Review One year in review 2018: gout L. Punzi1, A. Scanu2, P. Spinella3, P. Galozzi2, F. Oliviero2 1Centre for Gout and Metabolic Bone ABSTRACT In line with the editorial policy of this and Joint Diseases, Rheumatology, Gout is the most common form of inflam- journal to publish yearly updates on the SS Giovanni and Paolo, Venice, Italy matory arthropathy, and is associated most relevant topics of rheumatology, 2Rheumatology Unit, and 3Clinical with excruciating pain, major impair- we will provide here an overview of Nutrition Unit, Department of Medicine - DIMED, University of Padova, ltaly. ment of quality of life, and increased the recent literature on novel treatments risk of comorbidities and mortality. in gout (8-22). This article reviews the Leonardo Punzi, MD, PhD Anna Scanu, PhD Although gout has somehow been ne- new clinical and experimental evidence Paolo Spinella, MD glected by researchers and clinicians in about gout that emerged in 2017 and Paola Galozzi, PhD the past, in more recent times there has in the first half of 2018. Relevant pa- Francesca Oliviero, PhD been a renewed interest in this disease, pers published from January 2017 were Please address correspondence to: which has led to major improvements in identified by a PubMed search, last Prof. Leonardo Punzi, its management. update at the beginning of July 2018; Centre for Gout and Metabolic This article reviews the new clinical papers were then selected for inclusion Bone and Joint Diseases, and experimental evidence about gout according to the authors’ judgement. Padiglione Mendicanti I piano, that emerged in 2017 and in the first Ospedale Civile SS. Giovanni e Paolo, Castello 6777, half of 2018. Genetics 30122 Venezia, Italy A combination of inherited genetic E-mail: [email protected] Introduction variants and environmental exposure is Received on September 24, 2018; accepted Gout is the most common form of in- known to influence serum urate levels in revised form on October 15, 2018. flammatory arthropathy, with an es- and the risk of developing gout. Clin Exp Rheumatol 2019; 37: 1-11. timated prevalence of up to 4% in © Copyright CLINICAL AND Western countries (1). This condition is GWAS EXPERIMENTAL RHEUMATOLOGY 2019. caused by hyperuricaemia, which leads Over the past decade, several genome- to crystallisation, aggregation and dep- wide association studies (GWAS) have Key words: gout, urate crystals, osition, of monosodium urate (MSU) systematically assessed the genome for pathogenesis, diagnosis, diet, therapy crystals that accumulate in joints and urate-associated loci (23). These loci are soft tissues over time (2, 3). These crys- dominated by proteins involved in urate tals induce an acute inflammatory reac- transportation (i.e. SLC family genes) or tion characterised by a massive leuco- they are associated with metabolic path- cyte recruitment and the local release of ways (i.e. glucokinase regulatory gene cytokines, chemokines, reactive oxygen and members of aldehyde dehydroge- species and proteolytic enzymes (3). nase gene family and apolipoproteins Once established, gout is associated gene family). Nakayama et al. (24) per- with excruciating pain, joint swelling formed a follow-up GWAS of gout and and redness, as well as with several subtypes in 1,396 cases, replicating loci comorbidities related, in particular, to not reaching genome-wide significance kidney and cardiovascular conditions, in the original 2015 Japanese GWAS which lead to an increased risk of mor- (25). At a genome-wide level, novel as- tality in these patients, especially in sociations with gout at the urate trans- those with tophi (1, 4, 5). porter genes (SLC22A12, SLC17A1) Although gout has somehow been ne- and HIST1H2BF–HIST1H4E gene were glected by researchers and clinicians reported. Two more loci (NIPAL1 and in the past (6, 7), in more recent times FAM35A) were associated with renal there has been a renewed interest in underexcretion gout subtype. Competing interests: L. Punzi received this disease, which has led to major im- Another GWAS in 1,888 male Chinese consulting or speaker fees from BMS, provements in its management. Indeed, gout patients reported four novel loci Fidia, Grunenthal, Menarini, and MSD; the number of publications on gout has (PKC-ε, MARCKS, Pitx2 and MSX2) the other co-authors have declared no almost doubled from 2009 to the end of strongly associated with tophi occur- competing interests. 