- Gout Risk Factor Less about Diet, More about Genes
- Genetics, Not Diet, Is the ly Cause of Gout
- Did We Get Gout All Wrong? New Research Debunks Beliefs
- Gouty Arthritis Is Not a Result of Dietary Habits, Research Suggests
- Gout Is a Painful Form of Inflammatory Arthritis
- New Study Helps Removes Gout Stigma, an Obstacle to Treatment
- Genetic Factors Influence Gout Disease Development
- Diet Affected Gout Disease in Study Participants Only Minimally
- Prevention of Gout
- A Balanced Diet Is Still Important for Overall Health
- The Role of Trigger Foods in Gout Flare-Ups Is Not Understood
- Genetics of serum urate concentrations and gout in a high-risk population, patients with chronic kidney disease
- Gout Caused by Genetics More Than Diet
- Genetics Drive Gout Risk Far More Than Diet
- Common variants in the SLC28A2 gene are associated with serum uric acid level and hyperuricemia and gout in Han Chinese
- Genes that May Affect Uric Acid Levels
- SLC2A9 Gene – The Absorptive Urate Transporter
- ABCG2 Gene – The Multi-functional Transporter that Exports Urate
- SLC22A12 Gene – The Urate Transporter That Determines the Amount of Urate Present in the Blood
- SLC22A11 Gene – The Organic Anion Transporter That Reabsorbs Uric Acid
- SLC17A1 Gene – The Renal Urate Exporter
- SLC17A3 Gene – Transporter That Transports Intracellular Urate the Cell
- UMOD Gene: The Protein That Helps Control The Amount of Water in Urine
- HPRT1 Gene – The Enzyme That Recycles Purines
- PRPS1 Gene – The Enzyme That Helps Make Purines
Gout Risk Factor Less about Diet, More about Genes
Despite accumulating evidence that gout isn’t all about diet, the condition retains its reputation as the “rich man’s disease”—or the disease that afflicts those who eat richly, regardless of their fortunes. Back in 2008, a study appeared suggesting that about 12% of gout cases could be attributed to dietary causes.
A little later, additional studies identified genes that were associated with gout or gout’s chief risk factor, hyperuricemia, or elevated uric acid levels.
And now, a new study that has revisited the causes of hyperuricemia has concluded that in contrast with genetic contributions, diet explains very little of the variation in uric acid levels.
In the new study, scientists based in New Zealand found that diet scores explained less than 0.3% of variance in serum urate. In contrast, they determined that common, genome-wide single nucleotide variation explained 23.9% of the variance.
Additional details appeared recently in BMJ, in an article titled, “Evaluation of the diet wide contribution to serum urate levels: meta-analysis of population-based cohorts.
” The article described how the scientists analyzed dietary survey data for 8,414 men and 8,346 women of European ancestry from five U.S. cohort studies.
Participants were aged over 18 without kidney disease or gout, and were not taking urate-lowering or diuretic drugs.
Blood urate measurements and genetic profiles were recorded. Factors that could have affected the results, such as sex, age, body mass index, daily calorie intake, education, exercise levels, and smoking status, were also considered.
Elevated serum urate levels were associated with seven foods: beer, liquor, wine, potato, poultry, soft drinks, and meat (beef, pork, or lamb). Reduced serum urate levels were associated with eight foods: eggs, peanuts, cold cereal, skim milk, cheese, brown bread, margarine, and noncitrus fruits. Each of these foods, however, explained less than 1% of the variation in urate levels.
Similarly, three diet scores, healthy diet guidelines, were also associated with lowered urate levels, while a fourth, a diet high in unhealthy foods, was associated with increased urate levels.
Again, however, each of these diet scores explained very little (less than 0.3%) variance in urate levels.
In contrast, genetic analysis revealed that common genetic factors explained almost a quarter of the variation in urate levels.
“Our data are important in showing the relative contributions of overall diet and inherited genetic factors to the population variance of serum urate levels,” the authors of the BMJ research article indicated.
“Our results challenge widely held community perceptions that hyperuricaemia is primarily caused by diet, showing that genetic variants have a much greater contribution to hyperuricaemia in the general population than dietary exposure.”
In an accompanying editorial (“The role of diet in serum urate concentration“), researchers at Keel University pointed out that people with gten experience stigma from the misconception that it is a self-inflicted condition caused by unhealthy lifestyle habits and, as a result, are often reluctant to seek medical help.
