Genetics and gout

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SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout
Nature Genetics Published online: 9 March 2008 (http://www.nature.com/ng/journal/vaop/ncurrent/abs/ng.106.html)
Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200–500 M) compared with other mammals (3–120 M)1. About 70% of daily urate disposal occurs via the kidneys, and in 5–25% of the human population, impaired renal excretion leads to hyperuricemia2. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7–5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter3, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.

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The BBC (http://news.bbc.co.uk/2/hi/health/7283861.stm) are reporting:
Gene 'linked to higher gout risk'
A reason why millions worldwide fall prey to the painful joint condition gout may have been uncovered. A rise in UK gout cases has been blamed on increasingly unhealthy lifestyles.

However, genetic analysis of more than 12,000 people, published in the journal Nature Genetics, has found that a gene variant may also raise the risk.

Researchers at the MRC Human Genetics Unit, in Edinburgh, said the gene, and the protein it controls, might one day be targeted by new gout drugs.

In a healthy body, uric acid, a waste product found in the blood, is removed by the kidneys and passes out of the body in urine.

However, in some people the kidney cannot get rid of it properly and it builds up in the blood, forming crystals in the joints, leading to inflammation, stiffness and pain.

Various food types have been blamed, with the consensus that diets rich in refined sugars, protein and alcohol increase the risk.

Many thousands of people have a diet which appears to increase the risk of gout, but far fewer actually develop the illness.

Now scientists at the MRC Human Genetics Unit may have worked out why that is.

The gene variation they found, in the SLC2A gene, appears to make it harder for the body to remove uric acid from the blood.

Professor Alan Wright, who led the research, said: "The gene is a key player in determining the efficiency of uric acid transport across the membranes of the kidney."

His colleague Harry Campbell said: "Some people will have higher or lower risk of gout depending on the form of the gene they inherited.

"This discovery may allow better diagnostic tools for gout to be developed."

At the moment, drug treatment for patients is limited.

Although gout is a disease more usually found in a historical textbook, it is estimated that one million people in the UK suffer from it in some form.

Professor Stuart Ralston, from the British Society for Rheumatology, said that he often came across patients whose lifestyles did not fit the traditional view of over-consumption.

"Until recently you would associate gout with boozing and rich food, but there are plenty of other patients who are quite abstemious. This might be a genetic marker for gout risk.

"What is exciting is that it could be a target for new gout drugs."

Dr Andrew Bamji, president of the British Society for Rheumatology, said that the research supported a recent study which suggested that too many sugary soft drinks could trigger gout.

He said: "It appears that this gene also plays a role in the control of levels of fructose sugar in the body, which would explain the finding that soft drinks were linked to attacks." Full story (http://news.bbc.co.uk/2/hi/health/7283861.stm)

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Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study
The Lancet Early Online Publication, 1 October 2008 (http://www.thelancet.com/journals/lancet/article/PIIS0140673608613434/abstract?isEOP=true)
Background
Hyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout.

Methods
Genome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p<5·0×10−8) or the Rotterdam cohort (p<1·0×10−7) were evaluated with gout. The results obtained in white participants were combined using meta-analysis.

Findings
Three loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7·0×10−168 and 2·9×10−18 for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2·5×10−60 and 9·8×10−4), and rs1165205 in SLC17A3 (p=3·3×10−26 and 0·33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0·59 per T allele, 95% CI 0·52–0·68, p=7·0×10−14), rs2231142 (1·74, 1·51–1·99, p=3·3×10−15), and rs1165205 (0·85, 0·77–0·94, p=0·002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1·71, 1·06–2·77, p=0·028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272–351 μmol/L in the Framingham cohort, 269–386 μmol/L in the Rotterdam cohort, and 303–426 μmol/L in white participants of the ARIC study) and gout (frequency 2–13% in the Framingham cohort, 2–8% in the Rotterdam cohort, and 1–18% in white participants in the ARIC study).

Interpretation
We identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout.

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ScienceDaily (http://www.sciencedaily.com/releases/2008/10/081006202625.htm#) are reporting:
Drug Target for Gout? Gene SLC2A9 Is High-capacity Urate Transporter In Humans
An international team of researchers led by Professors Mark Caulfield and Patricia Munroe, from the William Harvey Research Institute at Barts and The London School of Medicine and Dentistry with Chris Cheeseman at the University of Alberta in Canada and Kelle Moley at the University of Washington in USA, have shown that the SLC2A9 gene, which encodes a glucose transporter, is also a high-capacity urate transporter, and thus possibly a new drug target for gout.

