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Choi HK, Atkinson K, Karlson EW, Curhan G. Obesity, Weight Change, Hypertension, Diuretic Use, and Risk of Gout in MenThe Health Professionals Follow-up Study. Arch Intern Med. 2005;165(7):742–748. doi:10.1001/archinte.165.7.742
Copyright 2005 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2005
Limited prospective information exists on the relation between obesity and weight change and the risk of gout. Similarly, both hypertension and diuretic use have been considered risk factors for gout; however, their independent contributions have not been established prospectively.
We prospectively examined over a 12-year period (1986-1998) the relation between adiposity, weight change, hypertension, and diuretic use and incident gout in 47 150 male participants with no history of gout at baseline. We used a supplementary questionnaire to ascertain the American College of Rheumatology criteria for gout.
During 12 years we documented 730 confirmed incident cases of gout. Compared with men with a body mass index (BMI) of 21 to 22.9, the multivariate relative risks (RRs) of gout were 1.95 (95% confidence interval [CI], 1.44-2.65) for men with a BMI of 25 to 29.9, 2.33 (95% CI, 1.62-3.36) for men with a BMI of 30 to 34.9, and 2.97 (95% CI, 1.73-5.10) for men with a BMI of 35 or greater (P for trend <.001). Compared with men who had maintained their weight (±4 lb) since age 21 years, the multivariate RR of gout for men who had gained 30 lb or more since age 21 years was 1.99 (95% CI, 1.49-2.66). In contrast, the multivariate RR for men who had lost 10 lb or more since the study baseline was 0.61 (95% CI, 0.40-0.92). The multivariate RRs of gout were 2.31 (95% CI, 1.96-2.72) for the presence of hypertension and 1.77 (95% CI, 1.42-2.20) for diuretic use.
Higher adiposity and weight gain are strong risk factors for gout in men, while weight loss is protective. Hypertension and diuretic use are also important independent risk factors for gout.
Gout is the most common inflammatory arthritis in adult men, affecting up to 3.4 million men in the United States.1,2 Although several prospective cohort studies have evaluated the association between obesity and gout,1,3-5 lack of data and a small number of gout cases have limited the comprehensive adjustment of relevant covariates. Specifically, no prospective information is available on the risk of gout associated with obesity after adjusting for dietary factors, which themselves may be risk factors for gout and vary with adiposity. Furthermore, most studies have analyzed the impact on the risk of gout of a single measurement of adiposity variables and hence have not assessed the importance of updating these variables over time.
A single study is available on the hazardous impact of weight gain on the risk of gout specifically in young adulthood.1 No other prospective study has supported or refuted the finding and no prospective information is available on the impact of weight gain later in life. Furthermore, important questions remain about the potential effect of weight loss on the incidence of gout. Since overweight and obesity are epidemic and their prevalence continues to rise,6 an accurate understanding of their impact on this common arthritis is essential.
Hypertension has been recognized as a risk factor for gout, and diuretic use has been shown to elevate serum uric acid levels.1,7,8 However, no prospective study has demonstrated the independent contributions to the risk of incident gout, primarily because of their tight association (ie, diuretics are often used to treat hypertension) and small study samples. Additionally, since hypertension is associated with other risk factors for gout (eg, adiposity, dietary/nutritional factors, alcohol intake, and chronic renal failure), it is important to adjust for them to examine hypertension as an independent risk factor for gout. Since hypertension and diuretic use are also common, a quantitative assessment of their impact on the risk of gout is important.
To examine these issues, we prospectively evaluated the relations between body mass index (BMI), weight change, hypertension, and diuretic use and incident gout in a cohort of 47 150 men with no history of gout.
The Health Professionals Follow-up Study is an ongoing longitudinal study of 51 529 male dentists, optometrists, osteopaths, pharmacists, podiatrists, and veterinarians who were predominantly white (91%) and were aged 40 through 75 years in 1986. The participants returned a mailed questionnaire in 1986 concerning diet, medical history, and medications. Of the 49 932 men who provided complete information on diet and age, 2782 (5.6%) reported a history of gout on the baseline questionnaire. These prevalent cases at baseline were excluded from this analysis.
