Further delineation of short-chain enoyl-CoA hydratase deficiency in the Pacific population.

Short-chain enoyl-coA hydratase (SCEH) deficiency due to biallelic pathogenic ECHS1 variants was first reported in 2014 in association with Leigh syndrome (LS) and increased S-(2-carboxypropyl)cysteine excretion. It is potentially treatable with a valine-restricted, high-energy diet and emergency regimen. Recently, Simon et al. described four Samoan children harbouring a hypomorphic allele (c.489G > A, p.Pro163=) associated with reduced levels of normally-spliced mRNA. This synonymous variant, missed on standard genomic testing, is prevalent in the Samoan population (allele frequency 0.17). Patients with LS and one ECHS1 variant were identified in NZ and Australian genomic and clinical databases. ECHS1 sequence data were interrogated for the c.489G > A variant and clinical data were reviewed. Thirteen patients from 10 families were identified; all had Pacific ancestry including Samoan, Maori, Cook Island Maori, and Tokelauan. All developed bilateral globus pallidi lesions, excluding one pre-symptomatic infant. Symptom onset was in early childhood, and was triggered by illness or starvation in 9/13. Four of 13 had exercise-induced dyskinesia, 9/13 optic atrophy and 6/13 nystagmus. Urine S-(2-carboxypropyl)cysteine-carnitine and other SCEH-related metabolites were normal or mildly increased. Functional studies demonstrated skipping of exon four and markedly reduced ECHS1 protein. These data provide further support for the pathogenicity of this ECHS1 variant which is also prevalent in Maori, Cook Island Maori, and Tongan populations (allele frequency 0.14-0.24). It highlights the need to search for a second variant in apparent heterozygotes with an appropriate phenotype, and has implications for genetic counselling in family members who are heterozygous for the more severe ECHS1 alleles. SYNOPSIS: Short-chain enoyl-CoA hydratase deficiency is a frequent cause of Leigh-like disease in Maori and wider-Pacific populations, due to the high carrier frequency of a hypomorphic ECHS1 variant c.489G > A, p.[Pro163=, Phe139Valfs*65] that may be overlooked by standard genomic testing.

Large-scale cross-ancestry genome-wide meta-analysis of serum urate.

Hyperuricemia is an essential causal risk factor for gout and is associated with cardiometabolic diseases. Given the limited contribution of East Asian ancestry to genome-wide association studies of serum urate, the genetic architecture of serum urate requires exploration. A large-scale cross-ancestry genome-wide association meta-analysis of 1,029,323 individuals and ancestry-specific meta-analysis identifies a total of 351 loci, including 17 previously unreported loci. The genetic architecture of serum urate control is similar between European and East Asian populations. A transcriptome-wide association study, enrichment analysis, and colocalization analysis in relevant tissues identify candidate serum urate-associated genes, including CTBP1, SKIV2L, and WWP2. A phenome-wide association study using polygenic risk scores identifies serum urate-correlated diseases including heart failure and hypertension. Mendelian randomization and mediation analyses show that serum urate-associated genes might have a causal relationship with serum urate-correlated diseases via mediation effects. This study elucidates our understanding of the genetic architecture of serum urate control.

The impact of CREBRF rs373863828 Pacific-variant on infant body composition.

In Maori and Pacific adults, the CREBRF rs373863828 minor (A) allele is associated with increased body mass index (BMI) but reduced incidence of type-2 and gestational diabetes mellitus. In this prospective cohort study of Maori and Pacific infants, nested within a nutritional intervention trial for pregnant women with obesity and without pregestational diabetes, we investigated whether the rs373863828 A allele is associated with differences in growth and body composition from birth to 12-18 months' corrected age. Infants with and without the variant allele were compared using generalised linear models adjusted for potential confounding by gestation length, sex, ethnicity and parity, and in a secondary analysis, additionally adjusted for gestational diabetes. Carriage of the rs373863828 A allele was not associated with altered growth and body composition from birth to 6 months. At 12-18 months, infants with the rs373863828 A allele had lower whole-body fat mass [FM 1.4 (0.7) vs. 1.7 (0.7) kg, aMD -0.4, 95% CI -0.7, 0.0, P = 0.05; FM index 2.2 (1.1) vs. 2.6 (1.0) kg/m2 aMD -0.6, 95% CI -1.2,0.0, P = 0.04]. However, this association was not significant after adjustment for gestational diabetes, suggesting that it may be mediated, at least in part, by the beneficial effect of CREBRF rs373863828 A allele on maternal glycemic status.

