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Gout is of particularly high prevalence in the Maori and Pacific (Polynesian) populations of Aotearoa New Zealand (NZ). Here, we investigated the contribution of common population-specific copy number variation (CNV) to gout in the Aotearoa NZ Polynesian population. Microarray-generated genome-wide genotype data from Aotearoa NZ Polynesian individuals with (n = 1196) and without (n = 1249) gout were analyzed. Comparator population groups were 552 individuals of European ancestry and 1962 of Han Chinese ancestry. Levels of circulating major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) were measured by enzyme-linked immunosorbent assay. Fifty-four CNV regions (CNVRs) appearing in at least 10 individuals were detected, of which seven common (>2%) CNVRs were specific to or amplified in Polynesian people. A burden test of these seven revealed associations of insertion/deletion with gout (odds ratio (OR) 95% confidence interval [CI] = 1.80 [1.01; 3.22], P = 0.046). Individually testing of the seven CNVRs for association with gout revealed nominal association of CNVR1 with gout in Western Polynesian (Chr6: 31.36-31.45 Mb, OR = 1.72 [1.03; 2.92], P = 0.04), CNVR6 in the meta-analyzed Polynesian sample sets (Chr1: 196.75-196.92 Mb, OR = 1.86 [1.16; 3.00], P = 0.01) and CNVR9 in Western Polynesian (Chr1: 189.35-189.54 Mb, OR = 2.75 [1.15; 7.13], P = 0.03). Analysis of European gout genetic association data demonstrated a signal of association at the CNVR1 locus that was an expression quantitative trait locus for MICA. The most common CNVR (CNVR1) includes deletion of the MICA gene, encoding an immunomodulatory protein. Expression of MICA was reduced in the serum of individuals with the deletion. In summary, we provide evidence for the association of CNVR1 containing MICA with gout in Polynesian people, implicating class I MHC-mediated antigen presentation in gout.
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Variaciones en el Número de Copia de ADN , Gota , Antígenos de Histocompatibilidad Clase I , Nativos de Hawái y Otras Islas del Pacífico , Humanos , Genotipo , Gota/etnología , Gota/genética , Antígenos de Histocompatibilidad Clase I/genética , Antígenos HLA , Nativos de Hawái y Otras Islas del Pacífico/genéticaRESUMEN
OBJECTIVES: The minor allele of the common rs2231142 ABCG2 variant predicts inadequate response to allopurinol urate lowering therapy. We hypothesize that additional variants in genes encoding urate transporters and allopurinol-to-oxypurinol metabolic enzymes also predict allopurinol response. METHODS: This study included a subset of participants with gout from the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients, whose whole genome was sequenced (n = 563). Good responders had a 4:1 or 5:1 ratio of good (serum urate (SU) <0.36 mmol/l on allopurinol ≤300 mg/day) to poor (SU ≥ 0.36 mmol/l despite allopurinol >300 mg/day) responses over 5-6 timepoints, while inadequate responders had a 1:4 or 1:5 ratio of good to poor responses. Adherence to allopurinol was determined by pill counts, and for a subgroup (n = 303), by plasma oxypurinol >20µmol/l. Using the sequence kernel association test (SKAT) we estimated the combined effect of rare and common variants in urate secretory (ABCC4, ABCC5, ABCG2, SLC17A1, SLC17A3, SLC22A6, SLC22A8) and reuptake genes (SLC2A9, SLC22A11) and in allopurinol-to-oxypurinol metabolic genes (AOX1, MOCOS, XDH) on allopurinol response. RESULTS: There was an association of rare and common variants in the allopurinol-to-oxypurinol gene group (PSKAT-C = 0.019), and in MOCOS, encoding molybdenum cofactor sulphurase, with allopurinol response (PSKAT-C = 0.011). Evidence for genetic association with allopurinol response in the allopurinol-to-oxypurinol gene group (PSKAT-C = 0.002) and MOCOS (PSKAT-C < 0.001) was stronger when adherence to allopurinol therapy was confirmed by plasma oxypurinol. CONCLUSION: We provide evidence for common and rare genetic variation in MOCOS associating with allopurinol response.
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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.
