Assessment of genetic polymorphisms associated with hyperuricemia or gout in the Hmong.
Ontology highlight
ABSTRACT:
SUBMITTER: Roman YM
PROVIDER: S-EPMC5539965 | biostudies-literature | 2016 Sep
REPOSITORIES: biostudies-literature
Publications
Assessment of genetic polymorphisms associated with hyperuricemia or gout in the Hmong.
Roman Youssef M YM Culhane-Pera Kathleen A KA Menk Jeremiah J Straka Robert J RJ
Personalized medicine 20160801 5
<h4>Aim</h4>Hyperuricemia commonly causes gout. Minnesota Hmong exhibit a two- to fivefold higher prevalence of gout versus non-Hmong. To elucidate a possible genomic contribution to this disparity, prevalence of risk alleles for hyperuricemia in Hmong was compared with European (CEU) and Han-Chinese (CHB).<h4>Methods</h4>In total, 235 Hmong were genotyped for eight SNPs representing five candidate genes (<i>SLC22A12</i>, <i>SLC2A9</i>, <i>ABCG2</i>, <i>SLC17A1</i> and <i>PDZK1</i>).<h4>Results< ...[more]
Similar Datasets
Project description:Genome-wide association studies that scan the genome for common genetic variants associated with phenotype have greatly advanced medical knowledge. Hyperuricemia is no exception, with 28 loci identified. However, genetic control of pathways determining gout in the presence of hyperuricemia is still poorly understood. Two important pathways determining hyperuricemia have been confirmed (renal and gut excretion of uric acid with glycolysis now firmly implicated). Major urate loci are SLC2A9 and ABCG2. Recent studies show that SLC2A9 is involved in renal and gut excretion of uric acid and is implicated in antioxidant defense. Although etiological variants at SLC2A9 are yet to be identified, it is clear that considerable genetic complexity exists at the SLC2A9 locus, with multiple statistically independent genetic variants and local epistatic interactions. The positions of implicated genetic variants within or near chromatin regions involved in transcriptional control suggest that this mechanism (rather than structural changes in SLC2A9) is important in regulating the activity of SLC2A9. ABCG2 is involved primarily in extra-renal uric acid under-excretion with the etiological variant influencing expression. At the other 26 loci, probable causal genes can be identified at three (PDZK1, SLC22A11, and INHBB) with strong candidates at a further 10 loci. Confirmation of the causal gene will require a combination of re-sequencing, trans-ancestral mapping, and correlation of genetic association data with expression data. As expected, the urate loci associate with gout, although inconsistent effect sizes for gout require investigation. Finally, there has been no genome-wide association study using clinically ascertained cases to investigate the causes of gout in the presence of hyperuricemia. In such a study, use of asymptomatic hyperurcemic controls would be expected to increase the ability to detect genetic associations with gout.
| S-EPMC4392805 | biostudies-literature
Project description:Hyperuricemia and gout are complex diseases mediated by genetic, epigenetic, and environmental exposure interactions. The incidence and medical burden of gout, an inflammatory arthritis caused by hyperuricemia, increase every year, significantly increasing the disease burden. Genetic factors play an essential role in the development of hyperuricemia and gout. Currently, the search on disease-associated genetic variants through large-scale genome-wide scans has primarily improved our understanding of this disease. However, most genome-wide association studies (GWASs) still focus on the basic level, whereas the biological mechanisms underlying the association between genetic variants and the disease are still far from well understood. Therefore, we summarized the latest hyperuricemia- and gout-associated genetic loci identified in the Global Biobank Meta-analysis Initiative (GBMI) and elucidated the comprehensive potential molecular mechanisms underlying the effects of these gene variants in hyperuricemia and gout based on genetic perspectives, in terms of mechanisms affecting uric acid excretion and reabsorption, lipid metabolism, glucose metabolism, and nod-like receptor pyrin domain 3 (NLRP3) inflammasome and inflammatory pathways. Finally, we summarized the potential effect of genetic variants on disease prognosis and drug efficacy. In conclusion, we expect that this summary will increase our understanding of the pathogenesis of hyperuricemia and gout, provide a theoretical basis for the innovative development of new clinical treatment options, and enhance the capabilities of precision medicine for hyperuricemia and gout treatment.