Vitamin B12 status and hyperhomocysteinemia in patients with Rheumatoid arthritis treated with methotrexate and folic acid.

BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory arthritis in which the immune system targets synovial joints. Methotrexate serves as the mainstay of treatment for RA due to its efficacy. However, patients treated with methotrexate are uniquely at risk for vitamin B12 deficiency and hyperhomocysteinemia due to coincident disease risk factors and the fact that methotrexate use is associated with malabsorption. The objective of this study was to assess for vitamin B12 deficiency among patients with RA treated with methotrexate and folic acid. METHODS: This cross-sectional study included 50 patients with RA treated with methotrexate and folic acid and 49 patients with RA treated with other therapies. Patients were matched by age, sex, race, renal function, and disease activity. We compared plasma vitamin B12, methylmalonic acid, and homocysteine levels between these two groups utilizing quantitative and categorical analyses. RESULTS: Thirty-seven (74%) RA patients on methotrexate and folic acid had elevated plasma homocysteine levels compared with only 27 (55%) RA patients receiving other therapies (P < 0.05). The proportion of patients with low vitamin B12 and high methylmalonic acid levels did not differ between the two groups. CONCLUSIONS: Our data show high plasma homocysteine levels among RA patients treated with methotrexate and folic acid. While plasma vitamin B12 levels were similar between the two groups, high plasma homocysteine is also a sensitive marker of vitamin B12 deficiency. Additional studies should evaluate for the presence of clinical features of vitamin B12 deficiency and hyperhomocysteinemia among RA patients treated with methotrexate and folic acid.

The gout epidemic in French Polynesia: a modelling study of data from the Ma'i u'u epidemiological survey.

BACKGROUND: Gout is the most common cause of inflammatory arthritis worldwide, particularly in Pacific regions. We aimed to establish the prevalence of gout and hyperuricaemia in French Polynesia, their associations with dietary habits, their comorbidities, the prevalence of the HLA-B*58:01 allele, and current management of the disease. METHODS: The Ma'i u'u survey was epidemiological, prospective, cross-sectional, and gout-focused and included a random sample of adults from the general adult population of French Polynesia. It was conducted and data were collected between April 13 and Aug 16, 2021. Participants were randomly selected to represent the general adult population of French Polynesia on the basis of housing data collected during the 2017 territorial census. Each selected household was visited by a research nurse from the Ma'i u'u survey who collected data via guided, 1-h interviews with participants. In each household, the participant was the individual older than 18 years with the closest upcoming birthday. To estimate the frequency of HLA-B*58:01, we estimated HLA-B haplotypes on individuals who had whole-genome sequencing to approximately 5× average coverage (mid-pass sequencing). A subset of individuals who self-reported Polynesian ancestry and not European, Chinese, or other ancestry were used to estimate Polynesian-ancestry specific allele frequencies. Bivariate associations were reported for weighted participants; effect sizes were estimated through the odds ratio (OR) of the association calculated on the basis of a logistic model fitted with weighted observations. FINDINGS: Among the random sample of 2000 households, 896 participants were included, 140 individuals declined, and 964 households could not be contacted. 22 participants could not be weighted due to missing data, so the final weighted analysis included 874 participants (449 [51·4%] were female and 425 [48·6%] were male) representing the 196 630 adults living in French Polynesia. The estimated prevalence of gout was 14·5% (95% CI 9·9-19·2), representing 28 561 French Polynesian adults, that is 25·5% (18·2-32·8) of male individuals and 3·5% (1·0-6·0) of female individuals. The prevalence of hyperuricaemia was estimated at 71·6% (66·7-76·6), representing 128 687 French Polynesian adults. In multivariable analysis, age (OR 1·5, 95% CI 1·2-1·8 per year), male sex (10·3, 1·8-60·7), serum urate (1·6, 1·3-2·0 per 1 mg/dL), uraturia (0·8, 0·8-0·8 per 100 mg/L), type 2 diabetes (2·1, 1·4-3·1), BMI more than 30 kg/m2 (1·1, 1·0-1·2 per unit), and percentage of visceral fat (1·7, 1·1-2·7 per 1% increase) were associated with gout. There were seven heterozygous HLA-B*58:01 carriers in the full cohort of 833 individuals (seven [0·4%] of 1666 total alleles) and two heterozygous carriers in a subset of 696 individuals of Polynesian ancestry (two [0·1%]). INTERPRETATION: French Polynesia has an estimated high prevalence of gout and hyperuricaemia, with gout affecting almost 15% of adults. Territorial measures that focus on increasing access to effective urate-lowering therapies are warranted to control this major public health problem. FUNDING: Variant Bio, the French Polynesian Health Administration, Lille Catholic University Hospitals, French Society of Rheumatology, and Novartis.