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Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Genoma , Genoma Humano , Genómica , Genotipo , Humanos , Secuenciación Completa del GenomaRESUMEN
RATIONALE & OBJECTIVE: The association between hyperuricemia and urolithiasis has been previously reported. However, this association is based on observational data, which are prone to residual confounding. The aim of this work was to use Mendelian randomization (MR) to evaluate if this relationship represents a causal effect of hyperuricemia. STUDY DESIGN: MR analysis using 2 approaches: 2-stage MR and 2-sample MR. SETTING & PARTICIPANTS: Participants aged 40-69 years from the UK Biobank Resource. EXPOSURE: Serum urate. OUTCOME: Urolithiasis. ANALYTICAL APPROACH: An observational analysis testing for an association between serum urate level and urolithiasis was performed using logistic regression. For MR analyses, serum urate-associated single-nucleotide polymorphisms, identified from genome-wide association data, were used as instrumental variables for serum urate. In the 2-stage MR analysis, a weighted genetic urate score was calculated from the instrumental variables, and a control function estimation model was fit. In the 2-sample MR analysis, multiple-instrument MR via the inverse-variance weighted method was performed. RESULTS: Individual-level data were available for 359,827 participants, of whom 6,398 (1.8%) reported urolithiasis. In the observational analysis, serum urate was positively associated with urolithiasis in an unadjusted analysis (odds ratio [OR], 1.47 [95% CI, 1.42-1.51]); however, after adjustment for relevant confounders, no association was observed (OR, 1.03 [95% CI, 0.99-1.08]). In the 2-stage MR analysis, no significant causal effect of serum urate level on urolithiasis was observed in the unadjusted (OR, 0.93 [95% CI, 0.81-1.08]) or adjusted (OR, 0.94 [95% CI, 0.80-1.09]) models. In the 2-sample MR analysis, multiple-instrument MR did not indicate a causal effect of serum urate on urolithiasis. LIMITATIONS: Stone composition and urinalysis data, including urine pH, were not available for this study. CONCLUSIONS: Our analyses do not support a causal effect of serum urate level on urolithiasis. The association between serum urate level and urolithiasis reported in observational studies is likely due to residual confounding.
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Hiperuricemia/genética , Ácido Úrico/sangre , Urolitiasis/genética , Adulto , Anciano , Causalidad , Femenino , Humanos , Hiperuricemia/epidemiología , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Oportunidad Relativa , Reino Unido , Urolitiasis/epidemiologíaRESUMEN
OBJECTIVE: The aim of this case-control study was to investigate the association between non-syndromic hypodontia and nineteen common variants of candidate genes ectodysplasin A (EDA), paired box 9 (PAX9), msh homeobox 1 (MSX1) and axis inhibition protein 2 (AXIN2). SETTINGS AND SAMPLE POPULATION: Sixty-one hypodontia cases were frequency-matched to 253 controls with no missing teeth (excluding the third molars). MATERIAL AND METHODS: Self-report data and DNA samples were collected from each participant. RESULTS: The sample had a mean age of 16.6 years (SD = 7.3), with most participants being female (59.6%), and of New Zealand European origin (75.4%). Using multiple logistic regression analysis, it was found that the T-allele of rs12853659 (EDA) and the G-allele of rs2428151 (EDA) were both associated with a higher risk of hypodontia (odds ratio, OR = 2.79, 95% CI = 1.11-7.01; and OR = 2.87, 95% CI = 1.04-7.94, respectively). The G-allele of rs2520378 (EDA) showed a protective effect with an OR of 0.61 (95% CI = 0.38-0.99). The EDA SNP findings were consistent with previous reports included in a meta-analysis. No associations were found with the PAX9, AXIN2 and MSX1 genes, after adjusting for sex and ethnicity. CONCLUSIONS: Common variants of the EDA genes are associated with specific phenotypes of non-syndromic hypodontia, thus confirming their role in the regulatory pathways of normal tooth development. However, larger samples are needed to investigate the association further.
