Genetic polymorphisms and decreased protein expression of ABCG2 urate transporters are associated with susceptibility to gout, disease severity and renal-overload hyperuricemia

Abstract

Gout is a common crystal induced disease of high personal and social burden, characterised by severe arthritis and comorbidity if untreated. Impaired function of ABCG2 transporter is causative in gout and may be responsible for renal-overload type hyperuricemia. Despite its importance, there is limited information on how clinical parameters correlate with protein expression and that with genetic changes. Urate and clinical parameters of 78 gouty patients and healthy controls were measured among standardised circumstances from a Hungarian population. ABCG2 membrane expression of red blood cells was determined by flow cytometry-based method and SNPs of this protein were analysed by TaqMan-based qPCR. The prevalence of ABCG2 functional polymorphisms in gouty and control patients were 32.1 and 13.7%, respectively. Most common SNP was Q141K while one sample with R236X, R383C and the lately described M71V were found in the gouty population. These polymorphisms showed strong linkage with decreased protein expression while the latter was also associated with higher fractional urate excretion (FUE) and urinary urate excretion (UUE). This study firstly evaluated ABCG2 protein expression in a clinically defined gouty population while also proving its associations between ABCG2 genetic changes and renal-overload hyperuricemia. The paper also highlighted relations between ABCG2 SNPs, gout susceptibility and disease severity characterised by an early onset disease with frequent flares and tophi formation.

Comparison Between Early-Onset and Common Gout: A Systematic Literature Review

“…Unanimous consensus among the authors to include all articles was reached. Of the 17 included publications, six focused on the genetic component of EOG [49][50][51][52][53][54], ten focused on the clinical aspects of EOG [55][56][57][58][59][60][61][62][63][64], and one had aspects of both [65]. Of the clinically focused publications, six were retrospective, cross-sectional comparisons between EOG and CG cohorts [57][58][59][60][61][62], three were prospective comparisons between EOG 1).…”

“…Our systematic literature review identified six full-length publications and one abstract with novel and relevant information related to EOG genetics. Patient and/or gout characteristics were briefly described in the presence of uratetransporter (ABCG2) [49][50][51][52][53], solute carrier (SLC) [53,54], or aldehyde dehydrogenase (ALDH) [53] mutations. Though these mutations are rare in the general population, nearly one-third of a small EOG cohort (7 of 26 patients [27%]) had a ''probably pathogenic'' ABCG2, SLC, or ALDH mutation [53].…”

Genetic Modulation of the GLUT1 Transporter Expression—Potential Relevance in Complex Diseases

“…In order to explore the genetic and regulatory background of GLUT1 expression, potentially related to various diseases, first we have studied the expression level of this protein in the human red blood cell membrane. As described earlier, a quantitative estimation of the erythrocyte membrane proteins can be achieved by using our antibody-based flow cytometry technology, which allows for exploring the genetic background of the alterations in membrane protein expression and the connected disease conditions [ 19 , 20 , 21 ]. We have documented that by using this erythrocyte ghost-forming method and applying well-established, specific monoclonal antibodies—in contrast to other technologies (e.g., Western blotting or direct chemical labeling)—even small differences in the red cell expression levels can be properly quantitated.…”