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Abstract Objectives Gout is caused by the response of the innate immune system to monosodium urate (MSU) crystals. A recent gout GWAS identified a signal of genetic association at a locus encompassing IL1RN-IL1F10. Colocalisation analysis using Genotype Tissue Expression Database (GTEx) eQTL data showed that the signal overlaps with genetic control of IL1RN/IL1F10 gene expression. We assess the functional implications of IL1RN rs9973741, the lead gout-associated variant. Methods We conducted functional validation of IL1RN rs9973741 in patients with gout and controls. The transcription level of IL1RN/IL1F10 was investigated in unstimulated or MSU-crystal co-stimulated PBMCs. Ex vivo functional assays were performed in PBMCs stimulated with C16 + MSU crystals or LPS for 24 h. Cytokine levels were assessed by ELISA. Results In unstimulated PBMCs, no association of IL1RN rs9973741 (gout risk allele G) to IL1RN expression was observed while IL-1F10 was hindered by low expression at both transcriptional and protein levels. However, G allele carriers showed lower IL1RN expression in PBMCs stimulated with C16/MSU crystal and lower concentrations of circulating IL-1Ra in both controls and gout patients. PBMCs depicted less spontaneous IL-1Ra release in GG homozygous controls and lower IL-1Ra production in response to C16 + MSU crystal costimulation in patients with gout. The G allele was associated with elevated IL-1β cytokine production in response to C16 + MSU crystal stimulation in controls. Conclusions The gout risk allele G associates with lower circulating IL-1Ra, lower IL-1Ra production in PBMC assays and elevated IL-1β production in PBMCs challenged with C16 + MSU crystals but not in unchallenged cells. Our data indicate that the genetic signal that associates with gout at IL1RN-IL1F10 region functions to alter expression of IL-1Ra when stimulated by MSU crystals.

Abstract 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.

Abstract In Māori 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 Māori 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.

Abstract 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.

Abstract 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.

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.

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.

Abstract The genetic determinants of the allopurinol dose‐concentration relationship have not been extensively studied. We aimed to clarify what factors, including genetic variation in urate transporters, influence oxypurinol pharmacokinetics (PKs). A population PK model for oxypurinol was developed with NONMEM (version 7.3). The influence of urate transporter genetic variants for ABCG2 (rs2231142 and rs10011796), SLC2A9/GLUT9 (rs11942223), SLC17A1/NPT1 (rs1183201), SLC22A12/URAT1 (rs3825018), SLC22A11/OAT4 (rs17300741), and ABCC4/MRP4 (rs4148500), as well as other participant factors on oxypurinol PKs was assessed. Data from 325 people with gout were available. The presence of the T allele for ABCG2 (rs2231142) and SLC17A1/NPT1 (rs1183201) was associated with a 24% and 22% increase in oxypurinol clearance, respectively, in univariate analysis. This effect was not significant in the multivariate analysis. In the final model, oxypurinol PKs were predicted by creatinine clearance, diuretic use, ethnicity, and body weight. We have found that genetic variability in the transporters examined does not appear to influence oxypurinol PKs.

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.

Summary: 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 Māori 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.

Abstract In observational studies, serum urate positively associates with cardiometabolic and kidney diseases. We analyzed data from a randomised placebo-controlled trial to determine whether moderate hyperuricemia induced by inosine affects cardiometabolic and kidney function markers. One hundred and twenty post-menopausal women were recruited into a 6-month randomised, double-blind, placebo-controlled trial of inosine for bone health. Change from baseline in the following pre-specified endpoints was analyzed: body mass index; blood pressure; lipid profile; C-reactive protein; fasting glucose; insulin; HbA1c; serum creatinine; and estimated glomerular filtration rate (eGFR). Despite increases in serum urate levels (+ 0.17 mmol/L at week 6, P

Abstract Objectives The objective of this study was to develop and validate a prediction model for renal urate underexcretion (RUE) in male gout patients. Methods Men with gout enrolled from multicenter cohorts in China were analyzed as the development and validation data sets. The RUE phenotype was defined as fractional excretion of uric acid (FEUA)