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Anodoncia , Ectodisplasinas , Adolescente , Anodoncia/genética , Estudios de Casos y Controles , ADN , Ectodisplasinas/genética , Femenino , Humanos , OdontogénesisRESUMEN
BACKGROUND: Pain experienced at teeth during orthodontic treatment varies largely over time, with the reasons for its interindividual variability being largely unknown: age, sex, clinical activations, psychosocial factors and genetic polymorphisms of candidate genes are putative factors that may account to explain this variability. We aimed to investigate the effect of clinical, demographic, psychological and genetic factors on pain levels experienced during fixed orthodontic treatment. METHODS: A convenience sample of 183 patients undergoing full-fixed orthodontic treatment were recruited. Participant's pain levels were assessed seven times over a three-day period via a smartphone app. Clinical, demographic and psychological data were collected via questionnaires. This included the Pain Catastrophising Scale (Child version), the Corah Dental Anxiety Scale and the State and Trait Anxiety Inventory. Participants provided a DNA sample either in the form of blood or saliva, which were used for genotyping COMT gene rs6269, rs4680, rs4646310, NR3C1 gene rs2963155 and the HTR2A gene rs9316233. RESULTS: Bond ups had the greatest influence on perceived levels of pain experienced on teeth during orthodontic treatment, accounting for over 20% of total variance in pain response. High-pain responders had higher scores on pain catastrophising (magnification subscale). Self-reported pain during fixed orthodontic treatment was not influenced by sex, age, time into treatment, anxiety, nor by polymorphisms of COMT, HTR2A or NR3C1 genes. CONCLUSIONS: Pain on teeth resulting from orthodontic fixed appliances is stronger during bonds-up and in patients with high catastrophising scores. Demographics, type of clinical activations and the genetic polymorphisms investigated in this research had little or no impact on perceived pain levels.
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Aparatos Ortodóncicos Fijos , Aparatos Ortodóncicos , Ansiedad/genética , Niño , Humanos , Dolor/genética , Encuestas y CuestionariosRESUMEN
BACKGROUND: Studies have shown strong positive associations between serum urate (SU) levels and chronic kidney disease (CKD) risk; however, whether the relation is causal remains uncertain. We evaluate whether genetic data are consistent with a causal impact of SU level on the risk of CKD and estimated glomerular filtration rate (eGFR). METHODS AND FINDINGS: We used Mendelian randomization (MR) methods to evaluate the presence of a causal effect. We used aggregated genome-wide association data (N = 110,347 for SU, N = 69,374 for gout, N = 133,413 for eGFR, N = 117,165 for CKD), electronic-medical-record-linked UK Biobank data (N = 335,212), and population-based cohorts (N = 13,425), all in individuals of European ancestry, for SU levels and CKD. Our MR analysis showed that SU has a causal effect on neither eGFR level nor CKD risk across all MR analyses (all P > 0.05). These null associations contrasted with our epidemiological association findings from the 4 population-based cohorts (change in eGFR level per 1-mg/dl [59.48 µmol/l] increase in SU: -1.99 ml/min/1.73 m2; 95% CI -2.86 to -1.11; P = 8.08 × 10(-6); odds ratio [OR] for CKD: 1.48; 95% CI 1.32 to 1.65; P = 1.52 × 10(-11)). In contrast, the same MR approaches showed that SU has a causal effect on the risk of gout (OR estimates ranging from 3.41 to 6.04 per 1-mg/dl increase in SU, all P < 10-3), which served as a positive control of our approach. Overall, our MR analysis had >99% power to detect a causal effect of SU level on the risk of CKD of the same magnitude as the observed epidemiological association between SU and CKD. Limitations of this study include the lifelong effect of a genetic perturbation not being the same as an acute perturbation, the inability to study non-European populations, and some sample overlap between the datasets used in the study. CONCLUSIONS: Evidence from our series of causal inference approaches using genetics does not support a causal effect of SU level on eGFR level or CKD risk. Reducing SU levels is unlikely to reduce the risk of CKD development.
