Hyperuricaemia is considered the most important risk factor for the development of gout. In a community-based, cross-sectional Taiwanese study of 3,185 adults aged over 30 years, the odds ratio (OR) for prevalent gout was 3.65 (95% confidence interval (CI) = 2.72, 5.09) between men with and without hyperuricaemia (SUA ≥ 7.0 mg/dl) 31. The 5-year cumulative incidence of gout was 18.8% in 223 men who had asymptomatic hyperuricaemia at baseline 32. A dose-dependent effect on the 5-year cumulative incidence of gout was seen with increasing SUA level (SUA 7.0 to 7.9 mg/dl, 10.8%; SUA 8.0 to 8.9 mg/dl, 27.7%; SUA ≥ 9.0 mg/dl, 61.1%) 32. The Normative Aging Study followed 2,046 male veterans aged 21 to 81 years over a period of 15 years, identifying 84 new cases of acute gouty arthritis 33. The 5-year cumulative incidence of gout increased as SUA increased (Figure 1). In the Framingham Heart Study, the risk of developing gout increased with increasing SUA level in both men and women (Figure 2) 29. Gout incidence rates increased exponentially with increasing SUA levels in both studies (Table 2) 2933.

Familial clustering is often evident in common primary gout, and twin studies show high heritability for both uric acid renal clearance (60%) and uric acid:creatinine ratio (87%) 3435. The usual mechanism of hyperuricaemia in primary gout relates predominantly to relative inefficiency in excretion rather than over-production. It is estimated that approximately 30% of the body's uric acid is excreted into the intestine by ill-defined mechanisms, and is broken down by colonic bacteria (which possess uricase) to allantoin. The kidney excretes the majority (70%) of uric acid excretion, however, and renal mechanisms appear key to the understanding of hyperuricaemia. Recent interest has therefore particularly focused on genes regulating renal urate transport 36.

The SLC22A12 gene codes for human urate transporter 1 (URAT1), a member of the organic anion transporter family that, together with other recently identified transporters, is important in controlling reabsorption of uric acid from the proximal renal tubules. URAT1 is the site of action for many drugs and ions that influence SUA. For example, lactate, nicotinate and pyrazinoate act as a substrate for URAT1 and increase reabsorption of uric acid (causing an increase in SUA), whereas benzbromarone, probenecid and losartan inhibit URAT1 to cause increased uricosuria and reduction in SUA 37. A polymorphism of this gene has been associated with relative under-excretion of uric acid and hyperuricaemia in German Caucasians 38, and inactivating mutations of URAT1 have been shown in Japanese patients to cause marked hypouricaemia 39.

The glucose and fructose transporter SLC2A9 (GLUT9) is another urate transporter in proximal renal tubules 40, and polymorphisms of this gene have been associated with increased SUA 4142 and with self-reported gout 43. The association between polymorphisms in SLC2A9 and both high SUA levels and risk of gout was confirmed in a genome-wide association study of three large cohorts 44. This study also identified two further gene associations in ABCG2 (a urate efflux transporter in proximal collecting duct cells) and SLC17A3 (encoding NPT4 - a proximal tubule sodium/phosphate co-transporter), allowing development of a genetic score to predict risk of gout. Polymorphisms in the SLC17A1 gene, which codes for NPT1, a sodium-dependent phosphate co-transporter, have also been shown to associate with gout 45. Two recent meta-analyses of genome-wide association studies have confirmed these associations, although except for SCL2A9, which may account for up to 5% of variance of uric acid levels, the other genetic associations each appear to account for less than 1% of variance 4647.

Two other reported genetic associations with hyperuricaemia are of special interest. Firstly, the 64Arg variant of the β₃-adrenergic receptor (ADRB3) gene - which may also induce insulin resistance through reduced lipolysis and increase in adipocytes, thus possibly providing an explanation for the link between these facets of the metabolic syndrome 48. Secondly, the 677T allele of the methylene tetrahydrofolate reductase (MTHFR) gene - which may facilitate availability of methylene tetrahydrofolate for de novo purine synthesis 49. Single gene mutations that cause hyperuricaemia and gout are very rare, but examples of these include, uromodulin, renin, the aldolase B (ALDOB) gene and hypoxanthine guanine phosphoribosylpyrophosphate - the cause of Lesch-Nyhan syndrome 49.