Abstract Background Patients with gout frequently have low urinary pH, which is associated with the nephrolithiasis. However, the specific distribution of urinary pH and potential relationship of acidic urine pH to broader manifestations of kidney disease in gout are still poorly understood. Methods A 2016–2020 population-based cross-sectional study was conducted among 3565 gout patients in the dedicated gout clinic of the Affiliated Hospital of Qingdao University to investigate the association between low urinary pH and kidney disease. We studied patients that we defined to have “primary gout”, based on the absence of > stage 2 CKD. All subjects underwent 14 days of medication washout and 3-day standardized metabolic diet. We obtained general medical information, blood and urine biochemistries, and renal ultrasound examination on the day of the visit. The primary readouts were urine pH, eGFR, nephrolithiasis, renal cysts, microhematuria, and proteinuria. Patients were assigned into 5 subgroups (urine pH ≤5.0, 5.0 6.9), aligning with the clinical significance of urine pH. Results Overall, the median urine pH and eGFR of all patients was 5.63 (IQR 5.37~6.09), and 98.32 (IQR 86.03~110.6), with acidic urine in 46.5% of patients. The prevalence of nephrolithiasis, microhematuria, and proteinuria were 16.9%, 49.5%, and 6.9%, respectively. By univariate analysis, eGFR was significantly associated with age, sex, duration of gout, tophus, body mass index, systolic blood pressure, diastolic blood pressure, fasting blood glucose, total cholesterol, serum utare, hypertension, diabetes, and urine pH. On multivariable analysis, eGFR was associated with age, sex, diastolic blood pressure, serum uric acid, hypertension, diabetes, and urine pH. Acidic urine pH, especially urine pH < 5.0, was significantly associated with the prevalence of kidney disease, including > stage 1 CKD, nephrolithiasis, kidney cyst, and microhematuria. Patients with 6.2 ≤ urine pH ≤ 6.9 and SU ≤ 480 μmol/L had the highest eGFR with the lowest prevalence of nephrolithiasis, microhematuria, and proteinuria. Conclusions Approximately half of gout subjects had acidic urine pH. Urine pH < 5.0 was associated with significantly increased nephrolithiasis, renal cyst, microhematuria, and proteinuria. The results support prospective clinical investigation of urinary alkalinization in selected gout patients with acidic urine pH.

BackgroundUnderstanding which group of patients with type 2 diabetes will have the most glucose lowering response to certain medications (which target different aspects of glucose metabolism) is the first step in precision medicine.AimsWe hypothesized that people with type 2 diabetes who generally have high insulin resistance, such as people of Māori/Pacific ethnicity, and those with obesity and/or hypertriglyceridemia (OHTG), would have greater glucose-lowering by pioglitazone (an insulin sensitizer) versus vildagliptin (an insulin secretagogue).MethodsA randomised, open-label, two-period crossover trial was conducted in New Zealand. Adults with type 2 diabetes, HbA1c>58mmol/mol (>7.5%), received 16 weeks of either pioglitazone (30mg) or vildagliptin (50mg) daily, then switched to the other medication over for another 16 weeks of treatment. Differences in HbA1c were tested for interaction with ethnicity or OHTG, controlling for baseline HbA1c using linear mixed models. Secondary outcomes included weight, blood pressure, side-effects and diabetes treatment satisfaction.Results346 participants were randomised (55% Māori/Pacific) between February 2019 to March 2020. HbA1c after pioglitazone was lower than after vildagliptin (mean difference -4.9mmol/mol [0.5%]; 95% CI -6.3, -3.5; p

Summary: Current understanding of lipid genetics has come mainly from studies in European-ancestry populations; limited effort has focused on Polynesian populations, whose unique population history and high prevalence of dyslipidemia may provide insight into the biological foundations of variation in lipid levels. Here, we performed an association study to fine map a suggestive association on 5q35 with high-density lipoprotein cholesterol (HDL-C) seen in Micronesian and Polynesian populations. Fine-mapping analyses in a cohort of 2,851 Samoan adults highlighted an association between a stop-gain variant (rs200884524; c.652C>T, p.R218∗; posterior probability = 0.9987) in BTNL9 and both lower HDL-C and greater triglycerides (TGs). Meta-analysis across this and several other cohorts of Polynesian ancestry from Samoa, American Samoa, and Aotearoa New Zealand confirmed the presence of this association (βHDL-C = −1.60 mg/dL, pHDL-C = 7.63 × 10−10; βTG = 12.00 mg/dL, pTG = 3.82 × 10−7). While this variant appears to be Polynesian specific, there is also evidence of association from other multiancestry analyses in this region. This work provides evidence of a previously unexplored contributor to the genetic architecture of lipid levels and underscores the importance of genetic analyses in understudied populations.

