The Surprising Cause of High Uric acid and What To Do About It

Uric acid is the final product of the metabolic breakdown of purine nucleotides. The presence of an excess amount of uric acid in the body may lead to various diseases. Read this article to know about the medical conditions associated with either high or low levels of uric acid and methods to increase or decrease it!

Contents

What is Uric Acid?

Uric acid (urate) is an end-product of purine degradation in humans. Purines are generated as a final product in the digestion of certain proteins in the diet, but some are synthesized in the body (R).

Uric acid has antioxidant properties but can be pro-oxidant depending on its chemical environment (R).

In normal conditions, uric acid is eliminated via urine (R). However, a number of factors can affect the ability of the kidneys to eliminate uric acid efficiently. This results in abnormal blood uric acid levels (too high or too low), which have been linked to a variety of diseases including kidney stones, gout,  high blood pressure, kidney disease, obesity, diabetes, and cognitive dysfunction (R).

Production in the Body

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Source: (R)

Uric acid is the last step in the breakdown pathway of purines. Purines are converted to hypoxanthine, then to xanthine and finally, to uric acid.

For the last two steps in conversion, we need the enzyme xanthine oxidase (uricase). In humans, the ability to further metabolize uric acid is lost due to two mutations that silence the gene encoding the enzyme uricase (R).

Consequently, humans have higher urate levels (around 240–360 μM) compared to other mammals (around 30–50 μM in mice) (R).

Disposal in the Body

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Source: (R)

Uric acid is removed from kidney and gut routes. It is almost completely filtered by the glomerulus of the kidneys. 98 – 100% is then reabsorbed in the proximal tubule and 50% is secreted by the distal tubule of the kidneys (R).

About 70% is removed from the urine and 30% is removed from the gut route (R).

Normal Range of Uric Acid in the Body

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Source: (R)

Humans have a higher uric acid level because they lack a functional uricase gene. Levels start to rise after puberty. Men have slightly higher levels than women until the female menopause (R).

Normal blood levels vary across laboratories but generally fall between 2.6 – 5.7 mg/dl for women and 3.5 – 7 mg/dl for men (R)

These levels depend on the balance between purine production and the ingestion of dietary purines, as well as the elimination of urates by the kidney and intestine. Abnormal levels (too high or too low) are detrimental and can lead to a variety of health conditions (R).

High Levels of Uric Acid and Diseases Associated with it

An excess of uric acid in the body is known as hyperuricemia.

Urates are found in urine, blood and in tissue. Urate deposits can lead to oxidative stress (R), inflammation and cellular dysfunction(endothelial) (R).

Most people with high uric acid don’t have symptoms and don’t need any clinical treatment. However, hyperuricemia can lead to several diseases including gout, heart disease, stroke, and kidney disease (R).

1) High Levels of Uric Acid Can Lead to Gout 

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Gout is inflammatory arthritis associated with hyperuricemia. It is a different form of arthritis because it occurs when there are high levels of uric acid in the circulating blood.  That can cause urate crystals to settle in the tissues of the joints (R).

The symptoms appear suddenly, overnight. It comes with agonizing pain, swelling, and redness of the joint. The attack may be precipitated by too much food, alcohol, by starting a diuretic or by dehydration (R).

Symptoms go away after 10-15 days and can keep recurring. Eventually, stone-like deposits known as tophi may build up in joints, ligaments, and tendons and therefore can lead to joint deformation (R).

2) High Uric Acid Increases the Risk of Kidney Stones

If your urine contains more calcium, oxalate and uric acid you are more likely to develop kidney stones (R).

The most common risk factor for uric acid stones is decreased urinary pH (<5.5). Because uric acid stones precipitate in acidic environments, patients should increase their alkaline load by eating more fruits and vegetables (R).

High Levels of Uric Acid are Associated with Hypertension and Chronic Kidney Diseases

Hyperuricemia is associated with hypertension (HTN) and chronic kidney disease (CKD) (R, R2).