Building capacity to conduct genetic epidemiology research on hyperuricaemia and gout in an Indigenous community in Guam.

Background: Gout, the most common inflammatory arthritis disease, and hyperuricaemia onset are influenced by environmental and genetic factors. We sought to investigate these factors in an Indigenous community in Guam. Methods: In this cross-sectional study, the University of Guam led the qualitative inquiry with the native community, training (pre-screening of participants, data collection methods, and biospecimen handling), study implementation (outreach and recruitment, data collection, and DNA extraction and quantification), and qualitative and epidemiologic data analyses. Recruitment targets were based on demographic representation in current census data. The University of Otago collaborated on ethics guidance, working with Indigenous communities, and led the genetic sequencing and genetic data analysis. Participants were recruited in Guam from Fall 2019 to Spring 2022. Results: Of the 359 participants, most self-identified as Native CHamorus (61.6%) followed by Other Micronesians (22.0%), and Filipinos (15.6%). The prevalence of metabolic conditions from highest to lowest were obesity (55.6%), hyperuricaemia (36.0%), hypertension (27.8%), gout (23.0%), diabetes (14.9%), cardiovascular disease (8.4%), kidney disease (7.3%), and liver disease (3.4%). Compared to Filipinos and Other Micronesians, significantly more CHamorus had hyperuricaemia (42.1% versus 26.8% in Filipinos and 25.3% in Other Micronesians), gout (28.5% versus 21.4% and 8.9%), diabetes (19.5% versus 8.9% and 6.3%), and hypertension (33.9% versus 19.6% and 16.5%). Conclusions: We estimated the prevalence of metabolic conditions, especially gout and hyperuricaemia, and found statistical differences among major ethnic groups in Guam, all while obtaining the Indigenous community's feedback on the genetic study and building gout research capacity. The results of ongoing genetic sequencing will be used to understand molecular causes of gout in Guam.

Regulation of SOCS3-STAT3 in urate-induced cytokine production in human myeloid cells.

OBJECTIVE: Hyperuricaemia is necessary for gout. High urate concentrations have been linked to inflammation in mononuclear cells. Here, we explore the role of the suppressor of cytokine signaling 3 (SOCS3) in urate-induced inflammation. METHODS: Peripheral blood mononuclear cells (PBMCs) from gout patients, hyperuricemic and normouricemic individuals were cultured for 24h with varying concentrations of soluble urate, followed by 24h restimulation with lipopolysaccharides (LPS)±monosodium urate (MSU) crystals. Transcriptomic profiling was performed using RNA-Sequencing. DNA methylation was assessed using Illumina Infinium® MethylationEPIC BeadChip system (EPIC array). Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was determined by flow cytometry. Cytokine responses were also assessed in PBMCs from patients with JAK2 V617F tyrosine kinase mutation. RESULTS: PBMCs pre-treated with urate produced more interleukin-1beta (IL-1ß) and interleukin-6 (IL-6) and less interleukin-1 receptor anatagonist (IL-1Ra) after LPS simulation. In vitro, urate treatment enhanced SOCS3 expression in control monocytes but no DNA methylation changes were observed at the SOCS3 gene. A dose-dependent reduction in phosphorylated STAT3 concomitant with a decrease in IL-1Ra was observed with increasing concentrations of urate. PBMCs with constitutively activated STAT3 (JAK2 V617F mutation) could not be primed by urate. CONCLUSION: In vitro, urate exposure increased SOCS3 expression, while urate priming, and subsequent stimulation resulted in decreased STAT3 phosphorylation and IL-1Ra production. There was no evidence that DNA methylation constitutes a regulatory mechanism of SOCS3. Elevated SOCS3 and reduced pSTAT3 could play a role in urate-induced hyperinflammation since urate priming had no effect in PBMCs from patients with constitutively activated STAT3.