This study, the Keel scientists wrote, “provides important evidence that much of patients' preponderance to hyperuricaemia and gout is nonmodifiable, countering these harmful but well-established views and practices and providing an opportunity to address these serious barriers to reducing the burden of this common and easily treatable condition.”
Genetics, Not Diet, Is the ly Cause of Gout
What’s the first thing that comes to mind when you hear the word gout? When most people think of gout, they picture a stout old Englishman, sitting by a fire with his foot up after yet another round of gluttony and excess. This “disease of kings” stereotype and stigma have led too many people to avoid seeking meaningful help.
Did We Get Gout All Wrong? New Research Debunks Beliefs
Research published in August 2015 in Clinical Rheumatology showed that people prefer to treat gout symptoms as they occur rather than plan a lifetime prevention approach.
Bad idea: If gout isn’t treated, each attack will last longer, you will have more attacks, and you may eventually suffer irreversible joint damage. You will also be at higher risk for kidney disease or kidney stones.
A study published in the BMJ published on October 10, 2018 posits that genetics (family history) may play a more important role in the disease development than diet.
RELATED: Sleep Apnea Increases the Risk for Gout, Study Suggests
Gouty Arthritis Is Not a Result of Dietary Habits, Research Suggests
“The study from New Zealand is an important step to try to correct these societal misconceptions that gout is caused by dietary habits.
People with gout should be reassured that high urate levels are influenced more by genes than by diet, countering the widespread misconception that gout is a self-inflicted disease,” comments Edward Roddy, MD, a coauthor of the Clinical Rheumatology study, a reader in rheumatology and an honorary consultant rheumatologist at the Research Institute for Primary Care and Health Sciences at Keele University, in Staffordshire, England.
Gout Is a Painful Form of Inflammatory Arthritis
First, some background: Gout is a form of arthritis involving hot, swollen, stiff joints caused by the buildup of uric acid, which forms painful needle- urate crystals. It will often appear in the big toe but can also affect ankles, heels, knees, wrists, fingers, and elbows. It is more prevalent in men older than 40, according to MedlinePlus.
New Study Helps Removes Gout Stigma, an Obstacle to Treatment
Up until now, it’s been believed that diet was the main driver of the disease. Many people don’t go for gout treatment because they believe that they don’t fit the stereotype or they are too ashamed to seek it.
“Diet is a well-established trigger of gout attacks in people who already have urate crystals in their joints. Because individual foods associate with small changes in urate levels, this has led to an incorrect belief that levels of urate can be managed by diet,” says one of the study's authors, Tony R.
Merriman, PhD, a professor in the department of biochemistry at the University of Otago, Dunedin, New Zealand.
RELATED: Rheumatoid Arthritis and Gout: What’s the Difference?
Genetic Factors Influence Gout Disease Development
This study shows that genetics play a bigger role in disease development than diet.
The researchers from University of Otago, Dunedin, New Zealand, compared dietary information from 8,414 men and 8,346 women older than 18 and of European ancestry from five U.S. cohort studies.
Participants did not have gout, and were not taking urate-lowering or diuretic drugs. In these studies, researchers looked at genetic profiles and urate levels.
Diet Affected Gout Disease in Study Participants Only Minimally
The team found that certain foods did minimally affect urate levels:
- Foods that raise urate levels: beer, liquor, wine, potatoes, poultry, soft drinks, and meat
- Foods that reduce urate levels: eggs, peanuts, cold cereal, skimmed milk, cheese, brown bread, margarine, and non-citrus fruits.
But the increases and decreases were very small — less than 1 percent variation. Genetic history, on the other hand, was responsible for nearly 24 percent of variations in urate levels.
“When we compared the dietary scores to the overall genetics of people, the effect was very different,” Dr. Merriman explains. “Diet was not an effective way of keeping urate levels down. The effect of genetics was much greater,” he adds. “Genetics explained in the general population a nearly 100-fold increased variance in urate levels than did diet.”
Prevention of Gout
In order to maintain low urate levels to prevent attacks and disease progression, your healthcare provider may prescribe the following medications:
“Taking urate-lowering drugs has been shown to be very effective because this treats the underlying cause of gout rather than focusing on preventing a symptom,” says another of the study's coauthors, Tanya Major, PhD.