It is proposed that hyperuricemia can directly cause hypertension. This is supported by animal studies showing that induced hyperuricemia and resultant hypertension was reversible with hypouricemic drugs including febuxostat and allopurinol (R).

Hypertension and chronic kidney disease are associated with higher risk of cardiovascular events (RR) like hardening of the arteries, heart failure, stroke, type 2 diabetes, metabolic syndrome, nonalcoholic fatty liver disease and others (R).

Potential mechanisms linking blood uric acid to heart disease include its harmful effects on blood vessel function, oxidative metabolism,  and platelet adhesiveness, as well as increased red blood cell aggregation (R, R2, R3).

Chronic hyperuricemia in patients with gout increases uric acid crystal build-up in kidney tissues, resulting in tissue injury and inflammation (R).

Hyperuricemia is Caused by Lesch-Nyhan Syndrome

Lesch-Nyhan syndrome, an extremely rare genetic disorder, is associated with very high blood uric acid levels (R).

In Lesch–Nyhan syndrome,  hypoxanthine-guanine phosphoribosyltransferase (HPRT), an enzyme involved in the recycling of purine nucleotides, is mutated. Consequently, this leads to increased uric acid production because purine nucleotides cannot be reused, so they are subsequently degraded (R).

Muscle tightness, involuntary movement, self-injury, cognitive retardation and gout formation are exhibited in cases of this syndrome (R).

Hyperuricemia is Linked to Type 2 Diabetes

FIG. 3.

Source: (R)

High blood uric acid is associated with higher risk of type 2 diabetes, independent of obesity, high cholesterol, and blood pressure (R). 

It is thought that hyperuricemia raises the risk for diabetes by increasing oxidative stress and inflammation (by increasing tumor necrosis factor-α), both of which are related to the development of diabetes (R).

High Uric Acid Levels May Lead to Metabolic Syndrome

Blood uric acid is significantly correlated with metabolic syndrome and its components, particularly blood triglycerides and waist circumference (R).

One study found that fructose-induced hyperuricemia may play a role in the development of metabolic syndrome. This observation is consistent with the increased consumption of fructose-containing beverages in the recent decades and the epidemic of diabetes and obesity (RR2).  

This may be because the rise in uric acid after fructose intake induces insulin resistance (by lowering nitric oxide), a key factor involved in metabolic syndrome (R).

Hypothyroidism Can Raise Uric Acid Levels

Hyperuricemia and gout are frequently found in patients with hypothyroidism (R).

Thyroid hormones (T4 and T3) stimulate metabolic processes and so their deficiency can affect purine metabolism, resulting in increases in uric acid levels and hyperuricemia (R).

Also, hypothyroidism can lead to a reduction in kidney blood flow and filtration rate, which elevates uric acid levels in the blood (R).

Tumor Lysis Syndrome Elevates Uric Acid Levels

Tumor lysis syndrome (TLS) is characterized by a group of metabolic abnormalities that occur during cancer treatment, where large amounts of tumor cells are killed at the same time by the treatment, resulting in the release of their contents into the bloodstream. High concentrations of uric acid are generated by tumor lysis (rupture), due to the large quantities of nucleic acids released from massive cell death and nuclear breakdown (R).

Chronic Lead Poisoning Can Lead to Hyperuricemia

Lead exposure is associated with impaired kidney function and increased blood uric acid levels (R).

High levels of lead damage the kidneys, causing inflammation and inhibiting urate excretion, which results in urate build-up and eventually, saturnine gout (i.e., lead gout) (R).

High Uric Acid Levels May Increase Bone Fracture Risk

Increased blood urate levels are associated with an increased risk of hip fractures in men (R).

High uric acid levels can induce inflammation in the bone, impair nitric oxide availability, and suppress vitamin D activation, all of which increase bone fragility and fracture risk (R,R2,R3).

Uric Acid Levels are Elevated in Down Syndrome

Patients with Down syndrome consistently report higher blood uric acid levels (R).