2017 (Fig. 1). rence (26). Clinical and Experimental Rheumatology 2019 1 One year in review 2018: gout / L. Punzi et al. gene (34), four high-risk genotypes of with urate transporters genes in manag- ALPK1 gene combined with ABCG2, ing the risk of hyperuricaemia and gout. SLC2A9 and ALC22A12 genes (35), and An interaction between alcohol and the rs4148500 in the ABCC4 gene (36). Yas- SNP rs671 at ALDH2 was described to ukochi et al. (37) instead add rs55975541 handle serum urate levels in a Chinese in the CDC42BPG gene at the suscepti- Han male cohort (44). It was also ob- bility locus for hyperuricaemia. served that an interaction between the Clear evidence from Japanese and alcohol intake and the risk of gout in a Czech re-sequencing studies (38, 39) New Zealand European cohort present- indicate that genotyping the rare and ing rs780094 at GCKR and rs10821905 common variants of ABCG2, a secre- at A1CF, loci predominantly involved in Fig. 1. The number of publications on gout and tory transporter, is essential for evaluat- glycolysis and lipid homeostasis (45). hyperuricaemia (PubMed) over the past 10 years ing the individual risk of gout. More- (2018 not included). over, non-synonymous allelic variants Mitochondrial dysgenesis in gout of ABCG2, among which rs2231142, Mitochondrial DNA (mtDNA) repre- In the largest GWAS in gout com- were associated with an earlier onset of sents a relatively new chapter in the pleted to date, preliminary data from gout and the presence of gout history genetics implied in gout pathogenesis. 7,431 European patients with gout (38,39). In an Aotearoa New Zealand The mtDNA is a double-stranded, cir- presented as an abstract at the Ameri- study (40), ABCG2 SNPs (rs2231142 cular molecule contains 37 genes cod- can College of Rheumatology (ACR) and rs10011796) were found to be as- ing for two rRNAs, 22 tRNAs and 13 meeting in 2017, which showed nine sociated with tophi in western Polyne- subunits of enzyme complexes of the loci (SLC2A9, ABCG2, GCKR, MLX- sian individuals with gout, independent oxidative phosphorylation system. Gos- IPL, SLC17A1–SLC17A4, SLC16A9, of other risk factors as serum urate con- ling et al. (46) investigated the role of SLC22A12, PDZK1 and TRIM46) with centrations or disease duration. mtDNA variation and copy number in genome-wide significance with an as- Zambo et al. (41) discovered a relative the risk of gout in New Zealand Māori sociation with gout (27). All nine loci frequent, novel rs148475733 mutation and Pacific people. The authors found were associated with serum uric acid in ABCG2 that reduced erythrocyte that both heteroplasmy and reduced (sUA) levels in a previous European membrane protein expression, preserv- mtDNA copy number did associate GWAS (28). ing transporter capability. Colchicine with gout. Mitochondrial conformation and other small molecule correctors differences, white blood cell population Common and rare variants were observed to restore ABCG2 surface differences or reduced mitochondrial This year great efforts have been made expression. biogenesis and mitophagy could poten- in the attempt of elucidating genetic The common SNPs explained only tially explain the reduced mtDNA copy factors contributing to positively pre- part of the hereditability of gout. Copy number. dict the risk of gout. number variants (CNVs), dosage im- Consistent with a role for mitochondrial Based on the above-mentioned path- balances of large segments of DNA, dysgenesis in gout, the SNP rs45520937 way analysis (29, 30), a novel gout-as- could play a role in genetic susceptibil- in PPARGC1B, an anti-inflammato- sociated gene SLC17A2 was identified ity to gout, as observed by Dong et al. ry mediator gene, is associated with and non-synonymous single nucleotide (42). The authors identified three novel gout and increased MSU-stimulated polymorphisms (SNPs) loci of P2X7R genes: ABCF1 and FCGR3A with high NLRP3 activation and IL-1β secretion (an ATP receptor) regulate the occur- copy number increased the risk of gout; in Twainese Chinese gout patients (47). rence and development of gout. and IL17REL with a low copy number A published abstract reported that this Since gout can be classified among acted as a protective factor for gout. allele is also associated with increased the autoinflammatory diseases (31), Overall, these findings emphasise the risk of gout in people of Polynesian an- some authors investigated autoinflam- importance of sUA control in gout, and cestry (48). matory-related genes in gout patients. point out to some genetic bases for this It was observed that MEFV variations disease. Epigenetics in gout affect the severity of gout (32). The A growing body of evidence has impli- GG genotype of NLRP3 rs10754558 Gene-environment interactions cated epigenetic factors, in particular, and the CGA haplotype of rs4612666, Some recent studies have reported altered patterns of DNA methylation rs10754558, rs1539019 are all inde- gene-environment interactions in the and microRNA (miRNA), in the patho- pendent risk factors for gout. regulation of sUA levels or risk of gout. genesis of gout. Dong et al. (33) identified two novel Beydoun et al. (43) highlighted the im- Given the important roles of miRNAs urate transporter genes (HNF4G and portant contributions of sex-gene and as negative post-transcriptional gene SLC17A4) associated with gout. Other gene-diet interactions in determining regulators in inflammatory diseases, novel variants, candidates for gout sus- sUA. Dietary factors, such as legumes including gout, Zhou et al. (49) ana- ceptibility, are rs889472 in the C-MAF and alcohol intake, potentially interact lysed the expression profiles of miR- 2 Clinical and Experimental Rheumatology 2019 One year in review 2018: gout / L.