| S-EPMC9259951 | biostudies-literature
Project description:In the past few decades, gout has increased not only in prevalence, but also in clinical complexity, the latter accentuated in part by a dearth of novel advances in treatments for hyperuricemia and gouty arthritis. Fortunately, recent research reviewed here, much of it founded on elegant translational studies of the past decade, highlights how gout can be better managed with cost-effective, well-established therapies. In addition, the advent of both new urate-lowering and anti-inflammatory drugs, also reviewed here, promises for improved management of refractory gout, including in subjects with co-morbidities such as chronic kidney disease. Effectively delivering improved management of hyperuricemia and gout will require a frame shift in practice patterns, including increased recognition of the implications of refractory disease and frequent noncompliance of patients with gout, and understanding the evidence basis for therapeutic targets in serum urate-lowering and gouty inflammation.
| S-EPMC2745774 | biostudies-literature
Project description:Gout is a chronic metabolic disease that seriously affects human health. It is also a major challenge facing the world, which has brought a heavy burden to patients and society. Hyperuricemia (HUA) is the most important risk factor for gout. In recent years, with the improvement of living standards and the change of dietary habits, the incidence of gout in the world has increased dramatically, and gradually tends to be younger. An increasing number of studies have shown that gene mutations may play an important role in the development of HUA and gout. Therefore, we reviewed the existing literature and summarized the susceptibility genes and research status of HUA and gout, in order to provide reference for the early diagnosis, individualized treatment and the development of new targeted drugs of HUA and gout.
| S-EPMC9351246 | biostudies-literature
Project description:OBJECTIVE:The language currently used to describe gout lacks standardization. The aim of this project was to develop a consensus statement on the labels and definitions used to describe the basic disease elements of gout. METHODS:Experts in gout (n = 130) were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach consensus on the labeling and definitions for the basic disease elements of gout. Disease elements and labels in current use were derived from a content analysis of the contemporary medical literature, and the results of this analysis were used for item selection in the Delphi exercise and face-to-face consensus meeting. RESULTS:There were 51 respondents to the Delphi exercise and 30 attendees at the face-to-face meeting. Consensus agreement (?80%) was achieved for the labels of 8 disease elements through the Delphi exercise; the remaining 3 labels reached consensus agreement through the face-to-face consensus meeting. The agreed labels were monosodium urate crystals, urate, hyperuric(a)emia, tophus, subcutaneous tophus, gout flare, intercritical gout, chronic gouty arthritis, imaging evidence of monosodium urate crystal deposition, gouty bone erosion, and podagra. Participants at the face-to-face meeting achieved consensus agreement for the definitions of all 11 elements and a recommendation that the label "chronic gout" should not be used. CONCLUSION:Consensus agreement was achieved for the labels and definitions of 11 elements representing the fundamental components of gout etiology, pathophysiology, and clinical presentation. The Gout, Hyperuricemia, and Crystal-Associated Disease Network recommends the use of these labels when describing the basic disease elements of gout.
| S-EPMC6252290 | biostudies-literature
Project description:BackgroundGout, an inflammatory condition, is characterized by the precipitation of monosodium urate crystals (MSU) in or around distal joints. The latter is caused by chronic hyperuricemia (HU)-high urate levels in the blood. Genetic variations in urate transporters play a significant role in determining urate levels within the human body, rendering some racial and ethnic groups more or less susceptible to developing either HU or gout. This study aims to estimate the frequencies of HU and gout risk alleles in Asian, Native Hawaiian, and Pacific Islander subgroups, using biorepository DNA samples.MethodsThe biospecimens repository at the University of Hawai'i provided DNA samples of consented post-partum women of Japanese, Filipino, Korean, Native Hawaiian, Samoan, and Marshallese descent. The DNA was previously extracted from maternal blood and genotyped at the Genomics and Bioinformatics Shared Resource, Cancer Center (Honolulu, HI). Nine urate genes: ABCG2, SLC2A9, SLC16A9, GCKR, SLC22A11, SLC22A12, LRR16A, PDZK1, and SLC17A1, were selected due to their significant association with HU and gout risk. Hardy-Weinberg Equilibrium (HWE) for genotype frequencies was assessed, using the Chi-Square test with p < 0.006 for statistical significance. Allele frequencies in our study were then compared to EUR from the 1000 Genomes Project Database Phase III, using Chi-square or Fisher's exact test, when appropriate. Bonferroni correction for multiple comparisons was used, with p < 0.006 for statistical significance.ResultsOur study involved 1059 post-partum women 18-year-old or older who self-reported their respective race and ethnicity, including Asian, Native Hawaiian, and Pacific Islander ancestry. The Asian subgroups included Japanese, Filipino, and Korean. The Pacific Islander subgroups included Marshallese and Samoan. None of the study participants had a history of gout. We excluded the PDZK1 gene from the final analysis due to its deviation from HWE (p < 0.006) across all the population subgroups, with eight loci remaining for cross-subgroup comparisons. Compared to EUR, the genetic polymorphism frequencies were significantly different-8/8 in Japanese, 6/8 in Korean, 6/8 in Filipino, 8/8 in Samoan, 6/8 in Native Hawaiian, and 6/8 in Marshallese. HU and gout risk alleles indices were 8, 6, 5, 5, 4, and 4 in Japanese, Filipino, Korean, Samoan, Marshallese, and Native Hawaiian, respectively. The percentage of cumulative risk alleles was 100% in both Japanese and Filipino, followed by 83.5% in Korean.ConclusionsCompared to EUR, Asian subgroups, particularly Japanese, Filipino, and Korean, had the highest percentage of the cumulative uric acid risk alleles. These results could partly explain the increased risk of developing gout among some Asian ancestral subgroups compared to EUR.