Hyperuricemia is Linked to Erectile Dysfunction

Erectile dysfunction is commonly observed in patients with gout. This is likely because high uric acid levels are strongly linked to endothelial dysfunction, hypertension, and microvascular disease, all of which are risk factors for erectile dysfunction (R).

What Causes High Uric Acid Levels?

Kidney Problems

Higher levels of uric acid can occur when your kidneys don’t eliminate it efficiently due to kidney dysfunction and/or influence by certain metabolites and medications (R).

Food Consumption

Studies have shown that each additional intake of meat portion per day increases the risk of gout by 21% (R).

In a crossover study design, the effect of ingesting some purine-rich foods like beef liver, haddock fillets and soybean was investigated. Results showed that the ingestion of all the test meals caused an increase in blood uric acid levels (R).

High Dietary Intake of Fructose

High dietary intake of fructose in foods and drinks increase the production of inosine and purines. Also, fructose competes with uric acid for secretion in the kidney (R).

Fructose rapidly raises uric acid levels as a consequence of its activation of fructokinase with ATP consumption, intracellular phosphate depletion, and stimulation of AMP deaminase,  which leads to the increased production of inosines (R).

In addition, fructose stimulates uric acid synthesis from amino acid precursors, such as glycine (R).

Diuretics

Diuretics are one of the most important causes of secondary hyperuricemia. Drugs increase blood uric acid levels by an increase of uric acid reabsorption and/or a decrease of uric acid secretion (R).

Alcohol

According to a population-based cohort study, alcohol-related diseases were significantly associated with gout risk. Also, severe alcohol-dependent patients were associated with an increased risk of gout (R).

This association may be attributed to alcohol’s ability to stimulate uric acid production by increasing the production of lactic acid, which reduces the excretion of uric acid in the kidneys (R).

Also, alcohol can accelerate the breakdown of purine nucleotides, thereby increasing the production of uric acid (R,R2).

Obesity

According to a population-based epidemiological study, Obesity resulted in an increased risk of developing hyperuricemia. If you are overweight your body produces more uric acid. As a result, the kidney has a more difficult time eliminating uric acid (R).

Blood uric acid levels positively correlate with leptin levels. Since obese individuals have higher leptin levels (due to leptin resistance), leptin may be linked to the development of hyperuricemia in obesity (R).

Genetics

According to one study, the gene UCP2 influenced blood urate concentration and the risk of hyperuricemia. The degree of association varies with gender and BMI levels (R).

Also, mutations in the secretory urate transporter genes, SLC2A9ABCG2, SLC17A1 or SLC17A3, can cause hyperuricemia (R).

Psoriasis

Blood uric acid levels were significantly higher in patients with psoriasis compared with controls (R). But these levels did not modulate the inflammation seen in these patients.

Male Gender

Men have higher blood uric acid levels than women and are more at risk for developing gout (R).

Estrogen is required for the normal secretion of urates. During the post-menopausal period, women have the same content of uric acid as men of similar age, suggesting that low estrogen may have a role in hyperuricemia development (R).

Older Age

Blood uric acid content increases with age (R).

Also, the prevalence of gout increases approximately four-fold to 4.1% by the age of 75 years (R).

Nutrient Deficiencies

Vitamin D insufficiency is significantly correlated with hyperuricemia in post-menopausal women (R).

Diet

A ketogenic diet reduces the ability of the kidney to excrete uric acid because of competition for transport between uric acid and ketones (R).

Higher intakes of sodium are associated with increased blood uric acid levels (R).

Hormones

Elevated blood parathyroid hormone levels are associated with higher blood uric acid levels in the general population. Although exact mechanisms are unclear, it is thought that parathyroid hormone increases blood uric acid by reducing kidney urate excretion (RR2).

Others

Niacin, renal insufficiency, and immune-suppressing drugs can cause hyperuricemia (RR2R3).

Low Levels of Uric Acid and Diseases Associated with it

Hypouricemia occurs when you have a low level of uric acid in your blood (2mg/dl or less) (R).

It is not considered to be a medical condition, but a useful medical sign.