Abstract Background Historically, geneticists have relied on genotyping arrays and imputation to study human genetic variation. However, an underrepresentation of diverse populations has resulted in arrays that poorly capture global genetic variation, and a lack of reference panels. This has contributed to deepening global health disparities. Whole genome sequencing (WGS) better captures genetic variation but remains prohibitively expensive. Thus, we explored WGS at “mid-pass” 1-7x coverage. Results Here, we developed and benchmarked methods for mid-pass sequencing. When applied to a population without an existing genomic reference panel, 4x mid-pass performed consistently well across ethnicities, with high recall (98%) and precision (97.5%). Conclusion Compared to array data imputed into 1000 Genomes, mid-pass performed better across all metrics and identified novel population-specific variants with potential disease relevance. We hope our work will reduce financial barriers for geneticists from underrepresented populations to characterize their genomes prior to biomedical genetic applications.

The enzyme cytochrome P450 2D6 (CYP2D6) metabolises approximately 25% of commonly prescribed drugs, including analgesics, anti-hypertensives, and anti-depressants, among many others. Genetic variation in drug metabolising genes can alter how an individual responds to prescribed drugs, including predisposing to adverse drug reactions. The majority of research on the CYP2D6 gene has been carried out in European and East Asian populations, with many Indigenous and minority populations, such as those from Oceania, greatly underrepresented. However, genetic variation is often population specific and analysis of diverse ethnic groups can reveal differences in alleles that may be of clinical significance. For this reason, we set out to examine the range and frequency of CYP2D6 variants in a sample of 202 Māori and Pacific people living in Aotearoa (New Zealand). We carried out long PCR to isolate the CYP2D6 region before performing nanopore sequencing to identify all variants and alleles in these samples. We identified twelve variants which have previously not been reported in the PharmVar CYP2D6 database, three of which were exonic missense variations. Six of these occurred in single samples and one was found in 19 samples (9.4% of the cohort). The remaining five variants were identified in two samples each. Identified variants formed twelve new CYP2D6 suballeles and four new star alleles, now recorded in the PharmVar database. One striking finding was that CYP2D6*71, an allele of uncertain functional status which has been rarely observed in previous studies, occurs at a relatively high frequency (8.9%) within this cohort. These data will help to ensure that CYP2D6 genetic analysis for pharmacogenetic purposes can be carried out accurately and effectively in this population group.

Abstract 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 was 12.2%. In an adjusted Cox proportional hazards model, compared to the referent baseline SU 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.

Abstract Objectives Hyperuricemia is a metabolic condition central to gout pathogenesis. Urate exposure primes human monocytes towards a higher capacity to produce and release IL-1β. In this study, we assessed the epigenetic processes associated to urate-mediated hyper-responsiveness. Methods Freshly isolated human peripheral blood mononuclear cells or enriched monocytes were pre-treated with solubilized urate and stimulated with LPS with or without monosodium urate (MSU) crystals. Cytokine production was determined by ELISA. Histone epigenetic marks were assessed by sequencing immunoprecipitated chromatin. Mice were injected intraarticularly with MSU crystals and palmitate after inhibition of uricase and urate administration in the presence or absence of methylthioadenosine. DNA methylation was assessed by methylation array in whole blood of 76 participants with normouricemia or hyperuricemia. Results High concentrations of urate enhanced the inflammatory response in vitro in human cells and in vivo in mice, and broad-spectrum methylation inhibitors reversed this effect. Assessment of histone 3 lysine 4 trimethylation (H3K4me3) and histone 3 lysine 27 acetylation (H3K27ac) revealed differences in urate-primed monocytes compared to controls. Differentially methylated regions (e.g. HLA-G, IFITM3, PRKAB2) were found in people with hyperuricemia compared to normouricemia in genes relevant for inflammatory cytokine signaling. Conclusion Urate alters the epigenetic landscape in selected human monocytes or whole blood of people with hyperuricemia compared to normouricemia. Both histone modifications and DNA methylation show differences depending on urate exposure. Subject to replication and validation, epigenetic changes in myeloid cells may be a therapeutic target in gout.

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.