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Insuficiencia Renal Crónica/etiología , Ácido Úrico/sangre , Adulto , Factores de Edad , Femenino , Estudio de Asociación del Genoma Completo , Tasa de Filtración Glomerular/genética , Humanos , Masculino , Análisis de la Aleatorización Mendeliana , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/genética , Factores Sexuales , Adulto JovenRESUMEN
AIMS/HYPOTHESIS: The A (minor) allele of CREBRF rs373863828 has been associated with increased BMI and reduced risk of type 2 diabetes in the Samoan populations of Samoa and American Samoa. Our aim was to test rs373863828 for associations with BMI and the odds of type 2 diabetes, gout and chronic kidney disease (CKD) in Maori and Pacific (Polynesian) people living in Aotearoa/New Zealand. METHODS: Linear and logistic regression models were used to analyse the association of the A allele of CREBRF rs373863828 with BMI, log-transformed BMI, waist circumference, type 2 diabetes, gout and CKD in 2286 adults. The primary analyses were adjusted for age, sex, the first four genome-wide principal components and (where appropriate) BMI, waist circumference and type 2 diabetes. The primary analysis was conducted in ancestrally defined groups and association effects were combined using meta-analysis. RESULTS: For the A allele of rs373863828, the effect size was 0.038 (95% CI 0.022, 0.055, p = 4.8 × 10-6) for log-transformed BMI, with OR 0.59 (95% CI 0.47, 0.73, p = 1.9 × 10-6) for type 2 diabetes. There was no evidence for an association of genotype with variance in BMI (p = 0.13), and nor was there evidence for associations with serum urate (ß = 0.012 mmol/l, pcorrected = 0.10), gout (OR 1.00, p = 0.98) or CKD (OR 0.91, p = 0.59). CONCLUSIONS/INTERPRETATION: Our results in New Zealand Polynesian adults replicate, with very similar effect sizes, the association of the A allele of rs373863828 with higher BMI but lower odds of type 2 diabetes among Samoan adults living in Samoa and American Samoa.
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Índice de Masa Corporal , Diabetes Mellitus Tipo 2/prevención & control , Nativos de Hawái y Otras Islas del Pacífico/genética , Obesidad/genética , Polimorfismo de Nucleótido Simple , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etnología , Diabetes Mellitus Tipo 2/genética , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Nueva Zelanda/epidemiología , Obesidad/diagnóstico , Obesidad/etnología , Fenotipo , Polinesia/etnología , Factores Protectores , Factores de RiesgoAsunto(s)
Gota , Hiperuricemia , Humanos , Hiperuricemia/genética , Ácido Úrico , Estudio de Asociación del Genoma Completo , Bancos de Muestras Biológicas , Gota/genética , Reino Unido , Glicoproteínas/genética , Fosfoproteínas/genética , Proteínas de la Matriz Extracelular/genética , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
Objective: ABCG2 rs2231142 (Q141K) has been reported to be associated with poor response to allopurinol, while there are conflicting data on the association between the genetically independent ABCG2 rs10011796 variant and allopurinol response. The aim of this study was to replicate the association of ABCG2 rs2231142 and rs10011796 with allopurinol response and perform a meta-analysis. Methods: Participants in the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO) (n = 299) were studied. In patients with evidence of adherence to allopurinol therapy (plasma oxypurinol >20 µmol/l), good response was defined as serum urate <6 mg/dl on allopurinol ⩽300 mg/day and poor response as serum urate ⩾ 6 mg/dl despite allopurinol >300 mg/day. Association of rs2231142 and rs10011796 with poor response was tested in logistic regression models that included age, sex, BMI, ethnicity and estimated glomerular filtration rate. Results from the LASSO study and a subset of participants in the Genetics of Gout in Aotearoa New Zealand study (n = 296, including 264 from a previously published report) were combined by meta-analysis. Results: There was evidence for association of rs2231142 with allopurinol response [odds ratio (OR) = 2.35, P = 7.3 × 10-4] but not for rs10011796 (OR = 1.21, P = 0.33) in the LASSO cohort using an adjusted logistic regression model. Meta-analysis provided evidence of a significant association of rs2231142 with allopurinol response (OR = 2.43, P = 6.2 × 10-7), but not rs10011796 (OR = 1.06, P = 0.69). Conclusion: This study has confirmed the significant association of ABCG2 rs2231142 with poor response to allopurinol.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Alopurinol/uso terapéutico , ADN/genética , Gota , Proteínas de Neoplasias/genética , Polimorfismo de Nucleótido Simple , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Predisposición Genética a la Enfermedad , Genotipo , Gota/tratamiento farmacológico , Gota/genética , Gota/metabolismo , Supresores de la Gota/uso terapéutico , Humanos , Proteínas de Neoplasias/metabolismoRESUMEN
OBJECTIVE: Gout is associated with dyslipidaemia. Association of the apolipoprotein A1-C3-A4 gene cluster with gout has previously been reported in a small study. To investigate a possible causal role for this locus in gout, we tested the association of genetic variants from APOA1 (rs670) and APOC3 (rs5128) with gout. METHODS: We studied data for 2452 controls and 2690 clinically ascertained gout cases of European and New Zealand Polynesian (Maori and Pacific) ancestry. Data were also used from the publicly available Atherosclerosis Risk in Communities study (n = 5367) and the Framingham Heart Study (n = 2984). Multivariate adjusted logistic and linear regression was used to test the association of single-nucleotide polymorphisms with gout risk, serum urate, triglyceride and high-density lipoprotein cholesterol (HDL-C). RESULTS: In Polynesians, the T-allele of rs670 (APOA1) increased (odds ratio, OR = 1.53, P = 4.9 × 10(-6)) and the G-allele of rs5128 (APOC3) decreased the risk of gout (OR = 0.86, P = 0.026). In Europeans, there was a strong trend to a risk effect of the T-allele for rs670 (OR = 1.11, P = 0.055), with a significant protective effect of the G-allele for rs5128 being observed after adjustment for triglycerides and HDL-C (OR = 0.81, P = 0.039). The effect at rs5128 was specific to males in both Europeans and Polynesians. Association in Polynesians was independent of any effect of rs670 and rs5128 on triglyceride and HDL-C levels. There was no evidence for association of either single-nucleotide polymorphism with serum urate levels (P ⩾ 0.10). CONCLUSION: Our data, replicating a previous study, supports the hypothesis that the apolipoprotein A1-C3-A4 gene cluster plays a causal role in gout.