Given its high heritability, further genetic studies are warranted. However, future studies require careful phenotypic characterisation. There should be clear distinction between studies examining the genetics of hyperuricaemia, which probably are best judged at a young age before development of co-morbidities, drug intake and age-related renal impairment, and those linking genetic associations with crystal deposition and gout, since different associations may emerge.

An association between gout and dietary factors has been recognised for centuries. Only recently, however, has this been confirmed in large, well-designed epidemiological studies (Table 3). The Health Professionals Follow-up Study (HPFS) was a large, prospective cohort study that followed 51,529 male health professionals, documenting 757 incident cases of gout over a 12-year period. Gout cases were required to meet the 1977 American Rheumatism Association preliminary criteria 24. Dietary intake was assessed using a semiquantitative food frequency questionnaire administered at baseline and at 4-year and 8-year follow-up 50. Dietary consumption of meat and seafood was associated with an increased risk of gout, whereas consumption of dairy products appeared to be protective 51. After adjustment for age, body mass index (BMI), diuretic use, hypertension, renal failure, alcohol intake, and other dietary factors, the multivariate relative risk (RR) of developing gout was 1.41 among men in the highest quintile of total meat intake compared with those in the lowest quintile (95% CI = 1.07, 1.86). The multivariate RR of developing gout in those among the highest quintile of seafood consumption versus the lowest quintile was 1.51 (95% CI = 1.17, 1.95). Consumption of purine-rich vegetables was not associated with the development of gout. The risk of developing gout decreased with increasing consumption of dairy products (highest versus lowest quintile; multivariate RR = 0.56, 95% CI = 0.42, 0.74). This association was seen for low-fat dairy products (multivariate RR = 0.58, 95% CI = 0.45, 0.77) but not for high-fat dairy products (highest versus lowest quintile; multivariate RR = 1.00, 95% CI = 0.77, 1.29).

In a subsequent HPFS study, the same authors examined the relationship between coffee consumption and the risk of developing gout 52. Consumption of six or more cups of coffee per day appeared to be protective against the development of gout (multivariate RR = 0.41, 95% CI = 0.19, 0.88) compared with no coffee consumption. Although the risk of developing gout was not significantly decreased in those drinking four or more cups of decaffeinated coffee per day compared with no consumption (multivariate RR = 0.73, 95% CI = 0.46, 1.17), a significant protective effect was seen in those drinking smaller amounts of decaeinated coffee and a statistically significant trend was seen across the groups. Tea consumption and total caffeine intake were not associated with development of gout. Subsequently, the authors explored the relationship between intake of sugar-sweetened soft drinks and fructose and the risk of incident gout 53. Fructose increases degradation of purine nucleotides, which act as a substrate for uric acid production 54. Consumption of two or more sugar-sweetened soft drinks per day was a risk factor for the development of gout (multivariate RR = 1.85, 95% CI = 1.08, 3.16) compared with less than one per month 53. Diet soft drinks did not appear to confer risk of developing gout. Increasing total fructose intake, however, increased the risk of incident gout (highest versus lowest quintile; multivariate RR = 1.81, 95% CI = 1.31, 2.50).

Most recently, the authors have examined the risk of developing gout with vitamin C consumption using 20-year follow-up data from the HPFS (including 1,317 incident gout cases) 55. Higher total vitamin C consumption appeared to be protective against the development of gout. The multivariate RR of developing gout was 0.55 (95% CI = 0.38, 0.80) in those consuming >1,500 mg dietary vitamin C per day compared with those consuming < 250 mg/day.

Local variation in the prevalence of gout has been suggested to be influenced by dietary habits. A cross-sectional study of 5,003 adults found the prevalence of gout across five coastal cities in the Shandong province of China to range from 0.50% to 2.55% 17. Consumption of meat and seafood was significantly higher in the city of Yantai where gout prevalence was the highest, compared with the city of Dongying that had the lowest prevalence of gout - raising the possibility that variations in the prevalence of gout might be directly attributable to lifestyle factors 56.

Similar to dietary factors, an association between gout and excess alcohol consumption has long been recognised. Although it is now thought that the epidemic of gout in nineteenth-century England was secondary to lead poisoning resulting from the high lead content of wines and port at this time 57, recent epidemiological data support the important relationship between alcohol consumption and risk of developing gout today.

