Background/Purpose: Tophi contribute to musculoskeletal disability, joint damage and poor health-related quality of life in people with gout. The aim of this study was to examine the clinical and genetic features of tophaceous gout.

Methods: Participants (n=1778) fulfilling the 1977 ARA gout classification criteria, recruited from primary and secondary care, attended a study visit which included a detailed clinical assessment. The presence of palpable tophi was recorded.  SLC2A9 rs11942223 and ABCG2 rs2231142 (SNPs associated with gout) and ABCG2 rs10011796 (SNP associated with allopurinol response in a US study population) were genotyped (linkage disequilibrium between the two ABCG2 SNPs r²<0.11 for all ancestral groups).  Clinical and genetic features of tophaceous gout were analysed using a case-control study design (tophi vs. no tophi). Polynesian ancestry was separated into Western Polynesian (Tonga, Samoa, Niue, Tokelau) and Eastern Polynesian (Māori, Cook Island).

Results: Compared to participants without tophi, those with tophi were older, had an earlier age of gout onset, longer disease duration and higher serum creatinine, and were more likely to be of Māori or Pacific (Polynesian) ancestry.  Participants with tophi also reported more frequent gout flares and higher use of colchicine, prednisone, non-steroidal anti-inflammatory drugs and urate lowering therapy.  There was no difference in frequency of the minor (protective) allele for SLC2A9 rs11942223 between the two groups (p=0.14, Table).  In contrast, the risk alleles for both ABCG2 SNPs were present more frequently in those with tophi (odds ratio (OR) 1.24 for rs2231142 and 1.33 for rs10011796, p<0.05 for both). Analysis of ABCG2 risk allele frequencies according to ancestry demonstrated that the effect of rs2231142 was present only in participants of Māori or Pacific ancestry (OR 1.50, p=0.004), with the strongest effect in those of Western Polynesian ancestry (OR 1.71, p=0.017).  The rs10011796 risk allele was strongly associated with tophi in the Western Polynesian group (OR 3.76, p=0.002), but not in the Eastern Polynesian group (OR 0.87, p=0.60).  The ABCG2 associations persisted in the Western Polynesian group after adjusting for age, sex, highest recorded serum urate, serum creatinine, age of gout onset, disease duration, and when including both ABCG2 variants in regression models.  

Conclusion: Tophaceous gout is associated with prolonged disease duration and severe manifestations of disease.  These data suggest that variation in ABCG2 function plays a role in development of tophaceous disease in some populations with high prevalence of severe gout.