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Apolipoproteína A-I/genética , Gota/genética , Familia de Multigenes/genética , Adulto , Apolipoproteína C-III/genética , Apolipoproteínas C/genética , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Nativos de Hawái y Otras Islas del Pacífico/genética , Factores de Riesgo , Ácido Úrico/metabolismo , Población Blanca/genéticaRESUMEN
INTRODUCTION: Rheumatic fever (RF) incidence among New Zealand (NZ) individuals of Polynesian (Maori and Pacific) ancestry remains among the highest in the world. Polymorphisms in the IL-6, IL1RN, and CTLA4 genes have been associated with RF, and their products are modulated by new medications. Confirmation of these previous associations could help guide clinical approaches. We aimed to test IL-6, IL-1RA (IL1RN), and CTLA4 functional SNPs in 204 rheumatic heart disease (RHD) patients and 116 controls of Maori and Pacific ancestry. MATERIAL AND METHOD: Self-reported ancestry of the eight great-grandparents defined ancestry of participants. Severity of carditis was classified according to the 2012 World Heart Federation guideline for the echocardiographic diagnosis of RHD. The IL-6 promoter rs1800797, IL1RN rs447713 and CTLA4 rs3087243 SNPs were genotyped by Taqman. Correlations were assessed by logistic regression analysis adjusting for gender and ancestry. RESULTS: The IL-6 rs1800797 variant was significantly associated with RHD with carriers of the GG genotype 6.09 (CI 1.23; 30.23) times more likely to develop RHD than the carriers of the AA genotype (P=0.027). No significant associations with RHD were found for the IL1RN rs447713 and CTLA4 rs3087243 SNPs. Patients carrying the G allele (GG plus AG genotype) for the IL1RN rs447713 SNP had 2.36 times (CI 1.00; 5.56) more severe carditis than those without this allele (the AA genotype) (P=0.049). CONCLUSION: The IL-6 promoter rs1800797 (-597G/A) SNP may influence susceptibility to RHD of people of Maori and Pacific ancestry living in NZ. The IL1RN rs447713 SNP may influence the severity of carditis in this population.
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Antígeno CTLA-4/genética , Predisposición Genética a la Enfermedad/genética , Proteína Antagonista del Receptor de Interleucina 1/genética , Interleucina-6/genética , Polimorfismo de Nucleótido Simple/genética , Cardiopatía Reumática/genética , Adolescente , Adulto , Alelos , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Genotipo , Humanos , Masculino , Nueva Zelanda , Regiones Promotoras Genéticas/genética , Adulto JovenRESUMEN
The Arg64 allele of variant rs4994 (Trp64Arg) in the ß3-adrenergic receptor gene has been associated with increased serum urate and risk of gout. Our objective was to investigate the relationship of rs4994 with serum urate and gout in New Zealand European, Maori and Pacific subjects. A total of 1730 clinically ascertained gout cases and 2145 controls were genotyped for rs4994 by Taqman(®). Maori and Pacific subjects were subdivided into Eastern Polynesian (EP) and Western Polynesian (WP) sample sets. Publicly available genotype data from the Atherosclerosis Risk in Communities Study and the Framingham Heart Study were utilized for serum urate association analysis. Multivariate logistic and linear regression adjusted for potential confounders was carried out using R version 2.15.2. No significant association of the minor Arg64 (G) allele of rs4994 with gout was found in the combined Polynesian cohorts (OR = 0.98, P = 0.88), although there was evidence, after adjustment for renal disease, for association in both the WP (OR = 0.53, P = 0.03) and the lower Polynesian ancestry EP sample sets (OR = 1.86, P = 0.05). There was no evidence for association with gout in the European sample set (OR = 1.11, P = 0.57). However, the Arg64 allele was positively associated with urate in the WP data set (ß = 0.036, P = 0.004, P Corrected = 0.032). Association of the Arg64 variant with increased urate in the WP sample set was consistent with the previous literature, although the protective effect of this variant with gout in WP was inconsistent. This association provides an etiological link between metabolic syndrome components and urate homeostasis.