In the HPFS, a graded association was observed between alcohol intake and the risk of developing gout on multivariate analysis (no alcohol intake, RR = 1.00; 0.1 to 4.9 g/day, RR = 1.09; 5.0 to 9.9 g/day, RR = 1.25; 10.0 to 14.9 g/day, RR = 1.32; 15.0 to 29.9 g/day, RR = 1.49; 30.0 to 49.9 g/day, RR = 1.96; ≥ 50.0 g/day, RR = 2.53) 58. The multivariate RR was 1.17 (95% CI = 1.11, 1.22) per 10 g increase in alcohol intake per day. Comparing those who drank two or more drinks per day with those who did not drink, the risk of developing gout was greatest for beer consumption (RR = 2.51, 95% CI = 1.77, 3.55) followed by spirits (RR = 1.60, 95% CI = 1.19, 2.16), whereas wine consumption conferred no risk (RR = 1.05, 95% CI = 0.64, 1.72) (Table 3). The multivariate RR per serving per day was 1.49 (95% CI = 1.32, 1.70) for beer, 1.15 (95% CI = 1.04, 1.28) for spirits, and 1.04 (95% CI = 0.88, 1.22) for wine.

Excess alcohol consumption has also been shown to be an important risk factor for the development of gout in women. In the Framingham Heart Study, alcohol consumption was categorised as heavy, moderate and abstinent/light 29. Compared with people whose alcohol intake was abstinent/light (0 to 1 ounce per week), the multivariate RR of developing gout in the heavy alcohol consumption category (≥ 7 ounces per week) was 3.10 (95% CI = 1.69, 5.68) in women and 2.21 (95% CI = 1.56, 3.14) in men.

Alcohol consumption has also been shown to trigger attacks of acute gout. In an Internet cross-over study of 321 acute attacks in 197 subjects, a dose-dependent relationship was found between the number of alcoholic drinks consumed in the previous 48 hours and an acute attack of gout (seven alcoholic drinks in 48 hours: OR = 2.5, 95% CI = 1.1, 5.9) 59.

Several mechanisms by which alcohol predisposes to hyperuricaemia have been proposed, including reduced renal urate excretion via lactic acidosis or lead poisoning, increased urate production via ethanol-induced accelerated degradation of purine nucleotides or the high purine content of beer enhancing substrate provision, and poor compliance with urate-lowering therapy 60.

Gout has an important association with the metabolic syndrome. A study undertaken using data from the Third National Health and Nutrition Examination Survey, conducted between 1988 and 1994, compared the prevalence of the metabolic syndrome - defined using the revised National Cholesterol Education Program Adult Treatment Panel III criteria 61 - between individuals with gout and control subjects without gout 6162. Amongst individuals with gout the prevalence of metabolic syndrome was 62.8%, compared with 25.4% among those without gout (age-adjusted and sex-adjusted OR = 3.05, 95% CI = 2.01, 4.61).

Other studies have reported the relationship between gout and various individual components of the metabolic syndrome. In the HPFS, on multivariate analysis, there was a clear graded association between increasing BMI and the risk of incident gout in men (BMI <21 kg/m², RR = 0.85; BMI 21 to 22.9 kg/m², RR = 1.00; BMI 23 to 24.9 kg/m², RR = 1.31; BMI 25 to 29.9 kg/m², RR = 1.95; BMI 30 to 34.9 kg/m², RR = 2.33; BMI ≥ 35 kg/m², RR = 2.97) 63. A similar relationship was seen between incident gout and waist:hip ratio. Compared with men who had maintained their weight, graded associations were also seen between weight gain since study entry and increased risk of gout (weight gain ≥ 30 lbs, multivariate RR = 1.72, 95% CI = 1.02, 2.91). Weight loss since study entry decreased the risk of gout (weight loss ≥ 10 lbs, multivariate RR = 0.61, 95% CI = 0.40, 0.92). The Framingham Heart Study also identified obesity as a risk factor for developing gout 29. The multivariate RR of developing gout was 2.74 (95% CI = 1.65, 4.58) in obese women (BMI ≥ 30 kg/m²) and 2.90 (95% CI = 1.89, 4.44) in obese men, compared with those with BMI <25 kg/m².

Several studies have examined the relationship between gout and hypertension. In a case-control study undertaken in the UK-GPRD that compared 56,483 gout cases with 150,867 controls subjects with osteoarthritis (OA), the age-adjusted and sex-adjusted OR for gout in patients with hypertension was 1.52 (95% CI = 1.48, 1.56) 13. The HPFS and Framingham Heart Study found multivariate RRs of incident gout with hypertension of 2.31 (95% CI = 1.96, 2.72) and 1.59 (95% CI = 1.12, 2.24), respectively, in men and 1.82 (95% CI = 1.06, 3.14) in women 2963.

