Gout: Genetic Links to High Uric Acid

Have you ever woken up to excruciating pain in your big toe or ankle?  If so you may be one of the millions of people worldwide with gout. In fact, a study from 2008 showed that about 8.3 million Americans had gout. Men are affected at about 3 times the rate as women. [ref]

Uric acid and gout:

When your body breaks down purines, a type of biological molecule, the eventual by-product of the process is uric acid. And just like it sounds like – uric acid is a normal part of the urine.

This biological process of breaking down purines and thus creating uric acid occurs for both purines created in the body and due to dietary factors. While it is easy to point the finger at the dietary component (alcohol, fructose, meat, and seafood), the purines produced in the body is a big part of your uric acid levels.

Almost all other mammals actually go one step further when metabolizing purines, and they break down the uric acid into allantoin. Humans and higher primates don’t make that final enzyme to convert uric acid into allantoin. (Dalmations also have a genetic defect that causes them to excrete uric acid instead of allantoin.) Researchers theorize that uric acid is important in humans, and possibly takes the place of ascorbic acid (which humans and higher primates also don’t produce). Uric acid acts as a potent antioxidant in the serum, but can act as a pro-oxidant at certain levels and inside cells. [ref][ref]

Metabolism of purines:

Purines are a class of biological molecules that include the nucleotides adenine and guanine – the A’s and G’s in your DNA. You naturally have some cells in the body that are broken down each day. Cellular turnover is high in certain tissues (like the intestines and skin) and low in other tissues (like the brain)  – but the net effect is that your body breaks down cellular components, including DNA and RNA,  all the time.

Guanine and adenine are broken down through a multistep process that eventually creates xanthine, which is acted on by the enzyme xanthine oxidase to form uric acid. (This is important in how gout drugs work.)

Uric acid levels:

Lab ranges may vary a bit on uric acid as far as what is considered normal vs. high. Basically, there comes a point when crystals will form when the concentration of uric acid gets too high.

The normal reference range for uric acid is:

  • 1.5 – 6.0 mg/dL for adult women
  • 2.5 to 7.0 mg/dL for adult men

In blood, uric acid crystals start to form at 6.8 mg/dL. [ref]  (I have no idea why the normal range for men goes a little higher than the point of crystals forming… )

Normally, about 70% of uric acid is disposed of each day via the kidneys, with the rest being excreted through feces.[ref]  High uric acid levels are mainly driven by inefficient renal excretion. [ref]

What causes high uric acid?

The levels of uric acid in the body are primarily due to a person’s rate of turnover of cells as well as the rate of excretion and reabsorption in the kidneys. [ref]

In addition to someone’s natural rate of uric acid production and excretion, the following can influence uric acid levels:

  • Diet – high intake of fructose and of purines (meat, seafood) increases uric acid[ref]
  • Genetics – uric acid levels are considered about 70% heritable (due to genetics)[ref]
  • Kidney disease doubles the risk of gout [ref]
  • Fasting and rapid weight loss increases uric acid (temporarily)
  • Type-2 diabetes [ref]
  • Medications
  • Blood cancers

Overproduction vs. Under Excretion:

There are two ways of looking at high uric acid levels:

  1. someone can be creating too much uric acid (genetics and/or diet)
  2. someone can have problems with excreting uric acid

The third phenotype here is a combination of both creating two much uric acid along with not excreting enough. [ref]

Figuring out which genetic variants you carry that impact these pathways may help you to determine the best method of decreasing uric acid levels – for you.

Kidney Excretion:

The kidneys excrete the majority of uric acid and are the regulators of uric acid levels in the body.  They control the balance through reabsorbing uric acid using the urate transporter 1 (SLC22A12 gene) and using the glucose transporter 9 (SLC2A9 gene).[ref]

How high is too high?

Lab ranges may vary a bit on uric acid as far as what is considered normal vs. high. Basically, there comes a point when crystals will form when the concentration of uric acid gets too high.

The normal reference range for uric acid is:

  • 1.5 – 6.0 mg/dL for adult women
  • 2.5 to 7.0 mg/dL for adult men

In blood, uric acid crystals start to form at 6.8 mg/dL. [ref]  (I have no idea why the normal range for men goes a little higher than the point of crystals forming… )

What exactly is gout?

Gout is a painful, acute arthritis condition that is caused when crystals of uric acid accumulate in the joints. Uric acid crystals can also form in the capillaries and skin, but for most people, the first onset of gout is heralded by pain and swelling in the big toe.