Height, current weight, and weight at 21 years old were reported by men in 1986. In addition, participants reported their current weight on the biennial mailed questionnaires. Waist-to-hip ratio was assessed in 1987. We calculated BMI as the weight in kilograms divided by the square of the height in meters. Weight change since age 21 years was calculated by subtracting the current weight (updated biennially) from the weight at age 21 years. Weight change since baseline was calculated by subtracting the current weight (1988 and onward) from the weight reported in 1986. We evaluated the accuracy of self-reported anthropometric measures among 123 Health Professionals Follow-up Study participants by having trained technicians visit those participants twice (6 months apart) to measure current weight.9 After adjustment for age and within-person variability, the Pearson correlations between self-report and the average of the two technician measurements were 0.97 for weight, 0.95 for waist circumference, and 0.88 for hip circumference.9
The baseline and biennial follow-up questionnaires inquired about physician-diagnosed hypertension. In this cohort, the diagnosis of hypertension is reported reliably, and self-reported blood pressure is a strong predictor of stroke.10 A study participant was considered to have hypertension from the time it was first reported on the questionnaire. Similarly, at baseline and every 2 years thereafter, the participants provided information on regular use of medications, including use of diuretics. The follow-up rate for this cohort was greater than 90% during the study period.
To assess dietary intake, we used a semiquantitative food-frequency questionnaire that inquired about the average use of more than 130 foods and beverages, including alcohol intake, during the previous year.11,12 The baseline dietary questionnaire was completed in 1986, and dietary information was updated in 1990 and 1994. Nutrient intake was computed from the reported frequency of consumption of each specified unit of food or beverage and from published data on the nutrient content of the specified portions.12 The reproducibility and validity of this dietary questionnaire in this cohort have been previously reported.11,13 The baseline and biennial follow-up questionnaires inquired about new onset of physician-diagnosed chronic renal failure, which was used as a covariate in our analyses.
On each biennial questionnaire, participants indicated whether they had received a physician diagnosis of gout. In 2001, we mailed to those subjects with self-reported incident gout between 1986 and 1998 (n = 1332) a supplementary questionnaire to confirm the report and to ascertain the American College of Rheumatology survey gout criteria.14 The primary end point in this study was an incident case of gout that met 6 or more of the 11 gout criteria.14 The response rate for the supplementary gout questionnaire was 80%, and 69% of the participants with self-reported gout who returned the questionnaire met the primary end point (n = 730). To confirm the validity of the survey gout criteria in our cohort, we reviewed the relevant medical records from a sample of 50 of the men who had reported having gout. The concordance rate of the gout survey criteria and the medical record review was 94% (47/50).
We computed person-time of follow-up for each participant from the return date of the 1986 questionnaire to the date of diagnosis of gout, death from any cause, or the end of the study period, whichever came first.
We used Cox proportional hazards modeling (PROC PHREG) to estimate the relative risk (RR) for incident gout in all multivariate analyses (SAS Institute Inc, Cary, NC). We grouped BMI values in 6 categories: less than 21, 21 to 22.9, 23 to 24.9, 25 to 29.9, 30 to 34.9, and 35 or greater. The last 3 categories were classified as overweight, obesity class 1, and obesity class 2, respectively, by the World Health Organization, Geneva, Switzerland.15 We grouped weight change values in 7 categories: more than −10 lb, −10 to −5 lb, −4 to +4 lb, +5 to +9 lb, +10 to +19 lb, +20 to +29 lb, and +30 lb or more (to convert pounds to kilograms multiply by 0.45). In addition, waist-to-hip ratios were categorized in quintiles. Presence of hypertension and use of diuretics were used as indicator exposure variables. Multivariate models were adjusted for age (continuous), total energy intake (continuous), presence of chronic renal failure (yes or no), meat intake (quintiles), seafood intake (quintiles), purine-rich vegetable intake (quintiles), dairy food intake (quintiles), alcohol intake (7 categories), animal protein intake (quintiles), and fluid intake (quintiles). Trends in BMI and weight changes were assessed in Cox proportional hazards models by using the median values for each category to minimize the influence of outliers. We calculated 95% confidence intervals (CIs) for all RRs. All P values are 2-sided.