Several urate transporters have already been identified but recently, using an approach called genome-wide association scanning, Caulfield and others found that some genetic variants of a human gene called SLC2A9 are more common in people with high serum urate levels than in people with normal levels. SLC2A9 encodes a glucose transporter (a protein that helps to move the sugar glucose through cell membranes) and is highly expressed in the kidney's main urate handling site. Professor Caulfield and his team investigated the possibility that the protein made by the SLC2A9 gene might be a urate transporter and tested whether genetic variations in SLC2A9 might be responsible for the association between serum urate levels and high blood pressure.

The team first expressed SLC2A9 in frog eggs, a type of cell that does not have its own urate transporter. They found that SLC2A9 transported urate about 50 times faster than glucose, and that glucose facilitated SLC2A9-mediated urate transport. Similarly, over expression of SLC2A9 in human embryonic kidney cells more than doubled their urate uptake. Conversely, when the researchers used a technique called RNA interference to reduce the expression of mouse SLC2A9 in mouse cells that normally makes this protein, urate transport was reduced.

Researchers then looked at two genetic variations within SLC2A9 that vary between individuals (so-called single polynucleotide polymorphisms) in nearly 900 men who had had their serum urate levels and urinary urate excretion rates measured. They found that certain genetic variations at these two sites were associated with increased serum urate levels and decreased urinary urate excretion. Finally, the researchers used a statistical technique called meta-analysis to look for an association between one of the SLC2A9 gene variants and blood pressure. In two separate meta-analyses that together involved more than 20,000 participants in several studies, there was no association between this gene variant and blood pressure.

Overall, these findings indicate that SLCA9 is a high capacity urate transporter, and suggest that this protein plays an important part in controlling serum urate levels. They provide confirmation that common genetic variants in SLC2A9 affect serum urate levels to a marked degree, although they do not show exactly which genetic variant is responsible for increasing serum urate levels. They also provide important new insights into how the kidneys normally handle urate and suggest ways in which this essential process may sometimes go wrong. The findings could eventually lead to new treatments for gout and possibly for other diseases that are associated with increased serum urate levels.

Professor Mark Caulfield said: "This MRC funded study shows how a team of international researchers can find a completely unsuspected mechanism for urate handling in the kidney. Such discoveries could pave the way for new medicines."Link to story (http://www.sciencedaily.com/releases/2008/10/081006202625.htm#)

SLC2A9 Is a High-Capacity Urate Transporter in Humans.
Caulfield et al.
PLoS Medicine, 2008; 5 (10): (http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pmed.0050197&ct=1)Background
Serum uric acid levels in humans are influenced by diet, cellular breakdown, and renal elimination, and correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Recent genome-wide association scans have found common genetic variants of SLC2A9 to be associated with increased serum urate level and gout. The SLC2A9 gene encodes a facilitative glucose transporter, and it has two splice variants that are highly expressed in the proximal nephron, a key site for urate handling in the kidney. We investigated whether SLC2A9 is a functional urate transporter that contributes to the longstanding association between urate and blood pressure in man.

Methods and Findings
We expressed both SLC2A9 splice variants in Xenopus laevis oocytes and found both isoforms mediate rapid urate fluxes at concentration ranges similar to physiological serum levels (200–500 μM). Because SLC2A9 is a known facilitative glucose transporter, we also tested whether glucose or fructose influenced urate transport. We found that urate is transported by SLC2A9 at rates 45- to 60-fold faster than glucose, and demonstrated that SLC2A9-mediated urate transport is facilitated by glucose and, to a lesser extent, fructose. In addition, transport is inhibited by the uricosuric benzbromarone in a dose-dependent manner (Ki = 27 μM). Furthermore, we found urate uptake was at least 2-fold greater in human embryonic kidney (HEK) cells overexpressing SLC2A9 splice variants than nontransfected kidney cells. To confirm that our findings were due to SLC2A9, and not another urate transporter, we showed that urate transport was diminished by SLC2A9-targeted siRNA in a second mammalian cell line. In a cohort of men we showed that genetic variants of SLC2A9 are associated with reduced urinary urate clearance, which fits with common variation at SLC2A9 leading to increased serum urate. We found no evidence of association with hypertension (odds ratio 0.98, 95% confidence interval [CI] 0.9 to 1.05, p > 0.33) by meta-analysis of an SLC2A9 variant in six case–control studies including 11,897 participants. In a separate meta-analysis of four population studies including 11,629 participants we found no association of SLC2A9 with systolic (effect size −0.12 mm Hg, 95% CI −0.68 to 0.43, p = 0.664) or diastolic blood pressure (effect size −0.03 mm Hg, 95% CI −0.39 to 0.31, p = 0.82).