Abstract 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 (

Abstract 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

Objective: The minor allele (A) of the rs373863828 variant (p.Arg457Gln) in CREBRF is restricted to indigenous peoples of the Pacific islands (including New Zealand Māori and peoples of Polynesia), with a frequency of up to 25% in these populations. This allele associates with a large increase in body mass index (BMI) but with significantly lower risk of type-2 diabetes (T2D). It remains unclear whether the increased BMI is driven by increased adiposity or by increased lean mass. Methods: We undertook body composition analysis using DXA in 189 young men of Māori and Pacific descent living in Aotearoa New Zealand. Further investigation was carried out in two orthologous Arg458Gln knockin mouse models on FVB/NJ and C57BL/6j backgrounds. Results: The rs373863828 A allele was associated with lower fat mass when adjusted for BMI (p < 0.05) and was associated with significantly lower circulating levels of the muscle inhibitory hormone myostatin (p < 0.05). Supporting the human data, significant reductions in adipose tissue mass were observed in the knockin mice. This was more significant in older mice in both backgrounds and appeared to be the result of reduced age-associated increases in fat mass. The older male knockin mice on C57BL/6j background also had increased grip strength (p < 0.01) and lower levels of myostatin (p < 0.05). Conclusion: Overall, these results prove that the rs373863828 A-allele is associated with a reduction of myostatin levels which likely contribute to an age-dependent lowering of fat mass, at least in males.

Abstract 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/m2) and low/normal BMI (

The common ABCG2 variant Q141K contributes to hyperuricemia and gout risk. Here, using a human interventional study and a new orthologous mouse model, the authors report a tissue specific pathobiology of the Q141K variant, and support a significant role for ABCG2 in urate excretion in both the kidney and intestine.

Plasma lipoprotein (a) [Lp(a)] levels are largely determined by variation in the LPA gene, which codes for apo(a). Genome-wide association studies (GWASs) have identified nonsynonymous variants in LPA that associate with low Lp(a) levels, although their effect on apo(a) function is unknown. We investigated two such variants, R990Q and R1771C, which were present in four null Lp(a) individuals, for structural and functional effects. Sequence alignments showed the R990 and R1771 residues to be highly conserved and homologous to each other and to residues associated with plasminogen deficiency. Structural modeling showed both residues to make several polar contacts with neighboring residues that would be ablated on substitution. Recombinant expression of the WT and R1771C apo(a) in liver and kidney cells showed an abundance of an immature form for both apo(a) proteins. A mature form of apo(a) was only seen with the WT protein. Imaging of the recombinant apo(a) proteins in conjunction with markers of the secretory pathway indicated a poor transit of R1771C into the Golgi. Furthermore, the R1771C mutant displayed a glycosylation pattern consistent with ER, but not Golgi, glycosylation. We conclude that R1771 and the equivalent R990 residue facilitate correct folding of the apo(a) kringle structure and mutations at these positions prevent the proper folding required for full maturation and secretion. To our knowledge, this is the first example of nonsynonymous variants in LPA being causative of a null Lp(a) phenotype.

Abstract Background The ABCG2 Q141K (rs2231142) and rs10011796 variants associate with hyperuricaemia (HU). The effect size of ABCG2 rs2231142 on urate is ~ 60% that of SLC2A9, yet the effect size on gout is greater. We tested the hypothesis that ABCG2 plays a role in the progression from HU to gout by testing for association of ABCG2 rs2231142 and rs10011796 with gout using HU controls. Methods We analysed 1699 European gout cases and 14,350 normouricemic (NU) and HU controls, and 912 New Zealand (NZ) Polynesian (divided into Eastern and Western Polynesian) gout cases and 696 controls. Association testing was performed using logistic and linear regression with multivariate adjusting for confounding variables. Results In Europeans and Polynesians, the ABCG2 141K (T) allele was associated with gout using HU controls (OR = 1.85, P = 3.8E− 21 and ORmeta = 1.85, P = 1.3E− 03, respectively). There was evidence for an effect of 141K in determining HU in European (OR = 1.56, P = 1.7E− 18) but not in Polynesian (ORmeta = 1.49, P = 0.057). For SLC2A9 rs11942223, the T allele associated with gout in the presence of HU in European (OR = 1.37, P = 4.7E− 06), however significantly weaker than ABCG2 rs2231142 141K (P Het = 0.0023). In Western Polynesian and European, there was epistatic interaction between ABCG2 rs2231142 and rs10011796. Combining the presence of the 141K allele with the rs10011796 CC-genotype increased gout risk, in the presence of HU, 21.5-fold in Western Polynesian (P = 0.009) and 2.6-fold in European (P = 9.9E− 06). The 141K allele of ABCG2 associated with increased gout flare frequency in Polynesian (P meta = 2.5E− 03). Conclusion These data are consistent with a role for ABCG2 141K in gout in the presence of established HU.

