Identification and functional analysis of genetic variants of the human ??-glucuronidase in a German population sample

Abstract

The deleterious consequences of total beta-glucuronidase deficiency, leading to symptomatic mucopolysaccharidosis type VII (MPS VII), have been firmly established. However, the question of whether sequence variations in beta-glucuronidase of non-MPS VII patients affect expression of the enzyme, thereby explaining the wide inter-individual expression, has not been addressed in a systematic manner. In the present study, a population of 965 subjects were screened for enzyme activity and relevant fractions of the beta-glucuronidase gene were sequenced in those individuals belonging to the highest or lowest decile of activity. The study showed a substantial inter-individual variability of beta-glucuronidase in plasma (range 0.5-150.2 micromol/min) and confirmed the association of beta-glucuronidase activity with gender (P < 0.001), age (r = 0.218; P < 0.001) and body mass index (r = 0.311; P < 0.001). We were able to identify six beta-glucuronidase single base substitutions (-1026A > G, -72G > T, -12G > A, +7728C > T, +14 209C > T and +14 604A > G) in 193 non-MPS VII patients at a rate of one single nucleotide polymorphism (SNP) per 520 bp sequenced. The GG genotype of +14 604A > G and the CT genotype of +14 209C > T were associated with higher beta-glucuronidase activity (P < 0.05). Subsequently, reporter gene assays were carried out to elucidate the effects of the SNPs -1026A > G, -72G > T and -12G > A, and the combined genotype -1026A > G and -12G > A observed in one of the subjects. Variant -12G > A reduced the promoter activity (75%; 95% confidence interval 70-84%, P < 0.05). The present study demonstrates that three of the described SNPs influence the activity and/or expression of beta-glucuronidase. Taken together, the data indicate a rather limited influence of genetic factors on inter-individual variability in beta-glucuronidase activity.

Dietary and Demographic Correlates of Serum β-Glucuronidase Activity

“…Our finding of a positive association in men is consistent with reports in humans (22, 32) and other data. For instance, in rodents, androgens are known to increase rates of β-glucuronidase gene transcription in the kidney (9, 33).…”

“…Our discrepant finding that higher energy intake was associated with lower ß-glucuronidase activity but being overweight (BMI ≥ 25 kg/m 2 ) was associated with higher enzyme activity is not clear. Our results for a positive association between BMI and ß-glucuronidase activity is supported by at least one other report (32). Inflammation may be one mechanism potentially underlying our positive finding for being overweight; immune cells (e.g., macrophages, neutrophils, etc.)…”

The flavonoid quercetin induces acute vasodilator effects in healthy volunteers: Correlation with beta-glucuronidase activity

“…A wide inter-individual variability in the activity of this enzyme has also been reported which may be accounted for by changes on its expression or by variations in its gene sequence [38]. Thus, we hypothesized that ␤-glucuronidase activity may influence the effectiveness of quercetin.…”

“…Because inhibition of ␤-glucuronidase is not feasible in humans, precluding the proper analysis of a cause-effect relationship, we measured its activity in an attempt to correlate it with the functional effects of quercetin. We measured glucuronidase activity in plasma which is considerably low, but it may be used as a surrogate for activity in tissues [38].…”

The Contribution of Common Genetic Variation to Nicotine and Cotinine Glucuronidation in Multiple Ethnic/Racial Populations

“…Variation in this enzyme could impact the levels of nicotine and cotinine glucuronide excreted. However, β-glucuronidase is a lysosomal enzyme, only a small amount is present in the plasma, so the influence of this enzyme on circulating nicotine levels would likely be small (53). …”