Genetics plays a big role in gout, with heritability being estimated at 73% (which is high!). [ref]

Gout occurs with high uric acid levels, but that level at which gout occurs varies a lot from person to person.

Getting more detailed:
High levels of uric acid for long periods of time causes the growth of monosodium urate crystals in and around the joints.  These crystals are asymptomatic at first, but they can be seen on ultrasound. The acute episodes of pain are thought to be caused by crystals moving from the cartilage surface into the space in the joint. Ouch! If uric acid remains elevated, the crystals keep forming and periodically moving into the joint space – leading to chronic gout that can damage the joint. [ref]

Another component of the pain of gout is the increase of inflammation due to the monosodium urate crystals.

Gout treatments:

Xanthin oxidase inhibitors, such as allopurinol and febuxostat, lower urate levels and help to prevent gout attacks.[ref]

Lifestyle interventions, such as dietary changes, have also been shown to be effective in lowering gout risk. See the Lifehacks section below.

Gout is not a new health problem, although it is on the increase. It was written about as far back as the ancient Egyptians and by Hippocrates. In the 1800s, gout was treated with lithium salts, since lithium binds to urate to make it more soluble. And this was (is) commonly used in studies when giving the test subjects uric acid. In fact, this is how lithium came to be used for bipolar disorder. A psychiatrist in 1949 started treating bipolar patients with lithium carbonate after noticing that lab animals were calmer after being treated with lithium plus uric acid. [ref]

High uric acid without gout:

The majority of people with high uric acid levels actually do not have gout. A study based on data from 2008 found that 3.9% of US adults had gout, while over 21% of adults had high uric acid levels. This study defined hyperuricemia as serum urate levels of >5.7 mg/dl for women and >7 mg/dl for men.

There are a lot of association studies that show that people with high uric acid also are more likely to have ‘co-morbidities’ or other health conditions. Questions remain, though, as to whether there is causation involved – for example: do high uric acid levels cause high triglycerides or do high triglycerides cause high uric acid. [ref] Is high uric acid just a byproduct (perhaps due to diet) or is it playing a role in causing chronic disease?

Obesity:
Obesity is one co-morbidity that occurs at a higher rate in people with higher uric acid. Some studies indicate that obesity causes high serum uric acid. [ref]  Other studies indicate that high uric acid levels cause an increase in obesity. [ref] In fact, some researchers theorize that humans found it to be an advantage to have higher uric acid levels because it promoted fat accumulation, something that was helpful for survival throughout history. [ref]

Interestingly, there seems to be a U-shaped curve for uric acid levels and BMI, with the lowest uric acid found in women with a BMI of 21.3 and men with a BMI of 19.1. [ref]

Serum uric acid vs. BMI. Creative Commons license (ref above).

 

While the complete picture isn’t clear here, obesity combined with higher uric acid levels is associated with a greater risk of high blood pressure than either condition separately. [ref]

Heart problems:
High uric acid levels are linked with a greater risk of heart problems. A study showed that cardiac patients with uric acid levels >8mg/dL had a more than 4-fold increase in the 2-year risk of cardiac mortality. The trend on this seemed to be fairly linear, with people with uric acid >8 at the highest risk for death, uric acid between 7 and 8 still at elevated risk – down to people with uric acid less than 6 being at the lowest risk for cardiac mortality. [ref]   Again – I’m not sure that causality is proven here as to whether uric acid increases heart problems or whether heart disease (and heart cell death) increases uric acid. 

Inflammation:
A really interesting study looked at the effects of giving uric acid to healthy people who had normal levels of uric acid. Giving the people uric acid, of course, raised their uric acid levels. The test subjects then were given a fast-food type meal that contained 900 calories and 50 grams of fat. The researchers then tested their inflammatory markers at 2-hour intervals. This was then compared with the same meal given a couple of days later – but with lowered uric acid levels.  The results showed that high uric acid, combined with the high-fat fast-food meal, causes a significant increase in the inflammatory cytokine, IL-6.

Low uric acid:

Like most things in the body, there seems to be a sweet spot for uric acid – neither too high nor too low.  Uric acid does act as a potent antioxidant in the serum, and it is thought to contribute about 60% to the plasma antioxidant capacity in the body.[ref]

Studies show that uric acid levels are lower in people with Parkinson’s disease, and that high uric acid levels are protective against Parkinson’s. [ref][ref] There is also a link between quicker progression in Alzheimer’s with low uric acid. And people with higher uric acid levels are at a reduced risk of Alzheimer’s.  [ref]

 


Genetic variants linked to gout:

The following genetic variants have been linked with gout.