| S-EPMC8734301 | biostudies-literature
Project description:ObjectivesMicroRNAs (miRNAs) are short single-stranded RNAs that play a role in the post-transcriptional regulation of gene expression. Their deregulation can be associated with various diseases, such as cancer, neurodegenerative, and immune-related diseases. The aim of our study was to compare miRNA levels in plasma that could potentially influence the progression of hyperuricemia to gout, since the mechanism of progression is still unclear.MethodsTotal RNA, including miRNA, was isolated from the plasma of 45 patients with asymptomatic hyperuricemia, 131 patients with primary gout (including 16 patients having a gout attack), and 130 normouricemic controls. The expression of 18 selected miRNAs (cel-miR-39 and cel-miR-54 as spike-in controls, hsa-miR-16-5p and hsa-miR-25-3p as endogenous controls, hsa-miR-17-5p, hsa-miR-18a-5p, hsa-miR-30a-3p, hsa-miR-30c-5p, hsa-miR-126-3p, hsa-miR-133a-3p, hsa-miR-142-3p, hsa-miR-143-3p, hsa-miR-146a-5p, hsa-miR-155-5p, hsa-miR-222-3p, hsa-miR-223-3p, hsa-miR-488-3p and hsa-miR-920) was measured using qPCR.ResultsWe found that hsa-miR-17-5p, hsa-miR-18a-5p, hsa-miR-30c-5p, hsa-miR-142-3p, and hsa-miR-223-3p were significantly upregulated (p < 0.001) in the plasma of hyperuricemia and gout patients compared to normouricemic individuals. As part of the follow-up of our previous study, we found a negative correlation between hsa-miR-17-5p, hsa-miR-30c-5p, hsa-miR-126-3p, hsa-miR-142-3p, and hsa-miR-223-3p with plasma levels of chemokine MCP-1. Additionally, we found a positive correlation between CRP and plasma levels of hsa-miR-17-5p, hsa-miR-18a-5p, hsa-miR-30c-5p, hsa-miR-126-3p, hsa-miR-142-3p, hsa-miR-146a-5p, hsa-miR-155-5p, hsa-miR-222-3p, and hsa-miR-223-3p. Five of those miRNAs (hsa-miR-126-3p, hsa-miR-142-3p, hsa-miR-146a-5p, hsa-miR-155-5p, and hsa-miR-222-3p) also had a positive correlation with serum creatinine and therefore a negative correlation with eGFR.ConclusionFive miRNAs were significantly upregulated in the plasma of patients with hyperuricemia and gout (and those during a gout attack) compared to normouricemic controls. We also found a correlation between the plasma levels of several miRNA and plasma levels of MCP-1, CRP, serum creatinine, and eGFR.