We calculated the population-attributable risk,16,17 an estimate of the percentage of gout cases in this population that would theoretically not have occurred if the BMI had been lower than 23, assuming a causal relation between BMI and incident gout.
There were 730 newly diagnosed cases that met the American College of Rheumatology criteria for gout during the 12-year follow-up. The baseline characteristics of the cohort according to BMI, weight gain, and waist-to-hip ratio categories are shown in Table 1. As expected, BMI, weight gain since age 21 years, and waist-to-hip ratio varied in the same direction. Body mass index tended to increase with increasing frequency of hypertension, with diuretic use, and with higher meat consumption. Weight gain since age 21 years and waist-to-hip ratio showed a similar relation with these variables. As expected, hypertension and diuretic use were tightly related and were more frequent with older age, higher BMI, higher weight, and weight gain. Other characteristics were similar across the categories.
We found a graded association between BMI updated every 2 years and the risk of gout (Table 2). Compared with those with a BMI of 21 to 22.9, the age-adjusted RRs of gout were 1.40 (95% CI, 1.00-1.95) for a BMI of 23 to 24.9, 2.35 (95% CI, 1.74-3.17) for a BMI of 25 to 29.9, 3.26 (95% CI, 2.28-4.65) for a BMI of 30 to 34.9, and 4.41 (95% CI, 2.59-7.51) for a BMI of 35 or higher (P for trend <.001). After further adjusting for other risk factors for gout, these multivariate RRs were attenuated but remained significant (P for trend <.001) (Table 2). When we used BMI from the 1986 baseline and at age 21 years, the multivariate RRs were attenuated further but remained significant (P for trend, <.001 and .002, respectively) (Table 2).
Similarly, increasing waist-to-hip ratio was associated with increasing risk of gout (Table 2). After adjusting for age, the RR for gout among men in the highest waist-to-hip ratio quintile (0.98-1.39) as compared with those in the lowest quintile (0.70-0.88) was 2.39 (95% CI, 1.83-3.13; P for trend <.001). After further adjustment for other risk factors, the RRs were attenuated but remained significant (Table 2).
As reflected in the person-year totals under weight change categories in Table 3, most men had experienced weight gain since age 21 years and only a small proportion had maintained or lost weight. In contrast, a substantially smaller proportion had gained weight since the 1986 study baseline (mean age, 54 years), and a much larger proportion had maintained or lost weight (Table 3).
There was a graded association between weight gain since age 21 years and since 1986 and the risk of gout (Table 3). After adjusting for age and weight at age 21 years, compared with men who maintained weight (±4 lb), the RR of gout was 1.57 (95% CI, 1.15-2.14) for a weight gain of 20 to 29 lb since age 21 years and 2.47 (95% CI, 1.86-3.28) for a weight gain of 30 lb or more since age 21 years (P for trend <.001). After further adjusting for other risk factors, the RRs were attenuated but remained significant. The RRs of weight gain since 1986 showed similar magnitudes with a significant trend (P for trend <.001), although the two largest categories (ie, weight gain ≥20 lb) together accounted for only 4% of total person-years (Table 3).
After adjusting for baseline weight and other risk factors for gout, men who had lost 10 lb or more since the study baseline had a 39% lower risk of gout compared with men who had maintained weight (±4 lb) (RR, 0.61, 95% CI, 0.40-0.92). Men who had lost 10 lb or more since age 21 years (accounting for 5% of total person-years) had a nonsignificantly lower risk of gout compared with men who had maintained weight (RR, 0.73; 95% CI, 0.44-1.22).