Interaction of genetic variation at ADH1B and MLXIPL with alcohol consumption for elevated serum urate level and gout among people of European ethnicity.

BACKGROUND: Alcohol consumption is a risk factor for hyperuricaemia and gout. Multiple single-nucleotide polymorphisms (SNPs) have been identified as associated with both alcohol consumption and serum urate or gout in separate genome-wide association studies (GWAS). This study aimed to identify and characterise interactions between these shared signals of genetic association and alcohol consumption for serum urate level, hyperuricaemia, and gout. METHODS: This research was conducted using the UK Biobank resource. The association of alcohol consumption with serum urate and gout was tested among 458,405 European participants. Candidate SNPs were identified by comparing serum urate, gout, and alcohol consumption GWAS for shared signals of association. Multivariable-adjusted linear and logistic regression analyses were conducted with the inclusion of interaction terms to identify SNP-alcohol consumption interactions for association with serum urate level, hyperuricaemia, and gout. The nature of these interactions was characterised using genotype-stratified association analyses. RESULTS: Alcohol consumption was associated with elevated serum urate and gout. For serum urate level, non-additive interactions were identified between alcohol consumption and rs1229984 at the ADH1B locus (P = 3.0 × 10-44) and rs6460047 at the MLXIPL locus (P = 1.4 × 10-4). ADH1B also demonstrated interaction with alcohol consumption for hyperuricaemia (P = 7.9 × 10-13) and gout (P = 8.2 × 10-9). Beer intake had the most significant interaction with ADH1B for association with serum urate and gout among men, while wine intake had the most significant interaction among women. In the genotype-stratified association analyses, ADH1B and MLXIPL were associated with serum urate level and ADH1B was associated with hyperuricaemia and gout among consumers of alcohol but not non-consumers. CONCLUSIONS: In this large study of European participants, novel interactions with alcohol consumption were identified at ADH1B and MLXIPL for association with serum urate level and at ADH1B for association with hyperuricaemia and gout. The association of ADH1B with serum urate and gout may occur through the modulation of alcohol metabolism rate among consumers of alcohol.

Natural Changbai mineral water reduces obesity risk through regulating metabolism and gut microbiome in a hyperuricemia male mouse model.

Access to clean and safe drinking water is essential. This study aimed to evaluate the effect of a kind of small molecular natural mineral water, C-cell mineral water on hyperuricemia male mice metabolism condition. A 13-week drinking water intervention study was conducted in Uox-knockout mice (KO). The hepatic metabolite profiling and related genes expression were detected by UPLC-TOF-MS and transcriptomic, and the gut microbiota of KO mice was determined by metagenomics sequencing. Results showed that the body weight of mice fed with C-cell water was remarkably lower than that of control mice on D 77 and D 91. Hepatic metabolite profiling revealed a shift in the pathway of glycine, serine and threonine metabolism, pantothenate and CoA biosynthesis, and biosynthesis of cofactors in KO mice fed with C-cell mineral water. Increased energy metabolism levels were related to increased hepatic expression of genes responsible for coenzyme metabolism and lipid metabolism. Gut microbiota was characterized by increasing activity of beneficial bacteria Blautia, and reducing activity of pathobiont bacteria Parasutterella. These genera have been reported to be associated with obesity. Small molecular mineral-rich natural water ingestion regulates metabolism and gut microbiota, protecting against obesity induced by hyperuricemia through mediating a microbiota-liver axis.

The development and evaluation of dose-prediction tools for allopurinol therapy (Easy-Allo tools).