The aims of this study were to determine factors that predict serum urate (SU) lowering response to allopurinol and the conversion of allopurinol to oxypurinol, and to determine a minimum therapeutic oxypurinol concentration. Data from 129 participants in a 24‐month open, randomized, controlled, parallel‐group, comparative clinical trial were analyzed. Allopurinol dose, SU, and plasma oxypurinol concentrations were available at multiple time points. The slope for the association between allopurinol dose and SU was calculated as a measure of sensitivity to allopurinol. The slope for the association between allopurinol dose and oxypurinol was calculated as a measure of allopurinol metabolism. Receiver operating characteristic (ROC) curves were used to identify a minimum oxypurinol concentration predictive of SU

IntroductionAchieving a goal of serum urate levels in patients with gout is an important way to prevent gout and its complications while it remains difficult with a low targeting rate worldwidely. Currently, hyperuricemia classification has not been widely applied to the management of gout owing to insufficient clinical evidences. This study aimed to evaluate the effectiveness of achieving target urate based on hyperuricemia classification in Chinese patients with gout.MethodsIn this prospective study, patients with gout receiving urate lowering therapy with benzbromarone were assigned to two groups, a renal underexcretion and an unclassified type. The primary endpoint was the proportion of patients achieving the serum urate target (

Elevated serum urate is the most important causal risk factor for developing gout. However, in longitudinal cohort studies, a small proportion of people with normal urate levels develop gout and the majority of those with high urate levels do not. These observations may be due to subsequent variations in serum urate over time. Our analysis examined whether single or repeat testing of serum urate more accurately predicts incident gout over time. Individual participant data from three publicly-available cohorts were included. Data from paired serum urate measures 3–5 years apart, followed by an assessment of gout incidence 5–6 years from the second urate measure were used to calculate the predictive ability of four measures of serum urate on incident gout: the first measure, the second measure, the average of the two measures, and the highest of the two measures. Participants with prevalent gout prior to the second measure were excluded. Receiver operator characteristic (ROC) curves and area under the curve (AUC) statistics were computed to compare the four measures. A total of 16,017 participants were included across the three cohorts, with a mean follow-up from the first serum urate test of 9.3 years (range 8.9–10.1 years). Overall, there was a small increase in the mean serum urate between the first and second measures (322 μmol/L (5.42 mg/dL) vs. 340 μmol/L (5.71 mg/dL), P

OBJECTIVES:. Inhaled epoprostenol is a continuously delivered selective pulmonary vasodilator that is used in patients with refractory hypoxemia, right heart failure, and postcardiac surgery pulmonary hypertension. Published data suggest that inhaled epoprostenol administration via vibrating mesh nebulizer systems may lead to unexpected interruptions in drug delivery. The frequency of these events is unknown. The objective of this study was to describe the incidence and clinical consequences of unexpected interruption in critically ill patients. DESIGN:. Retrospective review and analysis. SETTING:. Stanford University Hospital, a 605-bed tertiary care center. PATIENTS:. Patients receiving inhaled epoprostenol in 2019. INTERVENTIONS:. No interventions. MEASUREMENTS AND MAIN RESULTS:. Clinical indication, duration of inhaled epoprostenol delivery, mode of respiratory support, and documented unexpected interruption. In 2019, there were 493 administrations of inhaled epoprostenol in 433 unique patients. Primary indications for inhaled epoprostenol were right heart dysfunction (n = 394; 79.9%) and hypoxemia (n = 92; 18.7%). Unexpected delivery interruptions occurred in 31 administrations (6.3%). Median duration of therapy prior to unexpected interruption was 2 days (interquartile range, 2–5 d). Respiratory support at the time of unexpected interruption was mechanical ventilation (61.3%), high-flow nasal cannula (35.5%), and noninvasive positive pressure ventilation (3.2%). Adverse sequelae of unexpected interruption included elevated pulmonary artery pressures (n = 12), systemic hypotension (n = 8), hypoxemia (n = 8), elevated central venous pressure (n = 4), and cardiac arrest (n = 1). Therapeutic interventions following unexpected interruption included initiation of inhaled nitric oxide (n = 21), increase in vasoactive medication (n = 2), and increase in respiratory support (n = 2). Most of the adverse events were Common Terminology Criteria for Adverse Events grade 3 and 4 (93.5%). CONCLUSIONS:. A retrospective review of patients receiving inhaled epoprostenol via vibrating mesh nebulizer in 2019 revealed interruptions in 6.3% of administrations with most of these interruptions requiring therapeutic intervention. The true incidence of unexpected interruption and subsequent rate of unexpected interruption’s requiring intervention is unknown due to the reliance on unexpected interruption identification and subsequent documentation in the electronic medical record. Sudden interruption in inhaled epoprostenol delivery can result in severe cardiopulmonary compromise, and on rare occasion, death.

