High Genetically-predicted BMI Raises Risk for Rheumatoid Arthritis, Study Suggests

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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Having a higher genetic likelihood for greater body mass index (BMI), a measure of body fat, increases the risk for rheumatoid arthritis (RA), according to an analysis of data of more than 700,000 people.

The study, “Obesity‐related traits and the development of rheumatoid arthritis — evidence from genetic data,” was published in the journal Arthritis & Rheumatology.

RA is a chronic autoimmune disease in which the immune system wrongly attacks the joint linings, potentially causing bone erosion and deformities in joints.

Although researchers have found more than 100 gene spots, as well as several environmental risk factors linked to RA, the mechanisms underlying the disease are not fully understood.

A potential risk factor for RA is obesity, a condition that leads to a chronic, low-grade inflammatory status.

Adipocytes, major energy reservoirs of the body, play a role in hormone production. These cells secrete a number of adipokines, which are key molecules in the regulation of inflammation and autoimmunity.

Previous large studies have suggested that people with higher BMI have a 3% to 12% increased risk for developing RA.

A potential link between three obesity traits — BMI, waist-to-hip ratio (WHR), and WHR adjusted for BMI (WHRadjBMI) — and the risk of RA was investigated in the new study, conducted by researchers at the Karolinska Institute in Sweden and Harvard University in the U.S.

The team analyzed the largest genome-wide association study (GWAS) for obesity-related measures, taking together data from the UK Biobank and the GIANT consortium that included a total of around 700,000 individuals. All participants had European ancestry. GWAS allows researchers to find small variations in genes that occur more frequently in people with certain traits or diseases.

The scientists used an approach called mendelian randomization, which provides an unbiased estimate of the causal relation between genetic variability and risk.

They first observed that the three obesity measures — BMI, WHR, and WHRadjBMI — were strongly correlated with each other. Also, the team found a high genetic similarity between men and women for each trait.

When they conducted an overall and a sex-specific analysis, the researchers did not find a shared genetic basis between obesity traits and RA.

However, when they looked at specific locations in the genome (divided in 1,703 regions), they observed significant genetic correlations in various regions of chromosome 6 and chromosome 19 with RA.

Further correlations were also found in chromosomes 8 and 16 in women only.

Then, the investigators observed a 20% increased risk for RA for every 4.8 kg per square meter increase in BMI.

In contrast, “we did not find any association between genetically predicted WHR and RA,” the researchers wrote. Likewise, no relationship was found between RA and WHRadjBMI.

Because women are two to three times more likely to have RA, the researchers conducted an analysis of BMI and WHR that might explain that difference. They found that the BMI link with RA was similar between men and women, and although WHR had an increased effect in men, such difference was not significant.

“Our study demonstrates a putative causal relationship between BMI and risk of RA, which provides novel insights into the disease mechanism of RA and provides an actionable prevention strategy,” the researchers wrote.

“Future [mendelian randomization] analysis should also be carried out to explore treatment strategy and prognosis of RA in addition to disease onset,” they concluded.

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