| S-EPMC8272270 | biostudies-literature
Project description:OBJECTIVE: Primary hyperuricemia, an excess of uric acid in the blood, is a major public health problem. In addition to the morbidity that is attributable to gout, hyperuricemia is also associated with metabolic syndrome, hypertension, and cardiovascular disease. This study aims to assess the genetic associations between Apolipoprotein E (APOE) polymorphisms and hyperuricemia in a Chinese population. METHODS: A total of 770 subjects (356 hyperuricemic cases and 414 normouricemic controls) were recruited from the Ningxia Hui Autonomous Region, China. A physical examination was performed and fasting blood was collected for biochemical tests, including determination of the levels of serum lipid, creatinine, and uric acid. Multi-ARMS PCR was applied to determine the APOE genotypes, followed by an investigation of the distribution of APOE genotypes and alleles frequencies in the controls and cases. RESULTS: The frequencies of the APOE-ε2ε3 genotype (17.70% vs. 10.39%, P = 0.003) and the APOE-ε2 allele (10.53% vs. 5.80%, P = 0.001) were significantly higher in the hyperuricemic group than in the normouricemic group. Furthermore, male cases were more likely to have the APOE-ε2ε3 genotype and APOE-ε2 allele, compared with male controls. In both Han and Hui subjects, cases were more likely to have the APOE-ε2ε3 genotype and the APOE-ε2 allele compared with controls. Furthermore, multivariate logistic regression showed that carriers of the APOE-ε2ε3 genotype (P = 0.001, OR = 2.194) and the ε2 allele (P = 0.001, OR = 2.099) were significantly more likely to experience hyperuricemia than carriers of the ε3/ε3 genotype and the ε3 allele after adjustment for sex, body mass index (BMI), diastolic blood pressure (DBP), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), creatinine (Cr) and fasting blood glucose (FBG). CONCLUSIONS: The APOE-ε2ε3 genotype and the APOE-ε2 allele are associated with serum uric acid levels in Chinese subjects, indicating that individuals carrying the APOE-ε2 allele have a higher risk of hyperuricemia than non-carriers.
| S-EPMC4214707 | biostudies-other
Project description:The pathophysiological nature of the common ABCG2 gout and hyperuricemia associated variant Q141K (rs2231142) remains undefined. Here, we use a human interventional cohort study (ACTRN12615001302549) to understand the physiological role of ABCG2 and find that participants with the Q141K ABCG2 variant display elevated serum urate, unaltered FEUA, and significant evidence of reduced extra-renal urate excretion. We explore mechanisms by generating a mouse model of the orthologous Q140K Abcg2 variant and find male mice have significant hyperuricemia and metabolic alterations, but only subtle alterations of renal urate excretion and ABCG2 abundance. By contrast, these mice display a severe defect in ABCG2 abundance and function in the intestinal tract. These results suggest a tissue specific pathobiology of the Q141K variant, support an important role for ABCG2 in urate excretion in both the human kidney and intestinal tract, and provide insight into the importance of intestinal urate excretion for serum urate homeostasis.
| S-EPMC7265540 | biostudies-literature
Project description:BackgroundHmong men in Minnesota exhibit a high prevalence of gout and hyperuricemia. Although evidence of vitamin C's effectiveness as a treatment for gout is mixed, analysis of therapeutic benefit based on an individual's multiomic signature may identify predictive markers of treatment success.ObjectivesThe primary objective of the Hmong Microbiome ANd Gout, Obesity, Vitamin C (HMANGO-C) study was to assess the effectiveness of vitamin C on serum urate in Hmong adults with and without gout/hyperuricemia. The secondary objectives were to assess if 1) vitamin C impacts the taxonomic and functional patterns of microbiota; 2) taxonomic and functional patterns of microbiota impact vitamin C's urate-lowering effects; 3) genetic variations impact vitamin C's urate-lowering effects; 4) differential microbial biomarkers exist for patients with or without gout; and 5) there is an association between obesity, gut microbiota and gout/hyperuricemia.MethodsThis prospective open-labelled clinical trial was guided by community-based participatory research principles and conducted under research safety restrictions for SARS-CoV-2. We aimed to enroll a convenient sample of 180 Hmong adults (120 with gout/hyperuricemia and 60 without gout/hyperuricemia) who provided medical, demographic, dietary and anthropometric information. Participants took vitamin C 500mg twice daily for 8 weeks and provided pre-and post- samples of blood and urine for urate measurements as well as stool samples for gut microbiome. Salivary DNA was also collected for genetic markers relevant to uric acid disposition.Expected resultsWe expected to quantify the impact of vitamin C on serum urate in Hmong adults with and without gout/hyperuricemia. The outcome will enhance our understanding of how gut microbiome and genomic variants impact the urate-lowering of vitamin C and associations between obesity, gut microbiota and gout/hyperuricemia. Ultimately, findings may improve our understanding of the causes and potential interventions that could be used to address health disparities in the prevalence and management of gout in this underserved population.Trial registrationClinicalTrials.gov NCT04938024 (first posted: 06/24/2021).
| S-EPMC9891498 | biostudies-literature