A Balanced Diet Is Still Important for Overall Health
Sorry, this is not a hall pass to the all-you-can-eat buffet! While diet may have very little influence on the underlying cause of gout (you have to have high urate to get gout), you still should aim to eat a healthy diet.
RELATED: Treat-to-Target Therapy Improves Gout Outcomes
The Role of Trigger Foods in Gout Flare-Ups Is Not Understood
“Gout has been linked to diet for centuries because flares often occur after eating particular foods. It varies a lot between individuals which foods will cause a flare, and it can be inconsistent in an individual as well. We don’t really know how these foods relate to flares,” says Dr. Major.
Genetics of serum urate concentrations and gout in a high-risk population, patients with chronic kidney disease
- Chronic kidney disease
- Metabolic disorders
We evaluated genetics of hyperuricemia and gout, their interaction with kidney function and medication intake in chronic kidney disease (CKD) patients.
Genome-wide association studies (GWAS) of urate and gout were performed in 4941 CKD patients in the German Chronic Kidney Disease (GCKD) study. Effect estimates of 26 known urate-associated population-based single nucleotide polymorphisms (SNPs) were examined.
Interactions of urate-associated variants with urate-altering medications and clinical characteristics of gout were evaluated. Genome-wide significant associations with serum urate and gout were identified for known loci at SLC2A9 and ABCG2, but not for novel loci.
Effects of the 26 known SNPs were of similar magnitude in CKD patients compared to population-based individuals, except for SNPs at ABCG2 that showed greater effects in CKD. Gene-medication interactions were not significant when accounting for multiple testing. Associations with gout in specific joints were significant for SLC2A9 rs12498742 in wrists and midfoot joints.
Known genetic variants in SLC2A9 and ABCG2 were associated with urate and gout in a CKD cohort, with effect sizes for ABCG2 significantly greater in CKD compared to the general population. CKD patients are at high risk of gout due to reduced kidney function, diuretics intake and genetic predisposition, making treatment to target challenging.
Gout is a progressive painful debilitating disease, and the most common inflammatory arthritis in many Western countries1.
Population-based studies have identified genetic variants in multiple genes2 including SLC2A93,4,5 and ABCG25,6 associated with serum urate concentrations.
Individuals with chronic kidney disease (CKD) represent a high-risk population for hyperuricemia and gout due to decreased renal clearance of urate and consecutive increase in serum urate concentrations.
About ~25% of CKD patients from the prospective German Chronic Kidney Disease (GCKD) study reported a physician diagnosis of gout at study baseline and two thirds of patients were hyperuricemic7. This high prevalence of gout is most relevant given that CKD affects about 10% of the adult population in many countries8.
Despite the importance of CKD as a risk factor for gout, knowledge about genetic determinants of serum urate in the setting of CKD is limited.
One candidate gene study that focused on 11 urate transporters reported that the strength of association – as quantified by the association p-value – between genetic variants in ABCG2 was stronger in patients with CKD compared to 481 population-based individuals, while the opposite was observed for variants in SLC2A99. While the authors hypothesized that this could be interpreted by a compensatory role of the ABCG2 transporter in the intestine in the setting of reduced kidney function, they did not formally compare effect sizes or test for differences in effect. Additional aspects of urate genetics in CKD that have not been addressed are interactions between genetic risk variants for gout and medication intake as well as clinical characteristics of gout attacks.
We aimed to evaluate the genetic underpinnings of hyperuricemia and gout in a large cohort of CKD patients, by carrying out genome-wide association studies (GWAS) of serum urate concentrations and gout.
Effect sizes of known urate-associated variants detected in the general population were formally compared to their counterparts among CKD patients.
Interactions between medications influencing serum urate concentrations and commonly prescribed in CKD were evaluated, and associations between genetic risk variants and clinical characteristics of gout were examined.
Baseline clinical characteristics of 4,941 GCKD study participants with complete clinical information required for the GWAS are summarized in Table 1. A quarter of the patients reported diagnosis of gout at study baseline. Participants with gout compared to those without gout were significantly (p-value
Gout Caused by Genetics More Than Diet
One of the most common misconceptions about gout, according to an article by the Arthritis Foundation, is that diet is the primary cause.
Gout, or gouty arthritis, is a painful condition caused by a high level of uric acid in the blood that can lead to deposits of uric acid crystals in the joints and tissues.
Most often gout affects the big toe joint, but it can also occur in the hands, feet, wrists, ankles, knees, and elbows.
