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Current Rheumatology Reviews, 2011, 7, 114-122
Genetic and Environmental Risk Factors in Hyperuricaemia and Common Gout Tony R. Merriman*,1 and Nicola Dalbeth2 1
Department of Biochemistry, 710 Cumberland Street, University of Otago, P.O. Box 56, Dunedin, New Zealand
2
Department of Medicine, Park Road, University of Auckland, Private Bag 92019, Auckland, New Zealand Abstract: Gout results from hyperuricaemia. The most important cause of hyperuricaemia is reduced excretion of uric acid in the urine. Genome-wide association scans for genes regulating serum urate concentrations have identified two major regulators – the renal urate transporters SLC2A9 and ABCG2. The risk variants at each gene approximately double the risk for gout in people of Caucasian ancestry, with the urate and fructose transporter SLC2A9 also resulting in higher risk for gout in people of Polynesian ancestry, a diverse population characterized by a high prevalence of gout. Ongoing genetic association studies are identifying and confirming other genes (URAT1, OAT4, NPT1, PDZK1, GCKR) controlling serum urate concentrations; although genome-wide association studies in gout per se await recruitment of suitable case sample sets. The recent increase in gout incidence can only be explained by a change in the environment. One factor that fulfills most of the requirements for confirmation of an etiological role in gout is fructose. Fructose raises serum urate levels, which is exacerbated in people with genetic variants that reduce renal urate excretion, thus increasing the risk of gout. Use of GWAS approaches and application of new genomics technologies such as next-generation sequencing to very large well-phenotyped gout sample sets will enable identification of further genetic risk factors in gout. Intervention studies in cohorts characterized for genetic risk factors are needed to prove a direct link for environmental agents such as fructose in gout etiology.
Keywords: Gout, gene, urate transporter, association, genome, SLC2A9. INTRODUCTION Gout is the most common form of inflammatory arthritis primarily affecting men, occurring in 1-2% of Caucasian men in Westernized countries and up to 15% of men of Polynesian descent [1]. There is a gender bias in gout in all populations with 4-5 times more men affected than premenopausal women. The central biochemical cause of gout is excess urate. In most mammals urate is degraded by uricase to allantoin, which is highly soluble and readily excreted in the urine. During the Miocene period two parallel mutations occurred in early hominids that disabled the uricase gene, resulting in higher serum urate concentrations (hyperuricaemia) [2]. The parallel mutations suggest that inactivating the uricase gene was selectively advantageous to early hominids, possibly due to one, or a combination, of: the anti-oxidant activity of uric acid compensating for vitamin C deficiency; the ability of uric acid to maintain blood pressure under low-salt dietary conditions; the adjuvant activity of uric acid [3]. Hyperuricaemia is the key predictor for the development of gout. Elevated urate above super-saturation concentrations [6.8mg/dL at physiological pH and temperature] leads to the formation of monosodium urate (MSU) crystals within joints and subcutaneous tissues with the development of very painful attacks of gouty arthritis (characterized by recurrent episodes of self-limiting acute inflammatory attacks of monoarthritis), and formation of tophi (chalky deposits of sodium urate) and bony erosion if the gouty attacks are not resolved [4]. However, gout
*Address correspondence to this author at the Department of Biochemistry, University of Otago, P.O. Box 56, Dunedin, New Zealand; Tel: +64 3 479 5798; Fax: +64 3 479 7866; E-mail:
[email protected] 1573-3971/11 $58.00+.00
occurs only in a fraction (98% of Māori and Pacific Island patients homozygous for the risk allele compared with 79% of NZ Caucasian patients [28]. In contrast, however, the Caucasian
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Merriman and Dalbeth
Fig. (2). Uric acid transport in renal proximal tubule cells. Identified molecules include the fructose transporter SLC2A9 (GLUT9) [11], urate transporter 1 (URAT1; [12]), organic anion transporters 1,3,4 (OAT1, OAT3, OAT4), multi-drug resistance protein 4 (MRP4), sodiumcoupled monocarboxyl transporters SMCT1,2, and human ATP-binding cassette, subfamily G, 2 (ABCG2) [13]. Variants of SLC2A9 exchange uric acid with fructose and glucose from the proximal tubule lumen across the apical and basolateral membranes, leading to net reabsorption of uric acid [14]. SLC2A9 is inhibited by the uricosuric agent benzbromarone, but not by the commonly used uricosuric probenecid [11]. URAT1 is substrate specific (compared to the multispecific OAT1 and OAT3) and is also inhibited by uricosuric drugs such as benzbromarone and probenecid [12]. OAT4 is a low-affinity assymetric urate transporter that facilitates diuretic-associated hyperuricaemia, also inhibited by benzbromarone and probenecid [15]. MRP4 is an ATP-dependent efflux pump for urate. ABCG2 is a secretory urate transporter in the proximal tubule [13], currently there are no published data on effects of uricosuric drugs on ABCG2 activity. PDZK1 is a scaffolding protein likely involved in assembly of a transporter complex in the apical membrane [16].
risk variant does not alter risk in people from the Melanesian Solomon Islands or Chinese, because these populations are monomorphic for the risk allele (that is, the risk allele has a frequency of 100%) [29]. However, there is an independent non-synonymous variant in SLC2A9 (Arg265His; rs3733591) that confers about a 2-fold increased risk for gout in Solomon Island and Chinese people [29] –this variant does not have an appreciable effect on serum urate
levels in Caucasian [23]. Clearly, there is allelic heterogeneity between different populations in the case of SLC2A9 and genetic variants that influence the risk of gout (Table 1). The precise functional variant(s) within SLC2A9 controlling serum urate levels and influencing risk of gout have not been identified, but the variant with the strongest effect (rs11942223 or one in linkage disequilibrium) is likely to influence the relative expression levels of two SLC2A9
Genetic and Environmental Risk Factors in Hyperuricaemia and Common Gout
Table 1.