ObjectiveTo clarify the relationship between serum urate (SU) decrease and visceral fat area (VFA) reduction in patients with gout.MethodsWe retrospectively analyzed 237 male gout patients who had two sets of body composition and metabolic measurements within 6 months. Subjects included had all been treated with urate-lowering therapy (ULT) (febuxostat 20–80 mg/day or benzbromarone 25–50 mg/day, validated by the medical record). All patients were from the specialty gout clinic of The Affiliated Hospital of Qingdao University. The multiple linear regression model evaluated the relationship between change in SU [ΔSU, (baseline SU) – (final visit SU)] and change in VFA [ΔVFA, (baseline VFA) – (final visit VFA)].ResultsULT resulted in a mean (standard deviation) decrease in SU level (464.22 ± 110.21 μmol/L at baseline, 360.93 ± 91.66 μmol/L at the final visit, p

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 SLC2A9 and the three loci, most evident in women. We also found that insulin stimulates the expression of GLUT9 and increases [14C]-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 Xenopus oocytes revealed that the [14C]-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 SLC2A9 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.

Abstract Background Reduced renal clearance of uric acid is a major contributor to hyperuricemia. The aim of this study was to examine clinical and genetic variables associated with fractional excretion of uric acid (FEUA). Methods Participants (with and without gout) in the Genetics of Gout in Aotearoa study with available genotyping and FEUA data were included (n = 1713). Ten FEUA-associated loci detected within a genome-wide association study for serum urate in a European population were analysed. A polygenic score for FEUA was calculated in each ancestry group to model the cumulative effects of the genetic variants on FEUA. Associations between FEUA and both clinical variables and polygenic score were tested using linear regression models. Results The mean (SD) FEUA was 5.13 (2.70) % in Eastern Polynesian participants, 4.70 (5.89) % in Western Polynesian participants, and 5.89 (2.73) % in New Zealand European participants. Although association with FEUA was observed for SLC2A9 rs11942223 in New Zealand European participants (P = 2.39 × 10− 8), this association was not observed in Eastern or Western Polynesian participants. The polygenic score was positively associated with FEUA in all ancestry groups. In New Zealand European participants, body mass index, diuretic use, polygenic score, and male sex were associated with FEUA and explained 22% of FEUA variance in the regression model. In Eastern and Western Polynesian participants, the tested variables explained 10% and 4% of FEUA variance respectively. Conclusions Both clinical and genetic variables contribute to renal clearance of uric acid. SLC2A9 exerts effects on FEUA variance in people of European ancestry, but not in those of Polynesian ancestry. There is a large unexplained variance in FEUA, particularly in people of Polynesian ancestry.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Abstract Background Sex-specific differences in the effect of genetic variants on serum urate levels have been described. The aim of this study was to systematically examine whether serum urate-associated genetic variants differ in their influence on gout risk in men and women. Methods This research was conducted using the UK Biobank Resource. Thirty single nucleotide polymorphisms (SNPs) associated with serum urate were tested for their association with gout in men and women of European ancestry, aged 40–69 years. Gene-sex interactions for gout risk were analysed using an interaction analysis in logistic regression models. Results Gout was present in 6768 (4.1%) men and 574 (0.3%) women, with an odds ratio (95% confidence interval) for men 13.42 (12.32–14.62) compared with women. In men, experiment-wide association with gout was observed for 21 of the 30 serum urate-associated SNPs tested, and in women for three of the 30 SNPs. Evidence for gene-sex interaction was observed for ABCG2 (rs2231142) and PDZK1 (rs1471633), with the interaction in ABCG2 driven by an amplified effect in men and in PDZK1 by an absence of effect in women. Similar findings were observed in a sensitivity analysis which excluded pre-menopausal women. For the other SNPs tested, no significant gene-sex interactions were observed. Conclusions In a large population of European ancestry, ABCG2 and PDZK1 gene-sex interactions exist for gout risk, with the serum urate-raising alleles exerting a greater influence on gout risk in men than in women. In contrast, other serum urate-associated genetic variants do not demonstrate significant gene-sex interactions for gout risk.

