Prevalence and complications of hypouricemia in a general population: A large-scale cross-sectional study in Japan

Kuwabara, Masanari; Niwa, Koichiro; Ohtahara, Akira; Hamada, Toshihiro; Miyazaki, Shôzo; Mizuta, Einosuke; Oginö, Kazuhíde; Hisatome, Ichiro

doi:10.1371/journal.pone.0176055

Cited by 44 publications

(51 citation statements)

References 29 publications

(34 reference statements)

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“…The prevalence of subjects with uric acid ≤2.0 mg/dL in the present study was 0.3%, which was similar to the prevalence of hypouricemia (0.2-0.4%) in previous studies using Japanese subjects [4][5][6]. The number of subjects with a relatively low level of uric acid was larger in female subjects than in male subjects in the present study.…”

Section: Discussionsupporting

confidence: 87%

“…The population was the same as that in our previous study for investigating plasma XOR activity [28]. Hypouricemia is conventionally defined as a serum uric acid concentration of ≤2 mg/dL [4][5][6][12][13][14]. However, it has been reported that levels of uric acid are more than 3 mg/dL in some patients with renal hypouricemia who have heterozygote mutations of SLC22A12/URAT1 or SLC2A9/GLUT9/URATv1 [15,30].…”

Section: Study Populationmentioning

confidence: 99%

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Unexpected high plasma xanthine oxidoreductase activity in female subjects with low levels of uric acid

et al. 2018

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Hypouricemia is a high-risk factor of exercise-induced acute kidney injury (EIAKI) probably through a lack of an antioxidant effect of uric acid. Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the formation of uric acid from hypoxanthine and xanthine, leading to an increase in superoxide and reactive oxygen species. Activation of XOR has been proposed to promote oxidative stress-related tissue injury. We measured plasma XOR activity by a sensitive and accurate assay using a combination of liquid chromatography and triple quadrupole mass spectrometry in subjects with relatively low levels of uric acid (≤4.0 mg/dL) who were recruited from 627 subjects (male/female: 292/335) in the Tanno-Sobetsu Study, a population-based cohort. The numbers of subjects with uric acid ≤4.0 mg/dL, ≤3.0 mg/dL and ≤2.0 mg/dL were 72 (11.5%, male/female: 5/67), 13 (2.1%, all females) and 2 (0.3%, both females), respectively. Plasma XOR activities in 5 male subjects were below the median value of the 292 male subjects. In 12 (17.9%) of the 67 female subjects with uric acid ≤4.0 mg/dL, plasma XOR activities were above the upper quartile value of the 335 female subjects. Eleven of the 12 female subjects with high plasma XOR activity and a low uric acid level had liver dysfunction and/or insulin resistance. In conclusion, unexpected high plasma XOR activities were found in some female subjects with relatively low levels of uric acid. Measurement of plasma XOR activity may help to identify hypouricemic patients with a high risk for EIAKI.

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Section: Discussionsupporting

confidence: 87%

Section: Study Populationmentioning

confidence: 99%

Unexpected high plasma xanthine oxidoreductase activity in female subjects with low levels of uric acid

et al. 2018

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“…Consistently, a large-scale cross-sectional study showed that hypouricemic men had higher rates of kidney disease compared to non-hypouricemic subjects. However, the rates of other diseases including diabetes and urinary stones were not significantly different between hypouricemic and non-hypouricemic subjects [20]. In this regard, our longitudinal study showed that hypouricemia did not carry the lowest risk for developing cardiometabolic diseases.…”

Section: Discussionmentioning

confidence: 51%

“…We calculated eGFR using the Japanese GFR equation: eGFR (mL/min/1.73m 2 ) = 194 × serum creatinine −1.094 × age −0.287 (×0.739 if woman) [19]. Hypouricemia is defined as serum urate level lower than 3.0 mg/dL in men and 2.0 mg/dL in women in this study [20]…”

Section: Definition Of Hypertension Diabetes Dyslipidemia Ckd Andmentioning

confidence: 99%

The Optimal Range of Serum Uric Acid for Cardiometabolic Diseases: A 5-Year Japanese Cohort Study