AIMS: Dose escalation at the initiation of allopurinol therapy can be protracted and resource intensive. Tools to predict the allopurinol doses required to achieve target serum urate concentrations would facilitate the implementation of more efficient dose-escalation strategies. The aim of this research was to develop and externally evaluate allopurinol dosing tools, one for use when the pre-urate-lowering therapy serum urate is known (Easy-Allo1) and one for when it is not known (Easy-Allo2). METHODS: A revised population pharmacokinetic-pharmacodynamic model was developed using data from 653 people with gout. Maintenance doses to achieve the serum urate target of <0.36 mmol L-1 in >80% of individuals were simulated and evaluated against external data. The predicted and observed allopurinol doses were compared using the mean prediction error (MPE) and root mean square error (RMSE). The proportion of Easy-Allo predicted doses within 100 mg of the observed was quantified. RESULTS: Allopurinol doses were predicted by total body weight, baseline urate, ethnicity and creatinine clearance. Easy-Allo1 produced unbiased and suitably precise dose predictions (MPE 2 mg day-1 95% confidence interval [CI] -13-17, RMSE 91%, 90% within 100 mg of the observed dose). Easy-Allo2 was positively biased by about 70 mg day-1 and slightly less precise (MPE 70 mg day-1 95% CI 52-88, RMSE 131%, 71% within 100 mg of the observed dose). CONCLUSIONS: The Easy-Allo tools provide a guide to the allopurinol maintenance dose requirement to achieve the serum urate target of <0.36 mmol L-1 and will aid in the development of novel dose-escalation strategies for allopurinol therapy.

Hyperuricemia Subtypes Classified According to Renal Uric Acid Handling Manifesting Distinct Phenotypic and Genetic Profiles in People With Gout.

OBJECTIVE: Hyperuricemia can be stratified into four subtypes according to renal uric acid handling. The aim of this study was to comprehensively describe the biologic characteristics (including genetic background) of clinically defined hyperuricemia subtypes in two large geographically independent gout cohorts. METHODS: Hyperuricemia subtype was defined as renal uric acid overload (ROL), renal uric acid underexcretion (RUE), combined, or renal normal. Twenty single nucleotide polymorphisms (SNPs) previously identified as gout risk loci or associated with serum urate (SU) concentration in the East Asian population were genotyped. Weighted polygenic risk scores were calculated to assess the cumulative effect of genetic risks on the subtypes. RESULTS: Of the 4,873 participants, 8.8% had an ROL subtype, 60.9% RUE subtype, 23.1% combined subtype, and 7.2% normal subtype. The ROL subtype was independently associated with older age at onset, lower SU, tophi, and diabetes mellitus; RUE was associated with lower body mass index (BMI) and non-diabetes mellitus; the combined subtype was associated with younger age at onset, higher BMI, SU, estimated glomerular filtration rate (eGFR), and smoking; and the normal subtype was independently associated with older age at onset, lower SU, and eGFR. Thirteen SNPs were associated with gout with 6 shared loci and subtype-dependent risk loci patterns. High polygenic risk scores were associated with ROL subtype (odds ratio [OR] = 9.63, 95% confidence interval [95% CI] 4.53-15.12), RUE subtype (OR = 2.18, 95% CI 1.57-3.03), and combined subtype (OR = 6.32, 95% CI 4.22-9.48) compared with low polygenic risk scores. CONCLUSION: Hyperuricemia subtypes classified according to renal uric acid handling have subtype-specific clinical and genetic features, suggesting subtype-unique pathophysiologic mechanisms.

Clinical characteristics of adolescent-onset gout in Chinese: A hospital-based cross-sectional study.