Introduction Intubation-related complications are less frequent when intubation is successful on the first attempt. The rate of first attempt success in the emergency department (ED) and intensive care unit (ICU) is typically less than 90%. The bougie, a semirigid introducer that can be placed into the trachea to facilitate a Seldinger-like technique of tracheal intubation and is typically reserved for difficult or failed intubations, might improve first attempt success. Evidence supporting its use, however, is from a single academic ED with frequent bougie use. Validation of these findings is needed before widespread implementation.Methods and analysis The BOugie or stylet in patients Undergoing Intubation Emergently trial is a prospective, multicentre, non-blinded randomised trial being conducted in six EDs and six ICUs in the USA. The trial plans to enrol 1106 critically ill adults undergoing orotracheal intubation. Eligible patients are randomised 1:1 for the use of a bougie or use of an endotracheal tube with stylet for the first intubation attempt. The primary outcome is successful intubation on the first attempt. The secondary outcome is severe hypoxaemia, defined as an oxygen saturation less than 80% between induction until 2 min after completion of intubation. Enrolment began on 29 April 2019 and is expected to be completed in 2021.Ethics and dissemination The trial protocol was approved with waiver of informed consent by the Central Institutional Review Board at Vanderbilt University Medical Center or the local institutional review board at an enrolling site. The results will be submitted for publication in a peer-reviewed journal and presented at scientific conferences.Trial registration number ClinicalTrials.gov Registry (NCT03928925).

Background: 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 OPRM1 A118G, COMT Val158Met and DRD2 Taq1A and DRD4 C52IT, may predict addictive behaviors including alcohol consumption and impulsivity, although results have been mixed.Methods: 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.Results: 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 DRD2 Taq1A on the number of drinks per drinking day and for the interaction of gender and DRD2 Taq1A on the number of drinks per drinking day.Conclusion: These findings suggest that the DRD2 Taq1A, OPRM1 A118G, DRD4 C521T, or COMT Val158Met polymorphisms, are not associated with alcohol consumption in young adults, although there may be a relationship between DRD2 Taq1A and alcohol consumption in young adult males.

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.

Abstract Background Ferritin positively associates with serum urate and an interventional study suggests that iron has a role in triggering gout flares. The objective of this study was to further explore the relationship between iron/ferritin and urate/gout. Methods European (100 cases, 60 controls) and Polynesian (100 cases, 60 controls) New Zealand (NZ) males and 189 US male cases and 60 male controls participated. The 10,727 participants without gout were from the Jackson Heart (JHS; African American = 1260) and NHANES III (European = 5112; African American = 4355) studies. Regression analyses were adjusted for age, sex, body mass index and C-reactive protein. To test for a causal relationship between ferritin and urate, bidirectional two-sample Mendelian randomization analysis was performed. Results Serum ferritin positively associated with gout in NZ Polynesian (OR (per 10 ng ml− 1 increase) = 1.03, p = 1.8E–03) and US (OR = 1.11, p = 7.4E–06) data sets but not in NZ European (OR = 1.00, p = 0.84) data sets. Ferritin positively associated with urate in NZ Polynesian (β (mg dl− 1) = 0.014, p = 2.5E–04), JHS (β = 0.009, p = 3.2E–05) and NHANES III (European β = 0.007, p = 5.1E–11; African American β = 0.011, p = 2.1E–16) data sets but not in NZ European (β = 0.009, p = 0.31) or US (β = 0.041, p = 0.15) gout data sets. Ferritin positively associated with the frequency of gout flares in two of the gout data sets. By Mendelian randomization analysis a one standard deviation unit increase in iron and ferritin was, respectively, associated with 0.11 (p = 8E–04) and 0.19 mg dl− 1 (p = 2E–04) increases in serum urate. There was no evidence for a causal effect of urate on iron/ferritin. Conclusions These data replicate the association of ferritin with serum urate. Increased ferritin levels associated with gout and flare frequency. There was evidence of a causal effect of iron and ferritin on urate.

