failure with ticagrelor. Clopidogrel users were older with a higher prevalence of concomitant medications than ticagrelor users. Our study showed increased incidences of dyspnea and respiratory bleeding (mainly epistaxis) among current ticagrelor users compared with clopidogrel users, and increased risks of gout and acute renal failure after adjustment.

Impact of adiposity on risk of female gout among those genetically predisposed: sex-specific prospective cohort study findings over >32 years

ObjectivesTo evaluate the joint (combined) association of excess adiposity and genetic predisposition with the risk of incident female gout, and compare to their male counterparts; and determine the proportion attributable...

Association between female reproductive factors and gout: a nationwide population-based cohort study of 1 million postmenopausal women

BackgroundPrevious studies have shown that the incidence and risk factors of gout differs according to sex. However, little research has been done on the association between reproductive factors and gout. We conducted an analysis of a large nationwide population-based cohort of postmenopausal women to determine whether there is an association between reproductive factors and the incidence of gout.MethodsA total of 1,076,378 postmenopausal women aged 40–69 years who participated in national health screenings in 2009 were included in the study. The outcome was the occurrence of incident gout, which was defined using the ICD-10 code of gout (M10) in the claim database. Cox proportional hazard models were used for the analyses and stratified analyses according to body mass index (BMI) and the presence/absence of chronic kidney disease (CKD) were performed.ResultsThe mean follow-up duration was 8.1 years, and incident cases of gout were 64,052 (incidence rate 7.31 per 1000 person-years). Later menarche, earlier menopause, and a shorter reproductive span were associated with a high risk of gout. No association between parity and gout incidence was observed. Use of oral contraceptives (OC) and hormone replacement therapy (HRT) were associated with an increased risk of gout. The association between reproductive factors and gout was not statistical significant in the high BMI group. The effects of OC and HRT usage on gout were not significant in the CKD group.ConclusionShorter exposure to endogenous estrogen was associated with a high risk of gout. Conversely, exposure to exogenous estrogen such as OC and HRT was associated with an increased risk of gout.

Genetics of hyperuricemia and gout: Insights from recent genome-wide association studies and Mendelian randomization studies.

ABSTRACTGout is the most common form of inflammatory arthritis in adults. Elevation serum uric acid (SUA) concentration is known to be the key to gout pathogenesis. Since the first genome-wide association study (GWAS) for SUA was performed in 2007, the number of gene loci known to be associated with hyperuricemia and gout has grown rapidly. GWASs and Mendelian randomization studies have also reported numerous novel results regarding the genetics of hyperuricemia and gout since 2018. We concisely review recent advances in scholarship on the effects of genetics on hyperuricemia and gout risk. We also review data from genetic association studies in Taiwan and perform GWASs of SUA levels among Taiwan Biobank participants.

Association of Sodium-Glucose Transport Protein 2 Inhibitor Use for Type 2 Diabetes and Incidence of Gout in Taiwan

The use of sodium-glucose transport protein 2 (SGLT2) inhibitors is currently a standard intervention in patients with type 2 diabetes (T2DM) and exerts favorable pleiotropic effects to consistently lower blood urate levels. However, to date, no association between SGLT2 inhibitor use and the incidence of gout have been established. To investigate whether prescribed SGLT2 inhibitors are associated with lower gout incidence in patients with T2DM. In a cohort study, all patients with incident T2DM in Taiwan National Health Institution databases between May 1, 2016, and December 31, 2018, were retrospectively analyzed. As a comparator, patients using dipeptidyl peptidase 4 (DPP4) inhibitors were included. A total of 47 905 individuals receiving an SGLT2 inhibitor and 183 303 receiving a DPP4 inhibitor were evaluated, along with 47 405 pairs of patients using an SGLT2 inhibitor or DPP4 inhibitor in 1:1 propensity score-matched analyses. Data analysis was conducted from April 1 to June 30, 2021. A gout diagnosis was based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and the International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). Multiple Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% CIs. In total, 231 208 patients with T2DM were included in the population; 113 812 individuals (49.22%) were women, and the mean (SD) age was 61.53 (12.86) years. The overall gout incidence was 20.26 per 1000 patient-years for SGLT2 inhibitor users and 24.30 per 1000 patient-years for DPP4 inhibitor users. When potential risk factors were adjusted in the propensity score-matched population, use of SGLT2 inhibitors was associated with a lower risk of gout (HR, 0.89; 95% CI, 0.82-0.96) compared with DPP4 inhibitors, particularly for patients receiving dapagliflozin (HR, 0.86; 95% CI, 0.78-0.95). A sensitivity analysis, performed when a gout diagnosis was ascertained using the ICD-9-CM or ICD-10-CM code with gout-related medication, also showed a significantly lower risk for gout incidence of 15% with SGLT2 inhibitors (HR, 0.85; 95% CI, 0.74-0.97). Subgroup analysis indicated that SGLT2 inhibitor benefits in patients with T2DM to achieve a lower gout risk were not different across subgroups. The findings of this study suggest that patients with T2DM who are receiving SGLT2 inhibitors may have a lower risk for gout compared with those receiving DPP4 inhibitors.

