Genes and Obesity Tied to Higher Gout Risk in Women Save

Excess adiposity and genetic predisposition both contributed to risk of gout among U.S. women, with the risks being highest when both factors are present, a large prospective study found.

Analysis of data from the Nurses' Health Study (NHS) found that the relative risk for incident gout was 1.49 (95% CI 1.42-1.56) per 5 kg/m2 increase in BMI and was 1.43 (95% CI 1.35-1.52) per standard deviation increase in genetic risk score, according to Hyon K. Choi, MD, of Massachusetts General Hospital in Boston, and colleagues.

But among women with high BMI plus higher genetic risk scores, the relative risk was 2.18 (95% CI 2.03 to 2.36), they reported in the Annals of the Rheumatic Diseases.

"Gout, the most common inflammatory arthritis, leads to excruciatingly painful flares and joint damage and an excess burden of cardiometabolic-renal comorbidities. Indeed, the global burden of gout and comorbidity has increased in recent decades, disproportionately so among women," the authors wrote.

And while some cross-sectional data have linked adiposity and genetics with gout, no prospective studies have examined the risks for these factors among women specifically.

Choi and colleagues investigated the potential contribution of adiposity and genetics among women enrolled in NHS I and II, and also compared them with risks for men in the Health Professionals Follow-Up Study (HPFS).

The genetic risk score was constructed from 114 single nucleotide polymorphisms (SNPs) known to influence serum urate levels.

The analysis included 18,244 women from the NHS I whose mean age was 47, 8,246 women from the NHS II whose mean age was 37, and 10,888 men from the HPFS whose mean age was 54.

During a total follow-up of more than 1 million person-years, there were 1,360 cases of incident gout in NHS I and 188 cases in NHS II, with rates of obesity being 41% and 57% at the time of diagnosis, respectively.

In multivariate analyses, after adjustment for factors such as age, blood pressure, menopausal status, and diet, higher rates of adiposity and higher genetic risk scores were both significantly associated with gout in women. For instance, the relative risk for women in the highest BMI category (≥35) versus those in the lowest BMI category (<23) was 4.86 (95% CI 3.96-5.95), and the relative risk for those with the highest genetic risk score versus the lowest was 2.89 (95% CI 2.40-3.47).

There also was an additive interaction between the two risk factors for women, with the attributable proportions of the joint effect being 42% for BMI alone, 37% for genetic score alone, and 22% for the interaction of the two.

In contrast, among men in the HPFS, who had lower rates of obesity (21%) than women, the attributable proportions were 44% for BMI alone, 42% for genetic risk score alone, but with an additive interaction of only 14% for the two.

Further analysis revealed additive interactions between adiposity and the two strongest individual gout SNPs, with relative risks due to the interaction being 0.21 (95% CI 0.13-0.29) for SLC2A9 and 0.23 (95% CI 0.08-0.38) for ABCG2.

The investigators noted that the potential mechanisms for the interaction between risk factors in women remain to be established, but may include higher rates of obesity, which is associated with inflammatory markers and adipokines that may influence the inflammatory response to urate crystals.

The results of this study are similar to what was seen in the Global Burden of Disease Study, which demonstrated a notable increase in gout burden among women from 1990 to 2017.

"From a public health standpoint, our findings reinforce adiposity as a major target for reducing the incidence and burden of female gout, with its higher frequencies of coronary heart disease, type 2 diabetes, and other cardiometabolic-renal comorbidities than male gout, particularly for women born with a greater genetic predisposition to developing this disease," Choi and colleagues observed.

In addition, the investigators noted that an analysis of their Dietary Intervention Randomized Controlled Trial, three healthy weight loss diets (Mediterranean, low-carbohydrate, low-fat) all were associated with not only body weight reductions but also pronounced declines in serum urate levels.

"These findings suggest that addressing excess adiposity could prevent a large proportion of female gout cases," they concluded.

A study limitation was the possibility of residual confounding, as is the case for observational studies in general.

Nancy Walsh earned a BA in English literature from Salve Regina College in Newport, R.I.

Source Reference: McCormick N, et al "Impact of adiposity on risk of female gout among those genetically predisposed: sex-specific prospective cohort study findings over >32 years" Ann Rheum Dis 2021; doi:10.1136/annrheumdis-2021-221635.