OBJECTIVE: Adolescent-onset gout has a greater impact on the lives and health of patients than adult-onset gout. However, there is a relative lack of clinical information on adolescent-onset gout. Hence, we analyzed a Chinese cohort. METHODS: We studied clinical features of 9,003 Chinese patients. Gout onset age of 12 - 19 years is defined as adolescent-onset group (AG), 20 - 40 years as early-onset group (EG), and 41 - 64 years as late-onset group (LG). Multivariable regression analysis evaluated factors associated with recurrent flares, serum urate (SU) levels, and underexcretion type in AG. RESULTS: Compared with EG and LG, the AG had higher SU levels [AG: 9.5 (2.2) mg/dL, EG: 8.6 (2.1) mg/dL, LG: 7.73 (2.0) mg/dL, P < 0.001], higher percentage of positive family history of gout (AG: 41.8 %, EG: 29.6 %, LG: 24.6 %, P < 0.001), underexcretion type (AG: 62.4 %, EG: 62.5 %, LG: 58.8 %, P = 0.04), recurrent flares (AG: 78.1 %, EG: 70.3 %, LG: 68.9 %, P = 0.01). Urate-lowering therapy (ULT) initiated [OR 6.58 (95 % CI 1.35 - 32.00)] and hypercholesterolemia [OR 4.16 (95 % CI 1.28 - 13.53)] were associated with recurrent flares. eGFR was identified to be a significant variable of increasing SU levels [beta -0.24 (95 % CI -0.04 to -0.01)]. Hypertriglyceridemia [OR 0.35 (95 % CI 0.17 - 0.71)] was related to underexcretion type. CONCLUSION: Adolescent-onset gout patients had clinically distinctive features with higher SU levels, BMI, positive gout family history, underexcretion type and recurrent flares. These specific populations were less likely to achieve ULT target, requiring more clinical attention.

GWAS-identified hyperuricemia-associated IGF1R variant rs6598541 has a limited role in urate mediated inflammation in human mononuclear cells.

Gout is a common autoinflammatory joint diseases characterized by deposition of monosodium urate (MSU) crystals which trigger an innate immune response mediated by inflammatory cytokines. IGF1R is one of the loci associated with both urate levels and gout susceptibility in GWAS to date, and IGF-1-IGF-1R signaling is implicated in urate control. We investigate the role of IGF-1/IGF1R signaling in the context of gouty inflammation. Also, we test the gout and urate-associated IGF1R rs6598541 polymorphism for association with the inflammatory capacity of mononuclear cells. For this, freshly isolated human peripheral blood mononuclear cells (PBMCs) were exposed to recombinant IGF-1 or anti-IGF1R neutralizing antibody in the presence or absence of solubilized urate, stimulated with LPS/MSU crystals. Also, the association of rs6598541 with IGF1R and protein expression and with ex vivo cytokine production levels after stimulation with gout specific stimuli was tested. Urate exposure was not associated with IGF1R expression in vitro or in vivo. Modulation of IGF1R did not alter urate-induced inflammation. Developing urate-induced trained immunity in vitro was not influenced in cells challenged with IGF-1 recombinant protein. Moreover, the IGF1R rs6598541 SNP was not associated with cytokine production. Our results indicate that urate-induced inflammatory priming is not regulated by IGF-1/IGF1R signaling in vitro. IGF1R rs6598541 status was not asociated with IGF1R expression or cytokine production in primary human PBMCs. This study suggests that the role of IGF1R in gout is tissue-specific and may be more relevant in the control of urate levels rather than in inflammatory signaling in gout.

A stable liver-specific urate oxidase gene knockout hyperuricemia mouse model finds activated hepatic de novo purine biosynthesis and urate nephropathy.

Urate oxidase (Uox)-deficient mice could be an optimal animal model to study hyperuricemia and associated disorders. We develop a liver-specific conditional knockout Uox-deficient (UoxCKO) mouse using the Cre/loxP gene targeting system. These UoxCKO mice spontaneously developed hyperuricemia with accumulated serum urate metabolites. Blocking urate degradation, the UoxCKO mice showed significant de novo purine biosynthesis (DNPB) in the liver along with amidophosphoribosyltransferase (Ppat). Pegloticase and allopurinol reversed the elevated serum urate (SU) levels in UoxCKO mice and suppressed the Ppat up-regulation. Although urate nephropathy occurred in 30-week-old UoxCKO mice, 90 % of Uox-deficient mice had a normal lifespan without pronounced urate transport abnormality. Thus, UoxCKO mice are a stable model of human hyperuricemia. Activated DNPB in the UoxCKO mice provides new insights into hyperuricemia, suggesting increased SU influences purine synthesis.

Development and Internal Validation of a Clinical and Genetic Risk Score for Rheumatoid Arthritis-Associated Interstitial Lung Disease.