After we adjusted for potential confounders, including diuretic use, the RR of gout for men with hypertension as compared with men without hypertension was 2.31 (95% CI, 1.96-2.72) (Table 4). After adjusting for the presence of hypertension in the same model, the RR for men taking a diuretic as compared with those not taking a diuretic was 1.77 (95% CI, 1.42-2.20) (Table 4). The multivariate RR for men with chronic renal failure as compared with men without chronic renal failure was 3.61 (95% CI, 1.60-8.14). When we repeated the same analysis limited to those men without diuretic exposure during follow-up, the RR associated with hypertension did not change materially (multivariate RR, 2.28; 95% CI, 1.93-2.70), and the RR associated with chronic renal failure was larger (multivariate RR, 4.60; 95% CI, 1.88-11.25).
In our cohort, 41% of the incident gout cases were attributable to a BMI of 23 or greater. For men with a BMI of 25 or greater (overweight),15 52% of gout risk was attributable to excess weight. For men with BMI values of 30 or greater (obesity class 1)15 and 35 or greater (obesity class 2),15 60% and 66%, respectively, of gout risk was attributable to excess weight.
Our objective was to evaluate prospectively the relation between obesity and weight change and the incidence of gout in a large prospective cohort of men. We validated the self-reported cases of gout using the American College of Rheumatology criteria,14 and we found that adiposity was consistently associated with risk of gout. The risk was significantly higher for a BMI of 25 or greater (overweight15), and the magnitude of the association became larger with increasing BMI, representing a clear dose-response relation. These associations were independent of other purported risk factors for gout, such as age, diuretic use, history of hypertension or chronic renal failure, and diet.
We analyzed BMI measured at 3 different time points (age 21 years, baseline, and updated every 2 years during follow-up) and found a stronger association with gout when BMI information was updated. These findings suggest that risk of gout is more strongly influenced by current BMI than by BMI earlier in life (ie, a short-term effect).
These results expand on previous studies of adiposity and gout. The Johns Hopkins Precursor Study1 reported that an elevated BMI at age 35 years but not at baseline (mean age, 22 years) was associated with the risk of gout (RR, 1.12 for a 1-unit increase in BMI; P = .02). Small sample size (60 cases of incident gout) and lack of information on relevant variables limited a comprehensive adjustment of covariates, including dietary risk factors, and an evaluation of the impact of updated variables.1 The Normative Aging Study3 showed that BMI at baseline (mean age, 52 years) was significantly associated with hyperuricemia or gout, although the study had similar limitations. In the Framingham Study,4 there was a significantly higher BMI among gout patients after adjusting for age but no multivariate analysis results were presented. In the present study we observed a substantial attenuation of the RRs after adjustment for confounders, emphasizing the importance of multivariate models.
We found that weight gain since young adulthood was strongly associated with the risk of gout, even after adjusting for initial weight and other risk factors. These findings agree with those from the Johns Hopkins Precursor Study.1 We observed a clear dose-response relation, and men who had gained 30 lb or more had a twofold increased risk of gout compared with those who had maintained their weight. Similarly, weight gain since the study baseline (mean age, 54 years) was associated with the risk of gout.
In contrast, we found that weight loss greater than 10 lb since the 1986 study baseline was associated with a substantially reduced risk of gout. To our knowledge, our study is the first to document this important potential benefit of weight loss. By demonstrating an association between weight loss and the prevention of gout together with an association between weight gain and the development of gout, the present study makes a much stronger case for a causal relation than the previous studies. Furthermore, although these findings are based on incident gout, these findings support the current recommendation for weight reduction to prevent recurrent gout attacks.18,19 This is relevant because weight-intervention studies typically involve more than weight reduction alone (eg, manipulating diets or exercise) in a limited number of subjects,20 and therefore it is difficult to isolate the effect of weight reduction from those other interventions.