Uric acid is formed in the body naturally when compounds called purines are broken down.
Most uric acid (about two-thirds) is produced when our cells age and die, but about a third of uric acid in our bodies is produced by the breakdown of purines that are found in many foods and drinks.
Among the most purine-rich foods and drinks are red meat, shellfish, alcoholic beverages (especially beer), and sugary drinks. People with gout typically try to avoid foods and drinks these to try to lower the amount of uric acid in their bodies.
Various factors can contribute to elevated blood uric acid levels and the development of gout (e.g., joint damage, infection, medications, etc.
) The goals of a recent study published in The BMJ was to test various foods for links to uric levels and to determine within a general population the extent to which diet contributes to uric acid levels compared to inherited genetic variations.
Findings from the study suggest that, at least in a population without gout, genetics play a much larger role than diet in promoting high uric acid levels in the blood.
Importantly, the recognition of a significant genetic component to this condition may help reduce the stigmatization and embarrassment that some people have due to a condition that many see as self-inflicted and the result of unhealthy lifestyle habits. The hope is that this new information may help empower those people with gout who have been reluctant to seek help.
According to an accompanying editorial, the new research “provides important evidence that much of patients' preponderance to [high uric acid levels] and gout is [genetic and] non-modifiable, countering these harmful but well-established views and practices.”
The researchers collected and analyzed data from 8,414 men and 8,346 women of European ancestry from five ongoing population-based cardiovascular and nutrition studies in the United States.
Participants were excluded from this study if they had kidney disease or gout, or if they were taking uric acid-lowering drugs or diuretic drugs (water pills).
The participants filled out dietary surveys, had their blood uric acid levels measured, and underwent genetic testing.
By comparing the participants' survey answers with blood uric acid levels, the researchers found seven foods associated with raised uric acid levels (beer, liquor, wine, potato, poultry, soft drinks, and meat) and eight foods associated with lowered uric acid levels (eggs, peanuts, cold cereals, skim milk, cheese, brown bread, margarine, and non-citrus fruit). Even so, when they calculated how big an influence each of these foods had on uric acid levels, they found that individually, the food items explained less than 1% of variation in uric acid levels in all participants.
The researchers then used four diet scores to see if general diet patterns affected variations in uric acid levels. Overall, the diet scores explained less than 0.3% of the variation in urate levels in the study participants.
Next, the researchers looked at 30 gene variations previously linked to blood uric acid levels in Europeans (since the study participants were all of European descent). They discovered that these common inherited genetic variants in the participants' DNA could account for about 23.9% of the variation in uric acid levels.
For instance, variants in the SLC2A9 gene, a gene linked to the transport of uric acid in the kidneys, were the most strongly associated in varying uric acid levels, explaining about 4% of the variation in uric acid levels.
The researchers concluded that for their study participants, overall diet explained “much less variance in [uric acid] levels when compared with inherited genetic variants.”
The researchers acknowledged that the study had limitations. The data are specific to the European population without gout that they enrolled in their study. It is not clear whether their conclusions also apply to individuals with gout, since they were not studied.
This study was not designed to predict risk of developing gout or change treatment, and additional studies would be needed to determine whether individuals with these variants are more ly to develop gout. However, this work may impact people with gout and their healthcare providers by challenging “widely held community perceptions” that high uric acid levels are primarily caused by diet.
Genetics Drive Gout Risk Far More Than Diet
The assumption that gout is mainly caused by diet is wrong, according to a meta-analysis of diet and genetic variants in over 16,000 subjects. The analysis, which was published online today in BMJ, suggests that even the most “gout associated” foods and diets accounted for less than 1% of variance in serum urate levels, while nearly 24% of variance was explained by genetic factors.
“Our results challenge widely held community perceptions that hyperuricaemia is primarily caused by diet, showing that genetic variants have a much greater contribution to hyperuricaemia in the general population than dietary exposure,” write Tanya J. Major, PhD, and colleagues from University of Otago, New Zealand, and colleagues.
“People with gten experience stigma from the societal misconception that gout is a condition caused by dietary habits and an unhealthy lifestyle, a view which is also pervasive among healthcare professionals and in portrayals of gout in lay media,” write Lorraine Watson, PhD, and Edward Roddy, MD, from Keele University, UK, in an accompanying editorial.
“As a result, patients known to have gout are often reluctant to seek help for fear that they will not be taken seriously or will be blamed for their lifestyle habits….
