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 too 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.[refAgain - 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:

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