Uric Acid is Lower in Multiple Sclerosis, Parkinson’s Disease, and Motor Neuron Disease

Lower blood values have been associated with several nervous system disorders such as multiple sclerosis (MS)(R), Alzheimer’s disease (AD) (R), Huntington’s disease (HD), and Parkinson’s disease (PD) (R).

It has been proposed that higher blood uric acid levels may be neuroprotective. In a large population-based cohort study, a negative relationship was observed between gout and Parkinson’s disease in patients aged 65 and above. A similar trend has been shown between uric levels and Huntington’s disease, suggesting that uric acid may play a role in preventing neurodegeneration (R,R2).

Uric Acid is Reduced in Optic Neuritis

Uric acid levels are lower in patients with optic neuritis, an inflammatory demyelinating disease of the optic nerve that is often the first symptom of Multiple Sclerosis (R).

Wilson’s Disease Can Lead to Low Uric Acid Levels

Wilson’s disease, a disease in which copper accumulates in tissues of vital organs like the brain and liver, can lead to decreased blood uric acid levels because of associated kidney tubular dysfunction (i.e., Fanconi syndrome), which increases urinary uric acid excretion (R).

What Causes Low Uric Acid Levels?

Medication/Treatments

Hypouricemia can be found in 1% of hospitalized patients. In most cases, the cause is related to drugs like salicylates, allopurinol, x-ray contrast agents and glyceryl guaiacholate (R).

In addition, drugs like losartan  (an angiotensin II receptor antagonist drug), fenofibrate (drug of the fibrate class, mainly used to reduce cholesterol levels) and some non-steroidal anti-inflammatory drugs (NSAIDs) reduce the serum uric acid (SUA) levels (R).

Also, forced diuresis used mainly in the treatment of renal colic in suicide-attempt patients may result in hypouricemia (R).

Genetics

The human urate transporter 1 (URAT 1) and human glucose transporter-like protein 9 (GLUT 9) are two kidney urate transporters.

A genetic mutation in these two transporters is responsible for idiopathic hypouricemia (R).

The gene SLC2A9 encodes a protein that helps transport uric acid in the kidney. Variants of this gene are known to have significant associations with blood uric acid (R).

Malignant Diseases

Several malignant diseases including Hodgkin’s disease, sarcoma, glioblastoma and a variety of carcinomas have been associated with hypouricemia (R).

Diet

By following a low purine diet, uric acid levels are lowered by only 15% at most (R).

Mineral intake/deficiency

In a case study of molybdenum deficiency, blood hypouricemia was present (R).

Inadequate dietary Zinc intake can lead to lower uric acid levels. This effect is more common in women taking oral contraceptives (R).

Patients with high copper/Fe levels experience hypouricemia (R).

Magnesium intake is inversely correlated with hyperuricemia in males. This is possibly due to magnesium’s laxative effect, which may play a potential role in increasing the excretion of uric acid (R).

Hormones

Estrogen suppresses proximal tubule epithelial cell OAT (organic anion transporter) expression which explains the lower serum urate levels in postmenopausal women as opposed to men (R).

Investigations

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Blood test

A uric acid blood test is the most common test used to monitor people with gout, check kidney function, and kidney disorders or stones if you are under chemotherapy or radiation treatment (R).

Reference values for blood uric acid levels generally fall between 2.6 – 5.7 mg/dl for women and 3.5 – 7 mg/dl for men (R)

Urine test

24 hours urine is collected to measure the amount of uric acid in the urine and evaluate how the body produces and eliminates uric acid. The test can also be used to detect gout or hyperuricemia (R,R2).

Normal results for this test are:

  • Adults (normal diet): 250-800 mg/day
  • Adults (purine-free diet): <420 mg/day
  • Adults (low-purine diet) :
    • Males: <480 mg/day
    • Females: <400 mg/day
  • Adults (high-purine diet): <1000 mg/day

Source: (R).

Treatment

Treatment With Agents that Reduce Uric Acid Level

1) Non-Steroidal Anti-inflammatory Drugs

Most non-steroidal anti-inflammatory drugs increase urinary uric acid excretion and are recommended for the treatment of gout (R, R2).