The study by Major and colleagues provides important evidence that much of patients' predisposition to hyperuricaemia and gout is non-modifiable, countering these harmful but well established views and practices and providing an opportunity to address these serious barriers to reducing the burden of this common and easily treatable condition.”
Major and colleagues performed a meta-analysis of cross-sectional food frequency data from five US cohort studies. They systematically analyzed individual foods for associations with serum urate levels and compared the variances associated with dietary factors to those associated with common, genome-wide single-nucleotide variants.
The researchers also note that heritable differences include not only those directly associated with serum urate levels but also to differences in food preferences that might contribute to gout risk, such as consumption of coffee, alcohol, or sugar sweetened beverages.
The meta-analysis included 16,760 individuals of European ancestry (8414 men and 8346 women) from the US, all older than 18 years, without kidney disease or gout, and not taking urate lowering or diuretic drugs. The main outcome measures were average serum urate levels and variance in serum urate levels.
Mutivariable analyses included serum urate, dietary survey data, potential confounders (sex, age, body mass index, average daily calorie intake, years of education, exercise levels, smoking status, and menopausal status), and genome-wide genotypes.
To assess genetic risk, the team used 30 gene variants that have been previously associated with serum urate.
In the diet analysis, the researchers identified seven foods associated with raised serum urate levels, including beer, liquor, wine, potato, poultry, soft drinks, and meat (beef, pork, or lamb).
“The food items with the strongest urate raising effect (beer and liquor) were associated with a 1.38 μmol/L increase in serum urate per serving per week, equating to a 9.66 μmol/L (0.16 mg/dL) increase per daily serving.”
They also identified eight foods associated with reduced serum urate levels, including eggs, peanuts, cold cereal, skim milk, cheese, brown bread, margarine, and non-citrus fruits.
Diet scores were constructed on the basis of four different healthy diet guidelines; three were associated with lower serum urate levels, and one was associated with raised serum urate levels, but none of these scores explained more than ≤0.3% of the variance in serum urate.
Individually, the 14 food items associated with serum urate variance explained 0.06% to 0.99% of the variation; summed, they explained 3.28% of the variation, and the diet scores explained less of the variation than the most strongly associated individual food item.
“In comparison, 23.9% of variance in serum urate levels was explained by common, genome wide single nucleotide variation,” the authors write. This included 23.8% in the male cohort and 40.3% in the female cohort.
Watson and Roddy comment, “Despite the authors' caution against extrapolating their findings [to non-European subjects or to those with evident gout], it is unly that the cause of hyperuricaemia in the studied populations is substantially different to those with clinically evident gout. The study does not provide evidence to support a change in guideline recommendations that patients with gout should modify their diet to avoid consuming certain high risk foods excessively; it does have other broad implications for people with gout and those who care for them.”
Specifically, Watson and Roddy explain that gout is often poorly managed, that two thirds of patients are not prescribed urate-lowering drugs, and that only a minority of patients increase the dose to the level required to achieve the low serum urate level needed to rid the body of urate crystals, prevent flares, and shrink tophi.
They conclude, “The reasons for poor management of gout are not fully understood, but patients' and practitioners' suboptimal understanding of gout, its causes, and treatment are considered to be important factors.”
The study was supported by the Health Research Council of New Zealand and the University of Otag.
Co author Nicola Dalbeth, MD, has received consulting fees, speaker fees, or grants from the following companies that have developed or marketed urate-lowering drugs for management of gout: Takeda, Ardea Biosciences/AstraZeneca, Cymabay/Kowa, and Crealta/Horizon. Tony R. Merriman, PHD, has received grants from Ardea Biosciences/AstraZeneca and Ironwood Pharmaceutical.
BMJ. Published online October 10, 2018. Full text, Editorial
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Cite this: Genetics Drive Gout Risk Far More Than Diet – Medscape – Oct 10, 2018.
Common variants in the SLC28A2 gene are associated with serum uric acid level and hyperuricemia and gout in Han Chinese
Serum uric acid (SUA), hyperuricemia (HUA) and gout are complex traits with relatively high heritability. This study aims to identify whether a candidate gene, SLC28A2, exerts susceptibility for SUA fluctuation and incidence of HUA and gout in the Han Chinese population.