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Gota/genética , Hiperuricemia/genética , Polimorfismo Genético , Receptores Adrenérgicos beta 3/genética , Ácido Úrico/sangre , Biomarcadores/sangre , Estudios de Casos y Controles , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Gota/sangre , Gota/diagnóstico , Gota/etnología , Humanos , Hiperuricemia/sangre , Hiperuricemia/diagnóstico , Hiperuricemia/etnología , Modelos Lineales , Modelos Logísticos , Análisis Multivariante , Nativos de Hawái y Otras Islas del Pacífico/genética , Nueva Zelanda/epidemiología , Oportunidad Relativa , Fenotipo , Polinesia/epidemiología , Factores de Riesgo , Población Blanca/genéticaRESUMEN
Abdominal aortic aneurysm (AAA) is a common human disease with a high estimated heritability (0.7); however, only a small number of associated genetic loci have been reported to date. In contrast, over 100 loci have now been reproducibly associated with either blood lipid profile and/or coronary artery disease (CAD) (both risk factors for AAA) in large-scale meta-analyses. This study employed a staged design to investigate whether the loci for these two phenotypes are also associated with AAA. Validated CAD and dyslipidaemia loci underwent screening using the Otago AAA genome-wide association data set. Putative associations underwent staged secondary validation in 10 additional cohorts. A novel association between the SORT1 (1p13.3) locus and AAA was identified. The rs599839 G allele, which has been previously associated with both dyslipidaemia and CAD, reached genome-wide significance in 11 combined independent cohorts (meta-analysis with 7048 AAA cases and 75 976 controls: G allele OR 0.81, 95% CI 0.76-0.85, P = 7.2 × 10(-14)). Modelling for confounding interactions of concurrent dyslipidaemia, heart disease and other risk factors suggested that this marker is an independent predictor of AAA susceptibility. In conclusion, a genetic marker associated with cardiovascular risk factors, and in particular concurrent vascular disease, appeared to independently contribute to susceptibility for AAA. Given the potential genetic overlap between risk factor and disease phenotypes, the use of well-characterized case-control cohorts allowing for modelling of cardiovascular disease risk confounders will be an important component in the future discovery of genetic markers for conditions such as AAA.
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Proteínas Adaptadoras del Transporte Vesicular/genética , Aneurisma de la Aorta Abdominal/genética , Cromosomas Humanos Par 1/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Gout is a consequence of an innate immune reaction to monosodium urate crystals deposited in joints. Acute gout attacks can be triggered by dietary factors that are themselves associated with serum urate levels. Tomato consumption is an anecdotal trigger of gout flares. This study aimed to measure the frequency of tomato consumption as a self-reported trigger of gout attacks in a large New Zealand sample set, and to test the hypothesis that tomato consumption is associated with serum urate levels. METHODS: Two thousand fifty one New Zealanders (of Maori, Pacific Island, European or other ancestry) with clinically-ascertained gout were asked about gout trigger foods. European individuals from the Atherosclerosis Risk In Communities (ARIC; n = 7517) Study, Cardiovascular Health Study (CHS; n = 2151) and Framingham Heart Study (FHS; n = 3052) were used to test, in multivariate-adjusted analyses, for association between serum urate and tomato intake. RESULTS: Seventy one percent of people with gout reported having ≥1 gout trigger food. Of these 20% specifically mentioned tomatoes, the 4(th) most commonly reported trigger food. There was association between tomato intake and serum urate levels in the ARIC, CHS and FHS combined cohort (ß = 0.66 µmolL(-1) increase in serum urate per additional serve per week; P = 0.006) - evident in both sexes (men: ß = 0.84 µmolL(-1), P = 0.035; women: ß = 0.59 µmolL (-1), P = 0.041). CONCLUSIONS: While our descriptive and observational data are unable to support the claim that tomato consumption is a trigger of gout attacks, the positive association between tomato consumption and serum urate levels suggests that the self-reporting of tomatoes as a dietary trigger by people with gout has a biological basis.