2) Uricosuric Drugs

These drugs increase the secretion of uric acid in urine – probenecid, sulfinpyrazone, and benzbromarone (R).

Uricosuric drugs generally act on the proximal tubules in the kidneys, where they prevent the absorption of uric acid from the kidney back into the blood (by blocking the function of  URAT1) (R).

3) Xanthine Oxidase Inhibitors

Allopurinol is recommended because it prevents gout but it also can be given to you when you have a certain form of leukemia or lymphoma, to prevent a complication of chemotherapy or tumor lysis syndrome.

Also, due to its adverse effect, allopurinol is currently not indicated in asymptomatic hyperuricemia and its related cardiovascular disease or in the diseases other than gout (R).

4) Febuxostat

Febuxostat is a selective xanthine oxidase/xanthine dehydrogenase inhibitor (R).

It has several advantages over allopurinol including tolerability in allopurinol-hypersensitive patients, more effectiveness in kidney failure, and faster dissolution of tophi (R).

Febuxostat works quickly and treatment usually begins with doses of 40 mg/day. If blood uric acid level is not less than 6.0 mg/dL by two weeks, the dose can be increased to 80 mg/day. The average reduction in blood uric acid level is 40% and 56% at 40 mg/day and 80 mg/day respectively and is similar in individuals with and without kidney failure, in contrast to allopurinol (R).

5) Weight loss 

Research suggests that losing weight may help reduce high uric acid levels (R).

6) Purine – Restricted Diet

You should avoid alcohol, red meat, seafood, sugary beverages. Avoid/ limit refined carbs. The foods lowest in purine content include eggs, fruit, cheese, nuts and vegetables other than legumes (R).

7) Water

Keep yourself hydrated as dehydration can lead to elevated uric acid levels (R).

8) Vitamin C 

Vitamin C can increase the excretion of uric acid in the urine and thereby lower blood uric acid levels (R).

9) Coffee

Caffeine is a methylxanthine and may be a competitive inhibitor of xanthine oxidase (R). 

However, one study comparing the effects of coffee, tea, and caffeine intake on uric acid levels found that coffee consumption was associated with lower uric acid levels due to components in coffee other than caffeine, suggesting that coffee itself (regular or decaf) not caffeine, is responsible for the inverse association (R).

10) Dairy Products

Milk proteins (i.e., casein and lactalbumin) promote the excretion of uric acid in the urine (R).

11) Cherry Juice

Cherries can lower blood uric acid levels by increasing kidney filtration rate and decreasing tubular reabsorption. Cherries are also natural xanthine oxidase inhibitors (R,R2).

Treatment with Agents that Increase Uric Acid Levels

1) Inosine

Inosine, a uric acid precursor, is the most effective way to increase uric acid levels (R, R2).

2) Zinc

Zinc normalizes uric acid levels if you are deficient (R).

3) Animal Products

Animal products increase levels in general (R).

4) Alcohol Consumption

Alcoholic drinks increase uric acid levels (R).

5)  Sodium

A high sodium diet can lead to an increase in blood uric acid levels over time (R).

6) Intense Exercise

Uric acid levels rise after strenuous exercise, potentially a result of purine nucleotide degradation during conditions of high energy usage (R).

Genetics of Uric Acid:

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  (R).