ABCG2 gene codes for the ATP-binding cassette transporter G2.  There are multiple ATP-binding cassette (ABC) transporters in the body, and they generally move substances across the cell membrane. Researchers and drug manufacturers are particularly interested in several of the ABC genetic variants because they can cause medications (including chemotherapy drugs) to be transported back out of a cell. [ref]

The ABCG2 transporter also is most important in the excretion of uric acid in the intestines. Genetic variants that decrease ABCG2 are associated with increased uric acid levels. While the majority of uric acid is excreted by the kidneys, about a third still gets excreted through the intestines. So decreasing this pathway shifts the burden of excretion to the kidneys. [ref] The genetic variants that impact this pathway may be more of a problem for someone with diminished kidney function. [ref]

Check your genetic data for rs2231142 (23andMe v4, v5; AncestryDNA):

  • G/G: typical
  • G/T: increased risk of gout, higher uric acid levels, doesn’t respond as well to allopurinol
  • T/T: significantly increased risk of gout, higher uric acid levels [ref][ref][ref]; doesn’t respond as well to allopurinol [ref]

Check your genetic data for rs72552713 (23andMe v4, v5; AncestryDNA):

  • G/G: typical
  • A/G: increased risk of gout, higher uric acid levels [ref][ref]
  • A/A: significantly increased risk of gout, higher uric acid levels

 

SLC2A9 gene: codes for GLUT9, a urate transporter in the kidneys that is facilitated by glucose and fructose [ref] Variants here account part of the variation seen in uric acid levels in a healthy population.[ref]

There are quite a few SLC2A9 variants that are linked to a decreased risk of gout — alternatively, you could consider the more common genotype at a higher risk of gout.

Check your genetic data for rs6449213 (23andMe v4, v5; AncestryDNA):

  • T/T: most common genotype
  • C/T: decreased risk for gout
  • C/C: decreased risk for gout, decreased uric acid levels[ref][ref]

Check your genetic data for rs7442295 (23andMe v4, v5; AncestryDNA):

  • A/A: most common genotype
  • A/G: decreased risk for gout
  • G/G: decreased risk for gout, decreased uric acid levels[ref]

Check your genetic data for rs12510549 (23andMe v4; AncestryDNA):

  • T/T: most common genotype
  • C/T: decreased risk for gout
  • C/C: decreased risk for gout, decreased uric acid levels[ref]

Check your genetic data for rs12498742 (23andMe v4, v5; AncestryDNA):

  • A/A: most common genotype
  • A/G: decrease risk for gout
  • G/G: decreased risk for gout[ref]

Check your genetic data for rs16890979 (23andMe v4 only):

  • T/T: decreased risk of gout[ref]
  • C/T: decreased risk of gout
  • C/C: typical

Check your genetic data for rs1014290 (23andMe v4; AncestryDNA):

  • G/G: decreased serum uric acid [ref][ref]
  • A/G: slightly decreased serum uric acid
  • A/A: most common genotype

Check your genetic data for rs10805346 (23andMe v5; AncestryDNA):

  • T/T: decreased serum uric acid [ref]
  • C/T: slightly decreased serum uric acid
  • C/C: most common genotype

 

SLC22A12 gene codes for the urate transporter 1 (URAT1), which is a key player in uric acid reabsorption in the kidneys.

Check your genetic data for rs475688 (23andMe v4; AncestryDNA):

  • C/C: higher risk of gout (most common genotype) [ref]
  • C/T: intermediate risk of gout
  • T/T: lowest risk of gout

Check your genetic data for rs780094 (23andMe v4, v5; AncestryDNA):

  • C/C: decreased risk of gout [ref]
  • C/T: decreased risk of gout
  • T/T: typical

 

SLC28A2 gene: codes for an intestinal transporter that transports dietary purines into the body. Increased uptake of dietary purines could increase the risk for gout, depending on the diet.

Check your genetic data for rs2271437 (23andMe v5 only):

  • G/G: increased risk of gout[ref]
  • G/T: increased risk of gout
  • T/T: typical

Lifehacks:

Testing:

Your doctor can order a uric acid test for you if you suspect you have gout.

If for some reason you can’t order the test through your doctor, you can order it yourself online in the US through Ulta Lab tests and other online lab test ordering companies.  (UltaLabs Tests price – $18) This is also a good option if you are trying different lifestyle interventions and want to track the results.