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Summary of Replicated Genetic Associations with Gout and Sub-Phenotypes
Gene1
SLC2A9/GLUT9 Rs11942223 and associated variants
SLC2A9 R265H (rs3733591)
Phenotype
Effect Size [odds ratio] 2
Population
Serum urate
Not applicable
Caucasian
Hyperuricaemia
1.7-1.9
Caucasian
Gout
1.3-5.0
Caucasian, NZ Māori and Pacific Island, NOT Solomon Island, Chinese
Gout
2
Serum urate
Not applicable
Caucasian
1.7-2.0
Caucasian, AfricanAmerican
Molecular Mechanism
Refs. [14,23-26]
An influence on the relative levels of two SLC2A9 isoforms, one expressed on the basolateral and the other on the apical membrane of the renal collecting tubule.
[14] [14,23,2629]
Solomon Island
ABCG2 Gout
Unknown
Chinese, NOT Caucasian
[29] [26]
The 141Lys risk variant results in an ABCG2 molecule with 53% less uric acid secretory activity
[13,26,31]
Western Polynesian Reduced renal uric acid excretion
1.4
Caucasian
[Reviewed in 9]
Serum urate
Not applicable
Caucasian, Japanese
[Reviewed in 9]
Hyperuricaemia
1.4
Chinese
Reviewed in 9
Gout
1.2-1.8
Mexican-American, Solomon Island, Chinese
[38-40]
Serum urate
Not applicable
Caucasian
SLC22A12/URAT1
A possible influence on isoform levels
SLC17A1/NPT1
β-3-adrenergic receptor [ADRB3]
Methylene tetrahydrofolate reductase [MTHFR]
[26] Unknown
Caucasian
Gout
1.2-1.9
[26,37]
Serum urate
Not applicable
Chinese
Hyperuricaemia
1.1-2.4
Korean, Italian, Japanese
Hyperuricaemia
1.5-1.7
Korean, Iranian, Japanese
Japanese The 64Arg variant is associated with higher serum urate levels in 3 of 4 studies. This may induce insulin resistance as a result of lower lipolysis and increased adipose tissue. The 677T allele is associated with hyperuricaemia in 3 studies. It is possible that this variant allows greater availability of 5,10-methyltetrahydrofolate for de novo synthesis of purines.
[Reviewed in 9] [Reviewed in 9] [Reviewed in 9]
1
Restricted to common variants [polymorphisms] of genes; 2For single copy of risk variant.
isoforms that differ by the length of their cytoplasmic domains [14,23]. The long form is expressed on the basolateral membrane of renal collecting tubule epithelial cells, whilst the short form is expressed on the apical membrane [30]. It is of interest that SLC2A9 is also a fructose and glucose transporter that is widely expressed, including in the renal tubule, liver and articular cartilage. SLC2A9–mediated urate transport is facilitated by both glucose and fructose, providing a mechanism whereby fructose may increase uric acid re-uptake [11]. A non-synonymous single nucleotide polymorphism (rs2231142; Q141K) is the likely etiological variant explaining the association of the ABCG2 gene with gout [13,26]. The 141K allele confers a similar risk to gout as SLC2A9, approximately doubling risk in Caucasian, Western Polynesian (Samoan, Tongan, Niuean) and Chinese people, but with a considerably weaker (as yet unconfirmed) effect in Eastern Polynesian (New Zealand and Cook Island Māori) people (Table 1) [26,31,32]. Thus, like SLC2A9, there
appears to be allelic heterogeneity between populations. The 141K variant encodes an ABCG2 protein with 53% less urate transport activity, leading to a reduction in renal urate excretion. ABCG2 is also known as breast cancer resistance protein, functioning as an efflux pump with an influence on the pharmacokinetic profile of a variety of drugs. Consequently, there has been considerable work undertaken studying the biochemistry and modulation of ABCG2. For example, ABCG2 mRNA levels are up-regulated by statins in HepG2 cells [33]. This is promising in the context of improved therapies for gout. Meta-analysis of a number of GWAS, which included a total of 28,141 Caucasian individuals has revealed 7 further genes associated, at a genome-wide level of significance (P < 5x10-8) with genetic control of serum urate concentrations [34]; renal urate transporters (SLC22A12/URAT1, SLC22A11/OAT4, SLC17A1/NPT1); a monocarboxylic acid transporter (SLC16A9/MCT9) that may be a renal sodiumdependent transporter that influences renal uric acid
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excretion; PDZK1 that encodes a scaffolding protein called PDZ domain-containing 1 known to interact with OAT4, URAT1 and NPT1 (Fig. 2) [35]; the LRRC16A locus; and the gene encoding glucokinase regulatory protein (GCKR). A follow-up study in a population-based cohort replicated association of PDZK1, GCKR, SLC16A9 and OAT4 with serum urate levels [36]. Both URAT1 and NPT1 have previously been genetically implicated in gout [37-40]. Of the other loci OAT4 and PDZK1 are very strong candidates for gout risk factors. In the context of metabolic diseases in Caucasian populations, gout is unusual in that it has been associated with two genetic variants (within SLC2A9 and ABCG2) that have a relatively strong effect (Table 1; OR>2). In comparison, the genetic variant having the strongest effect in type 2 diabetes resides within TCF7L2 with an OR=1.4, and there has been > 20 other weak effects identified (OR
