NEW YORK – New research suggests the genetic overlap between type 2 diabetes (T2D) and osteoarthritis has ties to excess adiposity or obesity involving pathways for metabolic processes and skeletal development.
"Multimorbidity is becoming a significant challenge in the healthcare system as life expectancy continues to rise worldwide," Eleftheria Zeggini, a translational genomics researcher affiliated with Helmholtz Munich and the Technical University of Munich, said in an email, noting that that the "most common multimorbidity patterns worldwide are a combination of cardiometabolic and osteoarticular diseases."
For a study published in the American Journal of Human Genetics on Monday, Zeggini and colleagues from Germany and the UK brought together genotyping, multiomics, and functional data to explore the comorbidity between T2D and osteoarthritis.
"Both diseases are known to be epidemiologically positively correlated, and we demonstrated that part of this correlation is due to a shared genetic etiology," Zeggini explained, adding that the current findings "identify a genetic link between the studied comorbidity and obesity, providing proof-of-concept insights to the well-known epidemiological association between type 2 diabetes, osteoarthritis, and increased adiposity."
The investigators considered data from prior genome-wide association analyses on nearly 826,700 cases or controls, including 117,517 affected individuals with knee and/or hip osteoarthritis or a history of total knee replacement, total hip replacement, or total joint replacement surgeries. They also analyzed GWAS meta-analysis data from a past study that involved more than 898,100 individuals of European ancestry with or without T2D.
The team's Mendelian randomization causal inference analyses "showed evidence for a non-causal relationship between the two diseases," though the genetic correlation between knee osteoarthritis and T2D was more pronounced than the genetic overlap between hip osteoarthritis and T2D.
Together with available quantitative trait locus profiles for disease-related tissue types such as intact or degenerated cartilage, synovium, or pancreatic islet cells, along with RNA sequence and functional data, the genetic risk variant sets highlighted 18 T2D- and osteoarthritis-linked loci. Of those, 10 loci coincided with both hip and knee osteoarthritis and T2D, while the remaining loci were associated with T2D and one form of osteoarthritis.
With the combination of multiomics and functional data, the researchers analyzed more than 900 genes at sites near the risk loci, identifying an overrepresentation of suspected effector genes in pathways involved in metabolism, lipid storage and lipid localization pathways, cell differentiation, and skeletal formation.
After narrowing in on a high-confidence effector gene set of 19 genes, the investigators incorporated association data from the Online Mendelian Inheritance of Man catalog — as well as published data on adiposity genetics and cartilage or pancreatic tissue gene expression — to get a handle on the obesity and adiposity component of the genetic overlap.
Overall, the results highlighted the role that higher-than-usual adiposity may play in both T2D and osteoarthritis, Zeggini said. In particular, the team saw potential comorbidity-related roles for Wnt/beta-catenin pathway signaling and imbalanced osteoblast and adipocyte differentiation in the bone marrow.
She noted that the genes found so far "highlight drug repurposing opportunities in addition to new targets" and suggested that a similar strategy may be used to dig into the roots of other comorbid disease combinations in the future.
"[T]his approach is applicable to any combination of comorbid diseases and can help improve our understanding of the co-occurrence of chronic conditions," Zeggini said.