  1. RS10017674 
  2. RS10018204 
  3. RS1014290 – The “G” allele is associated with a lower age at onset of Parkinson’s disease (R).Individuals with the TT genotype had higher blood uric acid levels after increasing their consumption of soft drinks (R).The GG genotype is associated with significantly higher serum uric acid levels when compared with the TT/TG genotypes (R).
  4. RS1079128 
  5. RS10805346
  6. RS11722228– The “T” allele is linked to higher blood uric acid levels in females compared to males (R).
  7. RS12498150 
  8. RS12498742 – Each copy of the minor “G” allele reduces the risk of gout (R).
  9. RS12498956 
  10. RS13103879 
  11. RS13129697 – The “C” allele is linked to lower blood urate levels in the Croation population (R).
  12. RS13131257 – The “T” allele is associated with lower blood uric acid levels in Mexican Americans (R).
  13. RS13328050 
  14. RS16868246 
  15. RS16890979 
  16. RS17185835 
  17. RS17185870 
  18. RS1850744 
  19. RS2018643 
  20. RS3733585 – The “G” allele is associated with cleft palate (R).
  21. RS3733591 -The “C” allele increases the risk of severe gout for some populations (R).
  22. RS3775948 -The “G” allele is associated with an increased risk of gout (R).
  23. RS4311316 
  24. RS4312757 
  25. RS4314284 
  26. RS4339211 
  27. RS4455410 
  28. RS4473653 
  29. RS4475146 – The “A” allele is associated with gout (R).
  30. RS4481233 
  31. RS4519796 
  32. RS4580649 
  33. RS4621431 
  34. RS6449157 
  35. RS6449159 
  36. RS6449171 
  37. RS6449172 
  38. RS6449174 
  39. RS6449176 
  40. RS6449178 
  41. RS6449201 
  42. RS6449213 -This variant is associated with higher blood urate levels (R).
  43. RS6814664 
  44. RS6815001 
  45. RS6823361 
  46. RS6832439 -The “A” allele is associated with decreasing blood uric acid levels (R).
  47. RS6834893 
  48. RS6836706 
  49. RS6838021 
  50. RS6839490 
  51. RS6843873 
  52. RS6844316 
  53. RS6849729 
  54. RS6852441 
  55. RS6855911 -The “G” allele is associated with less uric acid (R).
  56. RS733175 
  57. RS734553 – The “T” allele is associated with gout (R).
  58. RS737267  – The GG genotype is associated with 1.25 times higher risk of gout (R).
  59. RS7376948 
  60. RS7378305 
  61. RS7378340 
  62. RS7435196 
  63. RS7442295  – The more common “A” allele is associated with higher blood urate levels and hyperuricemia (R).
  64. RS7658170 
  65. RS7671266 
  66. RS7672947 
  67. RS7676733 
  68. RS7677710 
  69. RS7680126 
  70. RS7686538 
  71. RS938554 
  72. RS9993410 
  73. RS9994266 

ABCG2 Gene- The Multi-functional Transporter That Exports Urate:

This gene encodes a multifunctional transporter that belongs to the ATP-binding cassette family and controls the export of various compounds including urate using ATP (R).

  1. RS13120400 
  2. RS1481012 – The “A” allele is associated with an increased risk of gout (R). Heterozygous carriers of the minor allele “G” have a lower risk of colorectal cancer (R).
  3. RS17731538 
  4. RS2199936 – The “A” allele is associated with incident gout (R).
  5. RS2231137 -The T” (minor) allele is associated with:
    • Increased activity of the drug Pravastatin in patients being treated for hyperlipidaemia (R).
    • Increased risk of tophaceous gout (R). This results in joint pain and arthritis.
    • Possible increase in drug-induced toxicity (R).
    • An increased survival rate in patients undergoing chemotherapy to treat Acute Myeloid Leukemia (R).
    • Increased chance of toxic response following chemotherapy to treat Acute Myeloid Leukemia (R).

    The C (major) allele is associated with:

    • Higher resistance to imatinib therapy in chronic myeloid leukemia patients (CC) (R).
  6. RS2231142 -The T (minor) allele is associated with:
    1. Increased risk of gout (R).
    2. Frequent diarrhea in lung cancer patients taking gefitinib (R).
    3. Heightened response to statins (R).
  7. RS2622604 -The T (minor) allele is associated with:
    •  Increased risk of developing myelosuppression and diarrhea in colorectal and lung cancer subjects being treated with irinotecan (R). This is because Irinotecan can be toxic to cells if it is not removed properly.
  8. RS2728124 
  9. RS2728125 -The “G” allele is associated with gout (R).
  10. RS3114018 
  11. RS4148152 
  12. RS4148155 
  13. RS72552713 -The “A” allele is associated with an increased risk of gout (R).