Three sample sets of 1376 gout patients, 1290 long-term HUA subjects (no gout attack) and 1349 normouricemic controls were recruited for this study. Eight polymorphisms in the SLC28A2 gene were genotyped using the ligase detection reaction-polymerase chain reaction (LDR-PCR) technology.
Rs16941238 showed the most significant associations with SUA level (minor allele “A”, BETA = − 13.84 μmol/L, P = 0.0041, Pperm = 0.0042) and HUA (OR = 0.7734, P = 0.0033, Pperm = 0.0020), but not with gout (OR = 0.8801, P = 0.1315, Pperm = 0.1491).
Rs2271437 was significantly associated with gout (minor allele “G”, OR = 1.387, P = 0.0277, Pperm = 0.0288), and was further confirmed in the meta-analysis with the previously published gout GWAS dataset (OR = 1.3221, P = 0.0089).
Each variant basically conferred consistent OR direction on gout and HUA, compared with the normouricemic control.
Our findings support the associations of the SLC28A2 gene with the SUA level, the HUA phenotype and gout in Han Chinese.
Gout is a metabolic disorder and manifests by a broad spectrum of clinical features including severe and episodic arthritis attack, chronic polyarthritis, palpable tophi and related kidney injuries, which are induced by elevated serum uric acid (SUA) concentrations and consequent deposition of supersaturated urate crystals.
Uric acid (UA), the final metabolite of either dietary or endogenous purines, is much higher in humans than in other mammals due to the urate oxidase inactivity resulting from mutational silence during hominoid evolution  as well as the effective reabsorption mechanisms mediated by urate transporters expressed in kidney .
Thus, humans are more susceptible to exceed the reference range of SUA concentrations and suffer from HUA, defined as SUA > 420 μmol/L in men and postmenopausal women or SUA > 360 μmol/L in premenopausal women . High SUA is the most causative factor of gout and the higher the SUA, the higher the gout incidence .
Besides, both HUA and gout always cluster with a variety of comorbidities including obesity, insulin resistance, type 2 diabetes, hypertension and other cardiovascular diseases [4, 5]. Due to the ever aging population worldwide, the changing of dietary structure and increased incidence of comorbidities etc.
, the prevalence of HUA and gout have been climbing dramatically and become major public healthcare issues .
SUA and HUA are complex traits and disorders with individual heritability reaching up to 70%  and 60% , respectively. Gout shows evident aggregation within families and reported a heritability of 35.1% in men and 17.0% in women, indicating the importance of genetics as well .
Thus, detecting genetic determinants associated with SUA, HUA and gout is a key step in exploring the pathogenesis and potential therapeutic targets of the related disorders. Extensive genetic studies, especially large-scale genome-wide association studies (GWAS), have identified dozens of susceptibility genes .
Despite, all these genetic determinants can only explain 0.0063, seen in Table 2). Allelic frequencies and association results are displayed in Table 2. In the gout versus control cohort: only rs2271437 showed significant association (minor allele “G”, OR = 1.387, P = 0.0277, Pperm = 0.0288).
In the HUA versus control cohort: rs16941238 showed the most significant association (minor allele “A”, OR = 0.7734, P = 0.0033, Pperm = 0.0020); the other two SNPs, rs2413769 and rs11639349, showed significant associations too (minor allele “T”, OR = 0.8406, P = 0.0184, Pperm = 0.0172 and minor allele “T”, OR = 1.363, P = 0.
0171, Pperm = 0.0219, respectively). In the gout versus HUA cohort: no significant difference was detected except for rs11639349 (minor allele “T”, OR = 0.7419, P = 0.0213, Pperm = 0.0211).
In the combined HUA + GOUT versus control analysis, all SNPs showed the same effect direction in the separate HUA and gout analysis and two SNPs, rs2413769 and rs16941238 reached the statistical significance (OR = 0.8645, P = 0.0202, Pperm = 0.0324 and OR = 0.8279, P = 0.0101, Pperm = 0.0140, respectively).
Considering that gout patients might be prescribed with urate lowering therapy that might affect SUA concentrations, we evaluated the effect of each SNP on SUA only in the HUA cohort combined with the normouricemic controls (seen in Table 3). Rs16941238 showed the most significant association with SUA level (minor allele “A”, BETA = − 13.