It is likely that higher BMI increases the risk of gout by increasing the serum uric acid level. Hyperuricemia has been associated with obesity via both increased production and decreased renal excretion of urate.18,19 Weight gain between the first and third visits was associated with rising serum uric acid levels in the Normative Aging Study.21 Conversely, the findings of small, open-label, interventional studies suggest that weight reduction may be associated with a decline in uric acid levels.20,22 Furthermore, hyperuricemia has been associated with the insulin resistance syndrome.23-25 While close associations have been reported between hyperuricemia and all components of the insulin resistance syndrome, including hyperinsulinemia, hypertension, dyslipidemia, and obesity, a large study demonstrated that BMI has the strongest correlation with hyperuricemia.25 Renal clearance of urate has been shown to have an inverse relation with both the degree of insulin resistance26 and visceral fat area as measured by abdominal computed tomography.27 Factors not related to uric acid, such as chronic joint trauma due to excess weight, have been proposed as an explanation for the association between obesity and gout.8,19
The population-attributable risk for incident gout due to increased BMI was substantial. In our cohort, 91% of gout cases occurred among men with a BMI of 23 or greater, which could explain 42% of all gout cases in this population, and men with higher BMIs showed higher attributable risk proportions, as expected. Since the prevalence of overweight and obesity continues to rise, having reached 66% for overweight (BMI ≥25) and 31% for obesity (BMI ≥30) in 1999-2000 according to the recent National Health and Nutrition Examination Survey,6 the absolute excess risk of gout due to excess weight is also expected to increase.
The presence of hypertension was strongly associated with the incidence of gout independent of diuretic use and chronic renal failure. Previous cohort studies were not able to evaluate an independent effect, possibly because of insufficient power, high correlation between hypertension and diuretic use, and lack of dietary/nutritional data.1,3,4,28 A more recent report from the Meharry-Hopkins Study had the same limitations and adjusted only for baseline BMI and race in multivariate models.5 We observed a substantial attenuation of the RRs after adjustment for confounders. Since more than half of the gout cases in our cohort occurred among those with hypertension, the potential impact of the prevention of hypertension on the incidence of gout is substantial.
Several strengths and potential limitations of our study deserve comment. Our study included the largest number of gout cases (n = 730) to date verified by the American College of Rheumatology criteria. As in other epidemiologic studies,1,3-5,28 our definition of gout did not require observation of urate crystal in joint fluid examination. Fulfillment of 6 of the 11 American College of Rheumatology survey criteria (our primary outcome definition) was associated with a sensitivity of 85% and a specificity of 93%, and there was a trade-off between the two depending on the number of the criteria required for the diagnosis.14 In our study, fulfillment of 6 of the 11 criteria14 showed a high degree of concordance with medical record review, and the incidence of gout fulfilling the criteria in our cohort closely agreed with that estimated among male physicians in the Johns Hopkins Precursor Study1 (1.5 and 1.7 per 1000 person-years, respectively). Potentially biased recall of diet was avoided in the present study because the intake data were collected before the diagnosis of gout. Our findings are most directly generalizable to men 40 years and older (the most gout-prevalent population3) with no history of gout. Whether these findings apply to women or men with existing gout remains to be studied.
In conclusion, our large prospective study indicates that increased adiposity and weight gain are strong risk factors for gout in men. In contrast, weight loss reduces the risk. Hypertension and diuretic use are also important independent risk factors for gout.
Correspondence: Hyon K. Choi, MD, DrPH, Rheumatology Unit, Bulfinch 165, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 (firstname.lastname@example.org).
Accepted for Publication: December 15, 2004.
Financial Disclosure: None.
Funding/Support: This work was supported in part by grant DK58573 from the National Institutes of Health, Bethesda, Md, and by a grant from TAP Pharmaceuticals, Lake Forest, Ill.
Acknowledgment: The authors thank Walter Willett, MD, DrPH, for his critical review of the manuscript.