Research led by the University of Exeter on a large group of people from the UK Biobank shows that carriers of certain genetic mutations are more likely to have an adverse reaction to oral corticosteroid medications.
The researchers found that a variant in the CYP3A4 gene raised osteoporosis risk and a variant in the CTLA4 gene increased the risk for multiple adverse outcomes including stroke and cataracts.
People with these variants were also more likely to have a higher cumulative exposure to corticosteroids over time, suggesting that genetic differences may blunt the clinical benefit of standard steroid doses, so they end up needing more treatment over time and therefore being at even higher risk of adverse events.
“We were also able to show a clear relationship between the dose of steroid and side effects,” said Deniz Turkmen, PhD, a postdoctoral researcher at the University of Exeter, who presented the work at the European Society of Human Genetics conference in Gothenberg this week. “This precise analysis shows the increased risk associated with long-term treatment.”
Oral corticosteroids are an effective and very common medication used to target excessive inflammation. They are widely used to treat conditions such as asthma, rheumatoid arthritis, lupus, and other autoimmune diseases, as well as severe allergies and some acute respiratory infections.
In the U.S., millions of people take oral steroid tablets each year, and roughly one in 100 adults is on them at any given time. However, even short courses can increase the risk of health problems like infections, fractures and blood clots, and long‑term use is linked to osteoporosis, diabetes, weight gain and cataracts, among other adverse effects.
Around one in 10 people are estimated to have side effects to these medications, but it has been difficult to predict who will respond poorly, which triggered Turkmen and colleagues to look into the genetics of how these drugs are metabolized.
In this study, the team evaluated information from almost 38,000 participants from the UK Biobank. These individuals had primary‑care prescriptions for oral corticosteroids for inflammatory and autoimmune conditions.
For each person, Turkmen and colleagues calculated cumulative steroid dose up to the point they had an adverse event or a follow‑up appointment. They also modelled dose–response relationships with outcomes such as osteoporosis, stroke and cataracts. In total, 21 candidate pharmacogenetic variants were assessed.
Median cumulative exposure to corticosteroid in the study was around 1.5 g. Increasing this dose from 1.5 g to 4.0 g was associated with an approximate 50% higher risk of osteoporosis. Variants in the genes CYP3A4 and CTLA4 were associated with higher cumulative dose and increased risk of adverse outcomes, but only in steroid‑treated individuals, consistent with pharmacogenetic effects on steroid metabolism and immune regulation.
Adding polygenic scores to the evaluation including multiple variants for osteoporosis‑related traits significantly improved prediction of steroid‑related osteoporosis beyond age and sex, with particular improvements seen in individuals under the age of 40 at first prescription.
A genome wide association study identified an area on the genome (HLA‑DQA1) where the allele linked to lower cumulative oral corticosteroid dose was not associated with adverse outcomes, hinting at biology that reduces steroid need without obvious toxicity signals.
“It was reassuring that the genetic findings involving CYP3A4 and CTLA4 aligned with their roles in steroid metabolism and immune regulation, but the improvement in prediction of osteoporosis when we incorporated polygenic risk scores data was remarkable, especially in younger patients,” said Turkmen.
“We hope that, in time, greater availability of genetic data at population level will mean that it will be possible to integrate genomics into everyday healthcare and hence into prescribing decisions. That will be a major step on the road to the provision of personalized medicine for all.”
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