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Increase of serum uric acid levels associated with APOE ε2 haplotype: a clinico-genetic investigation and in vivo approach.

ABSTRACT: Elevated serum uric acid (SUA)-hyperuricemia-is caused by overproduction of urate or by its decreased renal and/or intestinal excretion. This disease, which is increasing in prevalence worldwide, is associated with both gout and metabolic diseases. Several studies have reported relationships between apolipoprotein E (APOE) haplotypes and SUA levels in humans; however, their results remain inconsistent. This prompted us to investigate the relationship between APOE polymorphisms and SUA levels. Our subjects were 5,272 Japanese men, premenopausal women, and postmenopausal women. Multiple linear regression analyses revealed the ε2 haplotype of APOE to be independently associated with higher SUA in men (N = 1,726) and postmenopausal women (N = 1,753), but not in premenopausal women (N = 1,793). In contrast, the ε4 haplotype was little related to SUA levels in each group. Moreover, to examine the effect of Apoe deficiency on SUA levels, we conducted animal experiments using Apoe knockout mice, which mimics ε2/ε2 carriers. We found that SUA levels in Apoe knockout mice were significantly higher than those in wild-type mice, which is consistent with the SUA-raising effect of the ε2 haplotype observed in our clinico-genetic analyses. Further analyses suggested that renal rather than intestinal underexcretion of urate could be involved in Apoe deficiency-related SUA increase. In conclusion, we successfully demonstrated that the ε2 haplotype, but not the ε4 haplotype, increases SUA levels. These findings will improve our understanding of genetic factors affecting SUA levels.

SUBMITTER: Ogura M

PROVIDER: S-EPMC8490264 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Increase of serum uric acid levels associated with APOE ε2 haplotype: a clinico-genetic investigation and in vivo approach.

Ogura Masatsune M Toyoda Yu Y Sakiyama Masayuki M Kawamura Yusuke Y Nakayama Akiyoshi A Yamanashi Yoshihide Y Takada Tappei T Shimizu Seiko S Higashino Toshihide T Nakajima Mayuko M Naito Mariko M Hishida Asahi A Kawai Sayo S Okada Rieko R Sasaki Makoto M Ayaori Makoto M Suzuki Hiroshi H Takata Koki K Ikewaki Katsunori K Harada-Shiba Mariko M Shinomiya Nariyoshi N Matsuo Hirotaka H

Human cell 20210916 6

Elevated serum uric acid (SUA)-hyperuricemia-is caused by overproduction of urate or by its decreased renal and/or intestinal excretion. This disease, which is increasing in prevalence worldwide, is associated with both gout and metabolic diseases. Several studies have reported relationships between apolipoprotein E (APOE) haplotypes and SUA levels in humans; however, their results remain inconsistent. This prompted us to investigate the relationship between APOE polymorphisms and SUA levels. Ou ...[more]

PMID: 34532841

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Project description:Background. Leprosy reactions are acute inflammatory episodes that occur mainly in the multibacillary forms of the disease. The reactions are classified as type 1 (reverse reaction) or type 2 (erythema nodosum leprosum). Leprosy-associated oxidative stress has been widely demonstrated. Several recent studies have shown uric acid (UA) to have antioxidative effects under pathologic conditions. The objective of this study was to assess serum levels of UA in patients with leprosy reactions, with the aim of monitoring their levels before and after treatment, compared with levels in leprosy patients without reactions. Methods. The study included patients aged 18-69 years assisted at a leprosy treatment reference center in the Central Region of Brazil. Patients who were pregnant; were using immunosuppressant drugs or immunobiologicals; or had an autoimmune disease, human immunodeficiency virus infection, acquired immune deficiency syndrome, or tuberculosis were excluded. Upon recruitment, all individuals were clinically assessed for skin lesions and neural or systemic impairment. Some patients had already completed treatment for leprosy, while others were still undergoing treatment or had initiated treatment after being admitted. The treatment of the reactional episode was started only after the initial evaluation. Laboratory assessments were performed upon admission (baseline) and at approximately 30 and 60 days (time points 1 and 2, respectively). Results. A total of 123 leprosy patients were recruited between June 2012 and June 2015; among them, 56, 42, and 25 presented with type 1, type 2, and no reactions, respectively. Serum UA levels were significantly reduced in patients with type 2 leprosy reactions compared with patients in the control group and remained lower in the two subsequent assessments, after initiation of anti-reaction treatments, with similar values to those recorded before the treatment. Discussion. The decreased serum UA levels in patients with type 2 leprosy reactions might be due to the consumption of UA to neutralize the enhanced production of oxygen- and nitrogen-reactive species that occurs during type 2 reactions. The maintenance of the reduced levels in the follow-up assessments may indicate persistence of oxidative stress in the initial post-treatment stages, despite improved clinical conditions. The results of this study suggest that serum UA may play an antioxidative role during type 2 leprosy reactions.

Project description:AimsHyperuricemia has attracted increasing attention. However, limited concern has been paid to the potential dangers of lowering serum uric acid (SUA). We observed lower levels of SUA in patients with COVID-19. Therefore, we aim to explore whether patients with COVID-19 had SUA lower than normal and the relationship of SUA and the severity of COVID-19.MethodsThis was a case-control study based on 91 cases with COVID-19 and 273 age- and sex-matched healthy control subjects. We first compared SUA levels and uric acid/creatinine (UA/Cr) ratio between patients with COVID-19 and the healthy controls. Then, we examined the association of SUA levels and UA/Cr ratios with COVID-19 severity in COVID-19 cases only, defined according to the fifth edition of China's Diagnosis and Treatment Guidelines of COVID-19.ResultsSUA levels in patients with COVID-19 were 2.59% lower, UA/Cr ratios 6.06% lower at admission compared with healthy controls. In sex stratified analysis, levels of SUA and UA/Cr were lower in male patients with COVID-19 while only level of SUA was lower in female patients with COVID-19. Moreover, SUA and UA/Cr values were 4.27 and 8.23% lower in the severe group than that in the moderate group among male COVID-19 patients. Bivariate and partial correlations analysis showed negative correlations between SUA or UA/Cr ratio and COVID-19 after adjusting for age, sex, BMI and eGFR. A multiple linear regression analysis showed that SARS-CoV-2 infection and male sex were independent risk factors associated with lower SUA levels. Male patients with COVID-19 accompanied by low SUA levels had higher risk of developing severe symptoms than those with high SUA levels (incidence rate ratio: 4.05; 95% CI:1.11, 14.72) at admission. Comparing SUA and UA/Cr ratio at three time points (admission, discharge, and follow-up), we found that male patients experienced severe symptoms had lower SUA and UA/Cr ratio levels comparing to moderate patients, but no significant difference between three time points. On the contrary, female patients had lower SUA and UA/Cr ratio at discharge than those at admission, but no significant difference of SUA and UA/Cr ratio between moderate and severe group.ConclusionPatients with COVID-19 had SUA and UA/Cr values lower than normal at admission. Male COVID-19 patients with low SUA levels had a significantly higher crude risk of developing severe symptoms than those with high SUA levels. During disease aggravation, the level of SUA gradually decreased until discharge. At the follow-up exam, the level of SUA was similar to the levels at admission.

Dataset Information

Increase of serum uric acid levels associated with APOE ε2 haplotype: a clinico-genetic investigation and in vivo approach.

Publications

Increase of serum uric acid levels associated with APOE ε2 haplotype: a clinico-genetic investigation and in vivo approach.

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