OBJECTIVE: Although clinical and genetic risk factors have been identified for rheumatoid arthritis-associated interstitial lung disease (RA-ILD), there are no current tools allowing for risk stratification. We sought to develop and validate an ILD risk model in a large, multicentre, prospective RA cohort. METHODS: Participants in the Veterans Affairs RA (VARA) registry were genotyped for 12 single nucleotide polymorphisms (SNPs) associated with idiopathic pulmonary fibrosis. ILD was validated through systematic record review. A genetic risk score (GRS) was computed from minor alleles weighted by effect size with ILD, using backward selection. The GRS was combined with clinical risk factors within a logistic regression model. Internal validation was completed using bootstrapping, and model performance was assessed by the area under the receiver operating curve (AUC). RESULTS: Of 2,386 participants (89% male, mean age 69.5 years), 9.4% had ILD. Following backward selection, five SNPs contributed to the GRS. The GRS and clinical factors outperformed clinical factors alone in discriminating ILD (AUC 0.675 vs 0.635, p< 0.001). The shrinkage-corrected performance for combined and clinical-only models was 0.667 (95% CI 0.628, 0.712) and 0.623 (95% CI 0.584, 0.651), respectively. Twenty percent of the cohort had a combined risk score below a cut-point with >90% sensitivity. CONCLUSION: A clinical and genetic risk model discriminated ILD in a large, multicentre RA cohort better than a clinical-only model, excluding 20% of the cohort from low-yield testing. These results demonstrate the potential utility of a GRS in RA-ILD and support further investigation into individualized risk stratification and screening.

Cadmium exposure dysregulates purine metabolism and homeostasis across the gut-liver axis in a mouse model.

Cadmium (Cd) exposure has been associated with the development of enterohepatic circulation disorders and hyperuricemia, but the possible contribution of chronic low-dose Cd exposure to disease progression is still need to be explored. A mouse model of wild-type mice (WT) and Uox-knockout mice (Uox-KO) to find out the toxic effects of chronic low-dose Cd exposure on liver purine metabolism by liquid chromatography-mass spectrometry (LC-MS) platform and associated intestinal flora. High throughput omics analysis including metabolomics and transcriptomics showed that Cd exposure can cause disruption of purine metabolism and energy metabolism. Cd changes several metabolites associated with purine metabolism (xanthine, hypoxanthine, adenosine, uridine, inosine) and related genes, which are associated with elevated urate levels. Microbiome analysis showed that Cd exposure altered the disturbance of homeostasis in the gut. Uox-KO mice were more susceptible to Cd than WT mice. Our findings extend the understanding of potential toxicological interactions between liver and gut microbiota and shed light on the progression of metabolic diseases caused by Cd exposure.

Pangenome graphs in infectious disease: a comprehensive genetic variation analysis of Neisseria meningitidis leveraging Oxford Nanopore long reads.

Whole genome sequencing has revolutionized infectious disease surveillance for tracking and monitoring the spread and evolution of pathogens. However, using a linear reference genome for genomic analyses may introduce biases, especially when studies are conducted on highly variable bacterial genomes of the same species. Pangenome graphs provide an efficient model for representing and analyzing multiple genomes and their variants as a graph structure that includes all types of variations. In this study, we present a practical bioinformatics pipeline that employs the PanGenome Graph Builder and the Variation Graph toolkit to build pangenomes from assembled genomes, align whole genome sequencing data and call variants against a graph reference. The pangenome graph enables the identification of structural variants, rearrangements, and small variants (e.g., single nucleotide polymorphisms and insertions/deletions) simultaneously. We demonstrate that using a pangenome graph, instead of a single linear reference genome, improves mapping rates and variant calling for both simulated and real datasets of the pathogen Neisseria meningitidis. Overall, pangenome graphs offer a promising approach for comparative genomics and comprehensive genetic variation analysis in infectious disease. Moreover, this innovative pipeline, leveraging pangenome graphs, can bridge variant analysis, genome assembly, population genetics, and evolutionary biology, expanding the reach of genomic understanding and applications.

Metabolomics and Machine Learning Identify Metabolic Differences and Potential Biomarkers for Frequent Versus Infrequent Gout Flares.