The Association between Clonal Hematopoiesis and Gout

▪Background: Gout is a highly prevalent arthritis associated with debilitating joint pain and functional impairment. It is caused by elevated serum uric acid levels (hyperuricemia) and triggered by precipitation of urate crystals in and around joints. Urate crystals are ingested by macrophages and provoke an innate immune response with subsequent secretion of inflammatory cytokines including interleukin 1 beta (IL-1B). Clonal hematopoiesis of indeterminate potential (CHIP) is a precursor to hematologic malignancies defined by somatic mutations in hematopoietic cells that drive clonal expansion and inflammation. Specifically, CHIP is associated with an increased risk of cardiovascular events and can accelerate atherosclerosis. Mutations in TET2, one of the most commonly mutated genes in CHIP, lead to increased expression of IL-1B through inflammasome activation. Here we investigate the role of CHIP in the development of gout using a combination of human genetic studies and mouse models of CHIP.Methods: To determine the clinical association between CHIP and gout, we analyzed exome sequencing and clinical data from >50,000 individuals included in the UK Biobank (UKB) and Mass General Brigham Biobank (MGBB). To test whether mutant blood cells can promote gout, Tet2- and Dnmt3a-deficient mouse models were used.Results: CHIP was more prevalent in individuals with gout than without gout (MGBB: 12.3% vs. 7.9%, P=0.017; UKB: 8.2% vs. 5.8%, P=0.011) and individuals with CHIP were at increased risk of developing gout (UKB: hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.27-2.00; P<0.001). In multivariable analyses, CHIP with variant allele fraction (VAF) ≥10% was associated with higher risk of incident gout compared to no CHIP after adjusting for common gout risk factors (UKB: HR, 1.46; 95% CI, 1.07-2.01; P=0.019). To determine if somatically mutated blood cells directly contribute to the aberrant immune response in gout, we utilized a mouse model of MSU-mediated peritonitis. Compared to control animals, mice with hematopoietic-specific Tet2 deficiency demonstrated markedly increased IL-1B serum levels after injection with MSU (P<0.05). To study gene-specific contributions to joint tissue injury, we established an in vivo model that closely represents the clinical phenotype of gout. Following MSU treatment in situ, Tet2-deficient animals developed exacerbated paw edema compared to wild-type controls (P<0.05). We next generated bone-marrow derived macrophages (BMDM) from Tet2- and Dnmt3a-deficient mice to specifically investigate the MSU-induced cytokine profile in mutant macrophages. Consistent with our in vivo data, IL-1B was the most differentially secreted cytokine after MSU treatment in both Tet2-deficient and Dnmt3a-deficient BMDM compared to wild-type cells (P<0.05). RNA-sequencing confirmed a strong pro-inflammatory gene expression signature of MSU-treated Tet2- and Dnmt3a-deficient macrophages. Finally, we found that pharmacologic inhibition or genetic loss of inflammasome abrogated IL-1B secretion in Tet2- and Dnmt3a-deficient macrophages treated with MSU.Conclusion: CHIP is associated with an increased risk of having and developing gout in human cohorts and distinct mouse models confirm a direct influence of mutant hematopoietic cells on gout-induced inflammation and arthropathy. CHIP may provide a mechanistic explanation for the heterogeneity in clinical symptoms and inflammation due to gout. Our findings substantiate the biologic rationale for interventional strategies directed at CHIP-associated inflammatory conditions beyond cardiovascular disease and thereby define a path for clinical evaluation of targeted therapies for patients with CHIP-positive gout. DisclosuresMiller: Foundation Medicine: Consultancy. Neuberg: Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Other: Stock ownership. Natarajan: Amgen: Research Funding; Apple: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Boston Scientific: Research Funding; Blackstone Life Sciences: Consultancy; Genentech: Consultancy; Foresite Labs: Consultancy. Rao: Janssen: Honoraria, Research Funding; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; GlaxoSmithKline: Honoraria; Merck: Honoraria; Scipher Medicine: Honoraria.