Gout-associated genetic factors increase the risk of gout by nearly two and a half times among people with a close family history of the disease. The risk is approximately three 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 four times higher, according to a large population-based study from South Korea.
The increased familial risk of 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 of 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 Over 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 over 50 million people (the National Health Insurance database), as well as the National Health Screening Program (NHSP) 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 of 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 due to interaction of two 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 two drinks per week and at least five drinks on any day; for women, heavy drinking was defined as having at least two drinks per week and at least four 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 <30 kg/m2, and obesity was defined as BMI of ≥30 kg/m2.
Kim and co-authors note that both high BMI and heavy drinking were associated with an increased risk of 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 of 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, compared with 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, one 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.”
Kim and co-authors have disclosed no relevant financial relationships. Abhishek has received institutional research grants from AstraZeneca and Oxford Immunotech and personal fees from UpToDate, Springer, Cadilla Pharmaceuticals, NGM Bio, Limbic, and Inflazome. Rothschild has disclosed no relevant financial relationships.
Arthritis Care Res. Published online January 30, 2023. Abstract
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