The UK-GPRD study found a small but statistically significant association between gout and diabetes mellitus (age-adjusted and sex-adjusted OR = 1.11, 95% CI = 1.06, 1.16) 13. Interestingly, whereas most epidemiological studies concerning gout and components of the metabolic syndrome have focused on the risk of incident gout in people with individual co-morbid conditions, gout itself has been shown to be a risk factor for incident type 2 diabetes mellitus in men 64. A prospective cohort study of 11,351 men was nested within the Multiple Risk Factor Intervention Trial, a randomised clinical trial of a coronary risk reduction programme in men at high risk of cardiovascular disease (CVD). After exclusion of men with diabetes at baseline, the multivariate RR of incident type 2 diabetes mellitus was 1.34 (95% CI = 1.09, 1.64) in men who self-reported gout at baseline compared with those without a history of gout 64.

Diuretic use is a significant risk factor for the development of gout but this relationship is potentially confounded by the indication for diuretic therapy, such as hypertension, renal disease and cardiac failure, which may also predispose to gout. Diuretic-induced hyperuricaemia occurs via inhibition of renal urate excretion at the low-affinity asymmetric urate transporter, organic anion transporter 4 (OAT4) 65. Diuretics have been shown to be a risk factor for incident gout in men in the HPFS (RR = 1.77, 95% CI = 1.42, 2.20) 63 and in both sexes in the Framingham Heart Study (men RR = 3.41, 95% CI = 2.38, 4.89; women RR = 2.39, 95% CI = 1.53, 3.74) 29 after adjustment for multiple confounders, including hypertension. An association between diuretic use and gout was also seen in the UK-GPRD (OR = 1.72, 95% CI = 1.67, 1.76, adjusted for age and sex but not hypertension) 13. In contrast, a Dutch case-control study did not find an association between incident gout and prior diuretic use (incidence rate ratio = 0.6, 95% CI = 0.2, 2.0), although the study was small (70 gout cases) and several important confounding variables were not adjusted for 66. Diuretic use also predisposes to recurrent acute gout. In the Internet cross-over study described above, diuretic use in the preceding 48 hours was associated with acute attacks of gout (OR = 3.6, 95% CI = 1.4, 9.7) 67.

Chronic renal disease is an important risk factor for gout. It was associated with gout in both the HPFS (RR = 3.61, 95% CI = 1.60, 8.14, adjusted for multiple confounders including diuretic use) 63 and the UK-GPRD (age-adjusted and sex-adjusted OR = 4.95, 95% CI = 4.28, 5.72) 13. Gout can be particularly challenging in patients with end-stage renal disease or following renal transplantation. A retrospective study of 259,209 patients registered in the US Renal Data System found the incidence of gout to be 5.4% in the first year of dialysis and 15.4% in the first 5 years 68. In the UK-GPRD, gout was associated with both renal transplantation (OR = 25.13, 95% CI = 12.97, 48.68) and cyclosporin use (OR = 7.93, 95% CI = 5.97, 10.54), although risk estimates were only adjusted for age and sex 13.

Gout shows a striking predilection to affect certain joints, most strikingly the first MTP joint. Although it is not known why gout demonstrates such a characteristic pattern, the first MTP joint is also a target joint for OA and it has been postulated that MSU crystals may deposit more readily in osteoarthritic cartilage 69. Radiographic and clinical studies support the tendency of gout to occur at joints already affected by OA. A Polish hospital-based study of 262 subjects with gout found the presence of gout and radiographic OA to be significantly correlated at the first MTP joints, tarsal joints and knees 70. More recently, a community-based study of 164 subjects with gout found a strong association between sites of acute attacks of gout and the presence of clinical OA (multivariate OR = 7.94, 95% CI = 6.27, 10.05), especially at the first MTP joints, tarsal joints, knees and finger distal interphalangeal joints 71. Such cross-sectional associations cannot differentiate whether OA predisposes to or arises from MSU crystal deposition. The association between gout and OA at individual joint sites was not affected by gout duration 71, however, which does not support the latter hypothesis. Nodal OA was no more frequent in gout subjects than control subjects without gout from the same community 72. These findings suggest that OA predisposes to local MSU crystal deposition in individuals with gout, but is not a risk factor for gout per se.