84 μmol/L, P = 0.0041, Pperm = 0.0042) and rs2413769 was the second in significance (minor allele “T”, BETA = − 10.28 μmol/L, P = 0.0120, Pperm = 0.0143). Then, we present the frequency and mean SUA value for each genotype of the two most significant loci (rs16941238 and rs2271437) among gout, HUA and normouricemic controls, respectively (Additional file 1: Table S2).
Table 2 Results of the seven SNPs in gout versus control cohort, HUA versus control cohort, gout versus HUA cohort and gout+HUA versus control cohortTable 3 Results of the seven SNPs with SUA concentrations in combined HUA and control dataset
For the meta-analysis, there are seven SNPs having both data in the current study and the previous reported GWAS .
None of the seven SNPs (rs2413775, rs1060896, rs2271437, rs2413769, rs16941238, rs11639349 and rs765787) reached the nominal significance in the discovery stage of gout (P > 0.05), but the OR directions were basically in accordance with the present study (seen in Fig.
1 and Table 2). By meta-analysis, we noted two SNPs showed significant results (rs2413769, OR = 0.9009, P = 0.0328; rs2271437, OR = 1.3221, P = 0.0089).
Forest plot of the association between the seven SNPs and gout
At last, we estimated the linkage disequilibrium (r2 > 0.95) among the eight SNPs in gout patients, HUA cohort, normouricemic controls and the overall, respectively. Haplotype distributions were similar in the different sample sets and no specific haplotype block was identified, as shown in Fig. 2.
Linkage disequilibrium plot of the eight SNPs in the samples of gout patients (a), HUA cohort (b), normouricemic controls (c) and the overall (d)
The SLC28A2 gene encodes the transport protein of CNT2, which is mainly expressed in luminal membrane of intestine  and transports preferentially purine nucleosides including adenosine . Excessive circulating adenosine can be degraded into UA in human body .
On the other hand, adenosine is a kind of mediator to suppress inflammatory and immune responses through binding to surface receptor of A2AR.
Mechanism studies have confirmed that A2AR activation attenuates progression of experimental arthritis by inhibiting TNF-α  and IL-1β production , both of which are the key pro-inflammatory cytokines in the pathogenesis of inflammation flare.
There may exit such a phenomenon that risk allele carriers of the SLC28A2 gene are more prone to HUA but not gout attack. Concordantly, we found rs11639349 T allele significantly increased susceptibility to HUA (OR = 1.363, P = 0.0171, Pperm = 0.0219), rather than gout (OR = 1.016, P = 0.9077, Pperm = 0.
8571) while T allele showed protective effect on gout incidence compared to HUA cohort (OR = 0.7419, P = 0.0213, Pperm = 0.0211). In this study, we identified intron SNPs (rs16941238 and rs2413769) significantly associated with both SUA level and HUA phenotype, and another exonic SNP (rs2271437) associated with gout in the SLC28A2 gene. Nevertheless, the elaborate biological mechanisms caused by the SLC28A2 variants remain unclear.
In a SUA GWAS using European individuals, rs765787 locus which is in high linkage disequilibrium with the SLC28A2 gene was identified to be marginally associated with SUA fluctuation . In our study, this site failed to reach statistical significance even in the meta-analysis.
Rs2413775 is located in 5’-UTR region and T allele was found to enhance the SLC28A2 gene expression in comparison with A allele . However, we found no significant association for this variant in the present study. Its MAF (=0.198) was as the same of HapMap-HCB (=0.
205) and presents significant lower value than HapMap-CEU (=0.775), suggesting the existence of genetic heterogeneity among populations.
Overall, the allele frequencies of these selected SNPs are almost consistent with those of HapMap-HCB but present significant lower values than HapMap-CEU, except for rs2271437 and rs765787 (seen in Table 2 and Additional file 1: Table S1).
The intron variant rs16941238 showed the most significant associations with both SUA concentrations and HUA phenotype, with the minor allele conferring the same effect tendency on decreasing SUA (BETA
Genes that May Affect Uric Acid Levels
With the exception of some rare genetic diseases, these genes and their respective SNPs have only been associated with uric acid levels.
That does not mean having them will necessarily make you more ly to have how or low uric acid levels. More work is needed before we determine whether and how much they may increase a person’s risk of abnormal uric acid status.
It’s equally important to note that just because certain genotypes are associated with a disease, it doesn’t necessarily mean that everyone with that genotype will actually develop the disease! Many different factors, including other genetic and environmental factors, can influence the risk of gout and other diseases.
