Background/Purpose:  Hyperuricaemia and secondary
gout are well-recognised complications of diuretic use.  Variants in ABCG2 and SLC2A9 have
been identified as the two major genetic risk factors for gout in genome wide
association studies. The aim of this study was to examine the clinical and
genetic characteristics of diuretic-associated gout. 

Methods:  Participants (n=1,365), all fulfilling
the 1977 ARA gout classification criteria, were recruited from primary and
secondary care.  All participants
attended a study visit, which included a detailed clinical assessment.  Use of diuretic therapy at the time of
recruitment was recorded, and was confirmed by electronic dispensing data.  The gout-associated ABCG2 rs2231142 and SLC2A9
rs11942223 SNPs were genotyped.  Clinical
and genetic features of diuretic-associated gout were analysed using a
case-control study design (diuretics vs. no diuretics).  Loop and thiazide diuretics were also
analysed separately (participants taking both loop and thiazide diuretics were
included in loop diuretic group).

Results:
 There were
939 participants on no diuretics and 426 participants on at least one diuretic
(281 in the loop diuretic group and 145 in the thiazide diuretic group).  In the diuretic group, there were more women,
later onset of disease, higher rates of cardiac disease, hypertension and type 2 diabetes, higher body mass index, higher serum urate and
lower eGFR, compared to those not on diuretics (Table).  Gout disease duration, frequency of gout
flares and presence of tophi were similar in the two groups (Table).  The ABCG2
rs2231142 minor (risk) allele was present
less frequently in the diuretic group (36.1%) than in those not on diuretics
(47.6%, p=2.9E-04).  ABCG2 rs2231142 minor
(risk) allele positivity was lower in those taking loop diuretics (37.1%) and
thiazide diuretics (34.3%).  In contrast,
there was no significant difference in positivity for the minor (protective)
allele for SLC2A9 rs11942223 between
the two groups (p=0.074).

Conclusion: Diuretic-associated gout represents a medically complex condition
with frequent comorbid conditions.  The observed
differences in the ABCG2 risk allele frequency
suggest that some genetic factors play a less dominant role in the etiology of
diuretic-associated gout, compared to primary gout. 

Table:
Clinical and genetic features separated by use of diuretics. Unless specified, data are presented as mean (SD). For genotype
analysis, p values were generated by logistic
regression adjusting for ancestral group.