Clinical Context

Gout can be associated with significant chronic pain and disability, and the authors of the current study review risk factors for gout. These risk factors include male sex and overweight/obesity, along with Black race and alcohol consumption.

Family history is also a risk factor for gout. Genes that encode the urate transporters SLC2A9, SLC22A12, and ABCG2 are of particular interest in the pathology of gout. Approximately 10% of patients with gout have a family history of the disease, and first-degree relatives of adults with gout have an approximate 2-fold increase in the risk of developing gout themselves.

Still, the estimates of familial risk for incident gout can vary widely. The authors of the current study investigate the risk for gout associated with a positive case in a first-degree relative and how a family history of gout might modify other known gout risk factors.

Study Synopsis and Perspective

Gout-associated genetic factors increase the risk for gout by nearly 2 and a half times among people with a close family history of the disease. The risk is approximately 3 times higher among people with a family history of gout who are also heavy drinkers; for people with a family history of gout who are also overweight, the risk is 4 times higher, according to a large, population-based study from South Korea.

The increased familial risk for gout (hazard ratio [HR], 2.42) dropped only slightly after adjustment for lifestyle and biological risk factors (HR, 2.29), suggesting that genes are the key drivers for the risk for gout among first-degree relatives.

Risk was highest among individuals with an affected brother (HR, 3.00), followed by father (HR, 2.33), sister (HR, 1.97), and mother (HR, 1.68).

“Although the familial aggregation of gout [where a first-degree relative has the disease] is influenced by both genetic and lifestyle/biological factors, our findings suggest that a genetic predisposition is the predominant driver of familial aggregation,” first author Kyoung-Hoon Kim, PhD, from Health Insurance Review and Assessment Service, Wonju-si, South Korea, and colleagues write in Arthritis Care and Research.

However, lifestyle is still important, as suggested by comparisons with members of the general population who do not have a family history of gout or a high body mass index (BMI). The risk increased for persons with a family history of gout who were also overweight (HR, 4.39), and it increased further for people with obesity (HR, 6.62), suggesting a dose-response interaction, the authors write.

When family history was combined with heavy alcohol consumption, the risk rose (HR, 2.95) in comparison with the general population who had neither risk factor.

The study fills a gap in evidence on “familial risk of gout as opposed to hereditary risk of gout, which has long been recognized,” the researchers write.

In addition, the findings suggest the possibility of a dose-dependent gene-environment interaction, “as the combination of both a family history of gout and either high BMI or heavy alcohol consumption was associated with a markedly increased risk of disease, which was even further elevated among obese individuals.”

Abhishek Abhishek, MD, professor of rheumatology and honorary consultant rheumatologist at Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom, reflected on the minimal attenuation after adjustment for lifestyle and demographic factors. “This suggests that most of the familial impact is, in fact, genetic rather than due to shared environmental factors, and is an important finding.”

He told Medscape Medical News that the findings also confirmed the synergistic effect of genetic and lifestyle factors in causing gout. “Lifestyle factors such as alcohol excess and obesity should be addressed more aggressively in those with a first-degree relative with gout.

“Although not directly evaluated in this study, aggressive management of excess weight and high alcohol consumption may prevent the onset of gout or improve its outcomes in those who already have this condition,” he added.

Study of More Than Five Million Individuals With Familial Aggregation of Gout

The researchers drew on data from the government-operated mandatory insurance service that provides for South Korea’s entire population of more than 50 million people (the National Health Insurance database), as well as the National Health Screening Program database. Information on familial relationships and risk factor data were identified for 5,524,403 individuals from 2002 to 2018 who had a blood-related first-degree relative.

Familial risk was calculated by comparing the risk for individuals with and those without affected first-degree relatives. Interactions between family history and obesity or alcohol consumption were assessed using a scale that measured gout risk resulting from interaction of 2 factors.

Initially, adjustments to familial risk were made with respect to age and sex. Subsequently, possible risk factors included smoking, BMI, hypertension, and hyperglycemia.

Alcohol consumption levels were noted and categorized as nondrinker, moderate drinker, or heavy drinker, with different consumption levels for men and women. For men, heavy drinking was defined as having at least 2 drinks per week and at least 5 drinks on any day; for women, heavy drinking was defined as having at least 2 drinks per week and at least 4 drinks on any day.

Overweight and obesity were determined on the basis of BMI, using standard categories: overweight was defined as BMI of 25 to less than 30 kg/m², and obesity was defined as a BMI of 30 kg/m² or more.

Dr Kim and coauthors note that both high BMI and heavy drinking were associated with an increased risk for gout, regardless of whether there was a family history of the disease, and that the findings suggest “a dose-dependent interactive relationship in which genetic factors and obesity potentiate each other rather than operating independently.”

People who are both overweight and have a family history of disease had a combined risk for gout that was significantly higher than the sum of their individual risk factors (HR, 4.39 vs 3.43). This risk was accentuated among people with obesity (HR, 6.62 vs 4.74) and was more pronounced in men than in women.

In other risk analyses in which familial and nonfamilial gout risk groups were compared, the risk associated with obesity was higher in the familial group compared with the nonfamilial group (HR, 5.50 vs 5.36).

Bruce Rothschild, MD, a rheumatologist with Indiana University Health, Muncie, Indiana, and research associate at Carnegie Museum of Natural History, Pittsburgh, Pennsylvania, shared his thoughts on the study with Medscape Medical News and noted some limitations: “The findings of this study do not conflict with what is generally believed, but there are several issues that complicate interpretation,” he began. “The first is how gout is diagnosed. Since crystal presence confirmation is rare in clinical practice, and by assumption of the database used, diagnosis is based on fulfilment of a certain number of criteria, 1 of which is hyperuricemia--this is not actual confirmation of diagnosis.”

He pointed out that the incidence of gout depends on who received treatment, and the study excluded those who were not receiving treatment and those who were not prescribed allopurinol or febuxostat. “Single parents were also excluded, and this may also have affected results.

“Overweight and obesity were not adjusted for age, and the interpretation is age-dependent,” he added. “It really comes down to the way gout is diagnosed, and this is a worldwide problem because the diagnosis has been so dumbed down that we don’t really know what is claimed as gout.”

Dr Kim and coauthors have disclosed no relevant financial relationships. Dr Abhishek has received institutional research grants from AstraZeneca and Oxford Immunotech and personal fees from UpToDate, Springer, Cadilla Pharmaceuticals, NGM Bio, Limbic, and Inflazome. Dr Rothschild has disclosed no relevant financial relationships.

Arthritis Care Res. Published online January 30, 2023.^[1]

Clinical Implications

• Known risk factors for gout include male sex and overweight/obesity, along with Black race and alcohol consumption. Approximately 10% of patients with gout have a family history of the disease, and first-degree relatives of adults with gout have an approximate 2-fold increase in the risk of developing gout themselves.
• In the current study, having a first-degree relative with gout was associated with an HR for gout of 2.42. Overweight/obesity and alcohol consumption further increased the risk for gout beyond family history, with particular synergy between overweight and family history.
• Implications for the healthcare team: The healthcare team should work with patients with a family history of gout to reduce modifiable risk factors such as alcohol consumption and overweight/obesity.

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