OBJECTIVE: The objective of this study was to discover differential metabolites and pathways underlying infrequent gout flares (InGF) and frequent gout flares (FrGF) using metabolomics and to establish a predictive model by machine learning (ML) algorithms. METHODS: Serum samples from a discovery cohort of 163 patients with InGF and 239 patients with FrGF were analyzed by mass spectrometry-based untargeted metabolomics to profile differential metabolites and explore dysregulated metabolic pathways using pathway enrichment analysis and network propagation-based algorithms. ML algorithms were performed to establish a predictive model based on selected metabolites, which was further optimized by a quantitative targeted metabolomics method and validated in an independent validation cohort with 97 participants with InGF and 139 participants with FrGF. RESULTS: A total of 439 differential metabolites between InGF and FrGF groups were identified. Top dysregulated pathways included carbohydrates, amino acids, bile acids, and nucleotide metabolism. Subnetworks with maximum disturbances in the global metabolic networks featured cross-talk between purine metabolism and caffeine metabolism, as well as interactions among pathways involving primary bile acid biosynthesis, taurine and hypotaurine metabolism, alanine, aspartate, and glutamate metabolism, suggesting epigenetic modifications and gut microbiome in metabolic alterations underlying InGF and FrGF. Potential metabolite biomarkers were identified using ML-based multivariable selection and further validated by targeted metabolomics. Area under receiver operating characteristics curve for differentiating InGF and FrGF achieved 0.88 and 0.67 for the discovery and validation cohorts, respectively. CONCLUSION: Systematic metabolic alterations underlie InGF and FrGF, and distinct profiles are associated with differences in gout flare frequencies. Predictive modeling based on selected metabolites from metabolomics can differentiate InGF and FrGF.

Genetic testing for misclassified monogenic diabetes in Maori and Pacific peoples in Aotearoa New Zealand with early-onset type 2 diabetes.

Aims: Monogenic diabetes accounts for 1-2% of diabetes cases yet is often misdiagnosed as type 2 diabetes. The aim of this study was to examine in Maori and Pacific adults clinically diagnosed with type 2 diabetes within 40 years of age, (a) the prevalence of monogenic diabetes in this population (b) the prevalence of beta-cell autoantibodies and (c) the pre-test probability of monogenic diabetes. Methods: Targeted sequencing data of 38 known monogenic diabetes genes was analyzed in 199 Maori and Pacific peoples with BMI of 37.9 ± 8.6 kg/m2 who had been diagnosed with type 2 diabetes between 3 and 40 years of age. A triple-screen combined autoantibody assay was used to test for GAD, IA-2, and ZnT8. MODY probability calculator score was generated in those with sufficient clinical information (55/199). Results: No genetic variants curated as likely pathogenic or pathogenic were found. One individual (1/199) tested positive for GAD/IA-2/ZnT8 antibodies. The pre-test probability of monogenic diabetes was calculated in 55 individuals with 17/55 (31%) scoring above the 20% threshold considered for diagnostic testing referral. Discussion: Our findings suggest that monogenic diabetes is rare in Maori and Pacific people with clinical age, and the MODY probability calculator likely overestimates the likelihood of a monogenic cause for diabetes in this population.

A Polynesian-specific missense CETP variant alters the lipid profile.

Identifying population-specific genetic variants associated with disease and disease-predisposing traits is important to provide insights into the genetic determinants of health and disease between populations, as well as furthering genomic justice. Various common pan-population polymorphisms at CETP associate with serum lipid profiles and cardiovascular disease. Here, sequencing of CETP identified a missense variant rs1597000001 (p.Pro177Leu) specific to Maori and Pacific people that associates with higher HDL-C and lower LDL-C levels. Each copy of the minor allele associated with higher HDL-C by 0.236 mmol/L and lower LDL-C by 0.133 mmol/L. The rs1597000001 effect on HDL-C is comparable with CETP Mendelian loss-of-function mutations that result in CETP deficiency, consistent with our data, which shows that rs1597000001 lowers CETP activity by 27.9%. This study highlights the potential of population-specific genetic analyses for improving equity in genomics and health outcomes for population groups underrepresented in genomic studies.