SLC22A12 Gene-The Urate Transporter That Determines the Amount of Urate Present in the Blood:

This 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 (R).

  1. RS10897518 
  2. RS12800450 The “T” allele is associated with reduced blood urate levels (R).
  3. RS505802 – The “A” allele is associated with gout arthritis in Han Chinese males (R).
  4. RS524023 

SLC22A11 Gene-The Organic Anion Transporter That Reabsorbs Uric Acid:

The 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 (R,R2).

  1. RS17300741 – The minor “G” allele is associated with lower blood uric acid levels in women (R).
  2. RS2078267 
  3. RS505802 
  4. RS524023 
  5. RS7124676 

SLC17A1 Gene-The Renal Urate Exporter:

This 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 is also associated with a higher risk of gout and hyperuricemia (R).

  1. RS1165151 
  2. RS1165152 
  3. RS1165196-The  allele “C” is associated with an increased risk of gout in patients with normal uric acid excretion (R). It is also associated with a low-/high-density lipoprotein cholesterol ratio (R).
  4. RS1165209
  5. RS1183201 -The minor “A” allele is associated with a reduced risk of gout in European and western Polynesian populations (R).
  6. RS1185567 
  7. RS1408272
  8. RS17270561 
  9. RS17342717 
  10. RS2762353

SLC17A3 Gene-Transporter That Transports Intracellular Urate Out of the Cell:

The gene encodes a voltage-driven transporter that transports intracellular urate and organic anions from the blood into kidney tubule cells (R).

  1. RS1165205 -The “A” allele is associated with higher blood uric acid levels (R).
  2. RS13198474 – The “G” allele is associated with schizophrenia (R).
  3. RS1408272 -The “G” allele is associated with mean corpuscular hemoglobin (R).
  4. RS548987 The “C” is linked to homocysteine concentrations (R).
  5. RS6910741 -The “T” allele is associated with mean arterial pressure (R).

UMOD Gene: The Protein That Helps Control The Amount of Water in Urine:

This 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 (R).

  1. RS11859916 
  2. RS12444268 -The “A” allele linked to Type 1 Diabetes (R).
  3. RS12917707 – The minor “T” allele is associated with a lower risk of chronic kidney diseases (R).
  4. RS13333226 -The minor “G” allele is associated with a lower risk of hypertension (R).
  5. RS4293393 – The “T” allele is associated with kidney stones and chronic kidney disease. This SNP may also be associated with susceptibility to gout, hypertension, and diabetes (R).

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 can result in gout or Lesch-Nyhan syndrome (R).

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 (R).

Technical:

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Source: (R)

Uric acid antioxidant activities:

  • Uric acid acts as a strong antioxidant and scavenges reactive oxygen species and chelates transition metals (R,R2).
  • Uric acid prevents peroxynitrite-induced protein nitrosation, fat and protein peroxidation, and the inactivation of tetrahydrobiopterin BH4, a cofactor necessary for NOS (RR2, R3).
  • Uric acid protects low-density lipoprotein from Cu2+-mediated oxidation but increases the oxidation of already oxidized low-density lipoprotein (R).

Uric acid pro-oxidant and inflammatory activities:

  • By increasing arginase activity, uric acid diverts l-arginine from nitric oxide (NO) generation to urea production. Uric acid also directly reacts with nitric oxide (NO) to produce nitrosated uric acid, and the nitroso group can then be transferred to glutathione (GSH) for transport to another accepting molecule (R).
  • In the presence of oxygen, uric acid reacts with nitric oxide (NO) to produce 6-aminouracil (R).
  • Uric acid uptake in fat cells activates NADPH oxidase and stimulates the production of reactive oxygen species, which can initiate an inflammatory reaction (R).
  • Uric acid can activate the NF-κB and MAPK pathway in vascular smooth muscle cells and increase the production of cyclooxygenase and monocyte chemoattractant protein-1 (MCP-1) (R).

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