Abstract Background Increased coffee intake is associated with reduced serum urate concentrations and lower risk of gout. Specific alleles of the GCKR, ABCG2, MLXIPL, and CYP1A2 genes have been associated with both reduced coffee intake and increased serum urate in separate genome-wide association studies (GWAS). The aim of this study was to determine whether these single nucleotide polymorphisms (SNPs) influence the risk of gout through their effects on coffee consumption. Methods This research was conducted using the UK Biobank Resource. Data were available for 130,966 European participants aged 40–69 years. Gout status and coffee intake were tested for association with four urate-associated SNPs: GCKR (rs1260326), ABCG2 (rs2231142), MLXIPL (rs1178977), and CYP1A2 (rs2472297). Multiple regression and path analysis were used to examine whether coffee consumption mediated the effect of the SNPs on gout risk. Results Coffee consumption was inversely associated with gout (multivariate adjusted odds ratio (95% confidence interval (CI)) for any coffee consumption 0.75 (0.67–0.84, P = 9 × 10−7)). There was also evidence of a dose-effect with multivariate adjusted odds ratio (95% CI) per cup consumed per day of 0.85 (0.82–0.87, P = 9 × 10−32). The urate-increasing GCKR, ABCG2, MLXIPL, and CYP1A2 alleles were associated with reduced daily coffee consumption, with the strongest associations for CYP1A2 (beta −0.30, P = 8 × 10−40), and MLXIPL (beta −0.17, P = 3 × 10−8), and weaker associations for GCKR (beta −0.07, P = 3 × 10−10) and ABCG2 (beta −0.09, P = 2 × 10−9). The urate-increasing GCKR and ABCG2 alleles were associated with gout (multivariate adjusted p

Abstract Background Many gout comorbidities (e.g., hypertension) are correlated with serum urate. In this investigation, we identified risk factors (e.g., systolic blood pressure [SBP]), that (1) are associated with incident gout, (2) have effects on gout risk that cannot be fully explained by correlated differences in serum urate, and (3) may modulate the relationship between gout and serum urate. Methods Using data from the Atherosclerosis Risk in Communities (ARIC) study, we estimated the unadjusted associations between gout and risk factors by calculating ORs and using chi-square tests. The adjusted associations were analyzed using logistic regression by sequentially adding (1) one risk factor at a time or (2) all risk factors, to a baseline model that includes serum urate only. Stepwise selection was used to select main effects. Two-way interactions of variables from the main effects model were also analyzed. Results Average gout incidence was 2.7 per 1000 people per year. Serum urate was highly associated with incident gout, with odd ratios of 3.16 [95% CI 2.11, 4.76] and 25.9 [95% CI 17.2, 38.4] for moderately high (6–8 mg/dl) and high serum urate (> 8 mg/dl), relative to normal serum urate (

Context: Cardio-metabolic conditions in Aotearoa New Zealand (NZ) Māori and non-indigenous Polynesian (Pacific) populations have been increasing in prevalence and severity, especially over the last two decades. Objectives: To assess knowledge on genetic and non-genetic risk factors for cardio-metabolic disease in the Māori and Pacific populations residing in Aotearoa NZ by a semi-systematic review of the PubMed database. To outline possible future directions in genetic epidemiological research with Māori and Pacific communities. Results: There have been few studies to confirm that risk factors in other populations also associate with cardio-metabolic conditions in Māori and Pacific populations. Such data are important when interventions are considered. Genetic studies have been sporadic, with no genome-wide association studies done. Conclusions: Biomedical research with Māori and Pacific communities is important to reduce the prevalence and impact of the cardio-metabolic diseases, as precision medicine is implemented in other Aotearoa NZ populations using overseas findings. Genuine engagement with Māori and Pacific communities is needed to ensure positive outcomes for genetic studies, from data collection through to analysis and dissemination. Important is building trust, understanding by researchers of fundamental cultural concepts and implementing protocols that minimise risks and maximise benefits. Approaches that utilise information such as genealogical information and whole genome sequencing technologies will provide new insights into cardio-metabolic conditions—and new interventions for affected individuals and families.