SLC2A9 Gene – The Absorptive Urate Transporter
The SLC2A9 gene encodes the glucose transporter 9 protein (GLUT4). It transports fructose and aids in the reabsorption of filtered urate by proximal tubules in the kidney. Loss-of-function mutations in this gene can cause hereditary hypouricemia due to reduced urate absorption .
The following SNPs in this gene have been studied:
More research is needed to verify these associations, which are still largely experimental.
ABCG2 Gene – The Multi-functional Transporter that Exports Urate
The ABCG2 gene encodes a multifunctional transporter that belongs to the ATP-binding cassette family and controls the export of various compounds including urate using ATP .
Limited studies suggested the following associations, which have yet to be confirmed in large-scale investigations:
- RS1481012 – The “A” allele was associated with an increased risk of gout . Heterozygous carriers of the minor allele “G” had a lower risk of colorectal cancer in one small study .
- RS2199936 – The “A” allele was associated with incident gout .
- RS2231137 – The T” (minor) allele was associated with an increased risk of tophaceous gout , which causes joint pain and arthritis.
- RS2231142 – The T (minor) allele was associated with an increased risk of gout .
- RS2728125 – The “G” allele was associated with gout .
- RS72552713 – The “A” allele was associated with an increased risk of gout .
SLC22A12 Gene – The Urate Transporter That Determines the Amount of Urate Present in the Blood
The SLC22A12 gene encodes a protein that is a member of the organic anion transporter (OAT) family, and it transports urate. Found in the epithelial cells of the proximal tubule of the kidney, this protein helps control the amount of urate present in the blood.
This gene is thought to be the major luminal pathway for urate reabsorption in humans and mutations have been associated with raised blood urate levels and decreased fractional urate excretion in limited studies .
- RS12800450 – The “T” allele was associated with reduced blood urate levels .
- RS505802 – The “A” allele was associated with gout arthritis in Han Chinese males .
SLC22A11 Gene – The Organic Anion Transporter That Reabsorbs Uric Acid
The SLC22A11 gene encodes a protein that is involved in the transport and excretion of organic anions. It also aids in the reabsorption of uric acid on the apical membrane of the proximal tubule in the kidneys .
- RS17300741 – The minor “G” allele was associated with lower blood uric acid levels in women .
SLC17A1 Gene – The Renal Urate Exporter
The SLC17A1 gene encodes a sodium-dependent transporter that helps transport glucose and other sugars, bile salts and organic acids, metal ions and amine compounds, as well as urate. It was also associated with a higher risk of gout and hyperuricemia in some studies, but more research is needed .
- RS1165196 – The allele “C” was associated with an increased risk of gout in patients with normal uric acid excretion . It was also associated with a low-/high-density lipoprotein cholesterol ratio .
- RS1183201 – The minor “A” allele was associated with a reduced risk of gout in European and western Polynesian populations .
SLC17A3 Gene – Transporter That Transports Intracellular Urate the Cell
The SLC17A3 gene encodes a voltage-driven transporter that transports intracellular urate and organic anions from the blood into kidney tubule cells .
RS1165205 – The “A” allele was associated with higher blood uric acid levels .
UMOD Gene: The Protein That Helps Control The Amount of Water in Urine
The UMOD gene encodes uromodulin, a protein that is highly abundant in urine under physiological conditions. Defects in this gene are associated with various kidney diseases including glomerulocystic kidney disease with hyperuricemia .
- RS12444268 – The “A” allele linked to Type 1 Diabetes .
- RS12917707 – The minor “T” allele was associated with a lower risk of chronic kidney disease .
- RS13333226 – The minor “G” allele was associated with a lower risk of hypertension .
- RS4293393 – The “T” allele was associated with kidney stones and chronic kidney disease. This SNP may also be associated with susceptibility to gout, hypertension, and diabetes, but far more research is needed .
HPRT1 Gene – The Enzyme That Recycles Purines
This gene encodes hypoxanthine phosphoribosyltransferase 1, an enzyme that allows cells to recycle purines. Mutations in this gene have been associated with gout or Lesch-Nyhan syndrome .
PRPS1 Gene – The Enzyme That Helps Make Purines
The PRPS1 gene encodes an enzyme called phosphoribosyl pyrophosphate synthetase 1, or PRPP synthetase 1. This enzyme helps produce phosphoribosyl pyrophosphate (PRPP), which is involved in making purine and pyrimidine nucleotides .
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