Conclusions
This study provides evidence that SLC2A9 splice variants act as high-capacity urate transporters and is one of the first functional characterisations of findings from genome-wide association scans. We did not find an association of the SLC2A9 gene with blood pressure in this study. Our findings suggest potential pathogenic mechanisms that could offer a new drug target for gout.

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Common polymorphisms influencing serum uric Acid levels contribute to susceptibility to gout, but not to coronary artery disease.
Stark K, Reinhard W, Grassl M, Erdmann J, Schunkert H, Illig T, Hengstenberg C.
PLoS One. 2009 Nov 5;4(11):e7729.
(http://www.ncbi.nlm.nih.gov/pubmed/19890391?dopt=Abstract)BACKGROUND: Recently, a large meta-analysis including over 28,000 participants identified nine different loci with association to serum uric acid (UA) levels. Since elevated serum UA levels potentially cause gout and are a possible risk factor for coronary artery disease (CAD) and myocardial infarction (MI), we performed two large case-control association analyses with participants from the German MI Family Study. In the first study, we assessed the association of the qualitative trait gout and ten single nucleotide polymorphisms (SNP) markers that showed association to UA serum levels. In the second study, the same genetic polymorphisms were analyzed for association with CAD.

METHODS AND FINDINGS: A total of 683 patients suffering from gout and 1,563 healthy controls from the German MI Family Study were genotyped. Nine SNPs were identified from a recently performed genome-wide meta-analysis on serum UA levels (rs12129861, rs780094, rs734553, rs2231142, rs742132, rs1183201, rs12356193, rs17300741 and rs505802). Additionally, the marker rs6855911 was included which has been associated with gout in our cohort in a previous study. SNPs rs734553 and rs6855911, located in SLC2A9, and SNP rs2231142, known to be a missense polymorphism in ABCG2, were associated with gout (p = 5.6*10(-7), p = 1.1*10(-7), and p = 1.3*10(-3), respectively). Other SNPs in the genes PDZK1, GCKR, LRRC16A, SLC17A1-SLC17A3, SLC16A9, SLC22A11 and SLC22A12 failed the significance level. None of the ten markers were associated with risk to CAD in our study sample of 1,473 CAD cases and 1,241 CAD-free controls.

CONCLUSION: SNP markers in SLC2A9 and ABCG2 genes were found to be strongly associated with the phenotype gout. However, not all SNP markers influencing serum UA levels were also directly associated with the clinical manifestation of gout in our study sample. In addition, none of these SNPs showed association with the risk to CAD in the German MI Family Study.

[JohnAnderson]

I just don't see why so much research is focusing on limiting uric acid production. Uric acid is vital to neurological processes within the body. If your uric acid falls below 2.5ml/dL, your brain might not be able to send signals to your heart and chest cavity. This can cause fatalities.

I'm just curious as to why science is so involved in the process of uric acid production, but seems uninterested in the process of uric acid excretion. Several studies have told us the causes of uric acid production, but very few studies have told how to excrete more uric acid, other than the vitamin C study.

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The genetic basis of hyperuricaemia and gout.
Merriman TR, Dalbeth N.
Joint Bone Spine. 2010 May 14. [Epub ahead of print]
(http://www.ncbi.nlm.nih.gov/pubmed/20472486?dopt=Abstract)
Gout results from elevated urate concentrations in the blood (hyperuricaemia). When super-saturation of urate is reached, monosodium urate crystals form within the joint. In some individuals, these crystals elicit a painful self-limiting inflammatory response that is characteristic of acute gouty arthritis. The most important cause of hyperuricaemia is reduced excretion of uric acid in the urine. Uric acid excretion is coordinated by a suite of urate transport molecules expressed in the renal collecting tubules, and is a key physiological checkpoint in gout. Other checkpoints in gout are hepatic production of urate, monosodium urate crystal formation, and initiation of the acute inflammatory response. Genome-wide association scans for genes regulating serum urate concentrations have identified two major regulators of hyperuricaemia- 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 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 controlling serum urate concentrations; although genome-wide association studies in gout per se await recruitment of suitable case sample sets