Kuwabara

Hisatome

Niwa

et al. 2020

JCM

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The optimal range of serum uric acid (urate) associated with the lowest risk for developing cardiometabolic diseases is unknown in a generally healthy population. This 5-year cohort study is designed to identify the optimal range of serum urate. The data were collected from 13,070 Japanese between ages 30 and 85 at the baseline (2004) from the Center for Preventive Medicine, St. Luke’s International Hospital, Tokyo. We evaluated the number of subjects (and prevalence) of those free of the following conditions: hypertension, diabetes, dyslipidemia, and chronic kidney disease (CKD) over 5 years for each 1 mg/dL of serum urate stratified by sex. Furthermore, the odds ratios (ORs) for remaining free of these conditions were calculated with multiple adjustments. Except for truly hypouricemic subjects, having lower serum urate was an independent factor for predicting the absence of hypertension, dyslipidemia, and CKD, but not diabetes. The OR of each 1 mg/dL serum urate decrease as a protective factor for hypertension, dyslipidemia, and CKD was 1.153 (95% confidence interval, 1.068–1.245), 1.164 (1.077–1.258), and 1.226 (1.152–1.306) in men; 1.306 (1.169–1.459), 1.121 (1.022–1.230), and 1.424 (1.311–1.547) in women, respectively. Moreover, comparing serum urate of 3–5 mg/dL in men and 2–4 mg/dL in women, hypouricemia could be a higher risk for developing hypertension (OR: 4.532; 0.943–21.78) and CKD (OR: 4.052; 1.181–13.90) in women, but not in men. The optimal serum urate range associated with the lowest development of cardiometabolic diseases was less than 5 mg/dL for men and 2–4 mg/dL for women, respectively.

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“…Prevalence of hypouricemia is reported as 0.53% in Korea 13 which is similar to data from the west part of Japan. Japanese data reported a geometric difference in its prevalence (0.579% of West Japanese and 0.191% of East Japanese) 14 .…”

Section: Introductionmentioning

confidence: 98%

Genetic predisposition to hypouricemia on whole-exome sequencing analysis and its utilities in primary screening purposes

Cha

Gee²,

Cachau

et al. 2018

Preprint

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Running head:The genetic predisposition of hypouricemia Word count: Abstract 215; text 3,805 AbstractDifferentiating between inherited renal hypouricemia and transient hypouricemia is challenging. Here, we aimed to describe the genetic predisposition of hypouricemia patients using whole-exome sequencing (WES) and assess the feasibility for genetic diagnosis in primary screening. WES was performed for the discovery of diagnostic markers in discovery cohorts (N=31). Two known genetic markers SLC22A12 c.774G>A (p.Trp258*) and SLC22A12 c.269G>A (p.Arg90His) were identified, We genotyped for the 2 SLC22A12 SNPs among screened 50 hypouricemia subjects for the replication cohorts; 47 carried known SLC22A12 markers; three unexplained hypouricemic cases were analyzed by using WES. We used 46 healthy internal controls for the variant discovery. Four novel variants of SLC22A12, c.408C>A (p.Asn136Lys), c.674C>A (p.Thr225Lys), c.851G>A (p.Arg284Gln), and c.1285G>A (p.Glu429Lys), and one novel variant of SLC2A9, c. 376A>G (p.Met155Val), were identified. After filtering out known genes (SLC22A12 and SLC2A9), the p.Arg78His variant in ASB12 was overlapped in two unexplained conditions. This is the first attempt to investigate the effectiveness of integrating exome sequencing and genotype into the clinical care for hypouricemia and determine the value of genetic diagnostic screening for hypouricemia in the clinical setting. Screening of just two SNPs (p.Trp258* and p.Arg90His) identified 87.7% (71/81) of patients with hypouricemia. Early identification and intervention of hypouricemia is feasible using genetic screening to prevent acute kidney injury, especially for soldiers and athletics. Keywords: SLC22A12, SLC2A9, hypouricemia, screening testto the East Asian populations. Prevalence of hypouricemia is reported as 0.53% in Korea 13 which is similar to data from the west part of Japan. Japanese data reported a geometric difference in its prevalence (0.579% of West Japanese and 0.191% of East Japanese) 14 .Differentiating between inherited and transient hypouricemia is challenging because a low level of UA reflects malnutrition status 15 . Moreover, a genetic utility for the diagnosis has not been conducted so far.In this study, we investigated the genetic features of subjects with extremely low levels of UA using wholeexome sequencing (WES). Many exome-based studies have been able to detect the loss-of-function variants, missense variants and other types of variants due to changes in the triplet codon on particular genetic loci, especially in diseases with high heritability and low prevalence [16][17][18] . After the discovery of targeted SNPs, genetic diagnostic feasibility will be assessed in the different cohorts. MATERIALS AND METHODS Study participantsThis study was approved by the institutional review board of the Kangbuk Samsung Hospital (IRB# KBSMC 2016-12-016). We screened the subjects in the Korean genome and epidemiology study (KoGES) -KoGES health examinee study (Urban Cohort) and KoGES twin and family study. Out ...

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Prevalence and complications of hypouricemia in a general population: A large-scale cross-sectional study in Japan

Cited by 44 publications

References 29 publications

Unexpected high plasma xanthine oxidoreductase activity in female subjects with low levels of uric acid

Unexpected high plasma xanthine oxidoreductase activity in female subjects with low levels of uric acid

The Optimal Range of Serum Uric Acid for Cardiometabolic Diseases: A 5-Year Japanese Cohort Study

Genetic predisposition to hypouricemia on whole-exome sequencing analysis and its utilities in primary screening purposes

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