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Gota/sangre , Gota/inducido químicamente , Solanum lycopersicum/efectos adversos , Solanum lycopersicum/metabolismo , Ácido Úrico/sangre , Adolescente , Adulto , Anciano , Femenino , Gota/etnología , Humanos , Hiperuricemia/sangre , Hiperuricemia/inducido químicamente , Hiperuricemia/etnología , Masculino , Persona de Mediana Edad , Nativos de Hawái y Otras Islas del Pacífico/etnología , Nueva Zelanda/etnología , Encuestas y Cuestionarios , Población Blanca/etnología , Adulto JovenRESUMEN
OBJECTIVE: Consumption of high fructose corn syrup (HFCS)-sweetened beverages increases serum urate and risk of incident gout. Genetic variants in SLC2A9, that exchanges uric acid for glucose and fructose, associate with gout. We tested association between sugar (sucrose)-sweetened beverage (SSB) consumption and prevalent gout. We also tested the hypothesis that SLC2A9 genotype and SSB consumption interact to determine gout risk. METHODS: Participants were 1634 New Zealand (NZ) European Caucasian, Ma¯ori and Pacific Island people and 7075 European Caucasians from the Atherosclerosis Risk in Communities (ARIC) study. NZ samples were genotyped for rs11942223 and ARIC for rs6449173. Effect estimates were multivariate adjusted. RESULTS: SSB consumption increased gout risk. The OR for four drinks/day relative to zero was 6.89 (p=0.045), 5.19 (p=0.010) and 2.84 (p=0.043) for European Caucasian, Ma¯ori and Pacific Islanders, respectively. With each extra daily SSB serving, carriage of the gout-protective allele of SLC2A9 associated with a 15% increase in risk (p=0.078), compared with a 12% increase in non-carriers (p=0.002). The interaction term was significant in pooled (pInteraction=0.01) but not meta-analysed (pInteraction=0.99) data. In ARIC, with each extra daily serving, a greater increase in serum urate protective allele carriers (0.005 (p=8.7×10(-5)) compared with 0.002 (p=0.016) mmol/L) supported the gout data (pInteraction=0.062). CONCLUSIONS: Association of SSB consumption with prevalent gout supports reduction of SSB in management. The interaction data suggest that SLC2A9-mediated renal uric acid excretion is physiologically influenced by intake of simple sugars derived from SSB, with SSB exposure negating the gout risk discrimination of SLC2A9.
Asunto(s)
Bebidas , Sacarosa en la Dieta/efectos adversos , Interacción Gen-Ambiente , Proteínas Facilitadoras del Transporte de la Glucosa/genética , Gota/genética , Hiperuricemia/genética , Ácido Úrico/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Genotipo , Gota/epidemiología , Humanos , Hiperuricemia/epidemiología , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores de Riesgo , Adulto JovenAsunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Febuxostat/uso terapéutico , Supresores de la Gota/uso terapéutico , Gota/tratamiento farmacológico , Gota/genética , Proteínas de Neoplasias/genética , Adulto , Anciano , Alelos , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Farmacogenética , Polimorfismo de Nucleótido Simple , Resultado del TratamientoRESUMEN
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.
Asunto(s)
Gota , Hiperuricemia , Femenino , Humanos , Masculino , Alcohol Deshidrogenasa/genética , Consumo de Bebidas Alcohólicas/genética , Etnicidad , Estudio de Asociación del Genoma Completo , Gota/genética , Hiperuricemia/genética , Polimorfismo de Nucleótido Simple , Factores de Transcripción/genética , Ácido ÚricoAsunto(s)
Nativos de Hawái y Otras Islas del Pacífico , Peso Corporal , Niño , Preescolar , Humanos , PrevalenciaRESUMEN
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.