Fructose:

It is always interesting to see how researchers create an animal model of a human condition.  To create high uric acid levels, researchers simply give rats 10% fructose in their water. [ref]

In humans, there is a strong relationship between the intake of fructose and uric acid levels. When fructose is metabolized in the liver, it is broken down through a multistep process. When there is too much fructose consumed at once (e.g. drinking a large soda that contains high-fructose corn syrup), one of the components of the metabolism process can build up in the liver. This stimulates purine degradation, which produces uric acid. [ref]

Not all studies agree on the role that fructose plays in uric acid –including a large meta-analysis of controlled trials.[ref]

It may be the amount of fructose consumed at one time that is the key here, with larger amounts overwhelming the liver.[ref] Moderating fructose consumption and not consuming larger amounts at one time may be key here.

Specific Lifehacks for Variants:

ABCG2 variant carriers:
Carriers of the ABCG2 variant rs2231142 T-allele have decreased ABCG2.

Chicory has been shown in studies to decrease serum uric acid levels via increasing the expression of ABCG2 in the intestines.[ref]  Chicory is often consumed as a hot beverage, similar to coffee.

On the other hand, a high consumption of fructose decreases ABCG2 levels in the intestines (animal study). [ref]

SLC22A1 (urate transporter 1) variant carriers:

Citrus flavonoids – specifically nobiletin, hesperetin, and naringenin – have been shown in cell studies to inhibit SLC22A1.[ref]

Orange juice is the most common source of the citrus flavonoids in the diet.

  • A trial of alcoholic fermented and the pasteurized orange juice decreased uric acid levels by 8.9% in 2 weeks. [ref] Note that the orange juice was fermented, which would reduce the fructose level, but still fairly low in alcohol.
  • Another trial found that orange juice didn’t increase the risk of gout, despite having similar sugar content to cola. The study showed that uric acid levels in people who drank soda for two weeks stayed the same, but people who drank orange juice for two weeks had a decrease in uric acid.[ref]  (This may also be due to vitamin C reducing uric acid…)

Hesperetin and orange juice have also been shown in animal studies to inhibit xanthine oxidase (the enzyme allopurinol acts on). [ref]

SLC28A2 variant carriers:
This gene codes for a transporter that is involved in the absorption of purines from foods.  A low intake of dietary purines may work well to mitigate the impact of this variant.

Foods that are highest in purine include (mg/100g) [ref]:

  • all organ meats (e.g. beef, pork, chicken liver)
  • sardines
  • Monkfish liver
  • shrimp
  • krill
  • milt (striped pigfish)
  • dried fish (anchovy, whitebait, sardines)
  • powdered umami broth
  • dried shiitake mushrooms
  • beer yeast*
  • chlorella*
  • royal jelly*
  • spirulina*
  • parsley*
  • * keep in mind that this is per 100g

 

Affecting multiple pathways:

A recent animal study found the hydroxytyrosol, a component of olive leaves and olive oil, decrease uric acid levels and also moderated the levels of ABCG2, SLC22A1 (URAT1), and SLCA9 (GLUT9). [ref]

Animal studies showed that fucoidan and fucoxanthin (both found in brown algae) increased ABCG2 and decrease GLUT9 and URAT1. These two compounds also inhibited xanthine oxidase.[ref] [ref]

Dietary interventions:

A meta-analysis of 19 studies on diet and gout found that higher intake of the following foods increases the risk of gout (listed from greatest impact to lowest):[ref]

  • alcohol
  • fructose
  • seafood
  • red meat

The following foods are shown in multiple studies to decrease the risk of gout:

  • coffee
  • dairy (low fat, quick lowering effect)[ref]

Vitamin C:

Quite a few clinical trials, dating back to the 70s, show that supplemental vitamin C decreases uric acid levels in people with high uric acid. The studies used a range of doses from 500mg/day to 3 g/day. [ref][ref][ref]  The only study that I could find that concluded that vitamin C has no effect was one that had the control arm taking allopurinol… [ref]

Quercetin:

A randomized, double-blinded, placebo-controlled crossover trial found that 500mg/day of quercetin decreased uric acid levels in men who had high-normal levels at baseline.[ref]

What probably doesn’t work:

Tart cherry juice was recently shown to have no effect on uric acid or gout flares, although previous studies had indicated there could be a benefit.[ref]



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between scientific research and the lay person's ability to utilize that information. To contact Debbie, visit the contact page.