Approved Research

Examination of body mass index and inflammation as contributors to end stage osteoarthritis

Lay summary

Osteoarthritis (OA) is a debilitating disease that results in long term pain and mobility issues. Current treatment strategies are focused on managing symptoms only. There are currently no successful preventative interventions. The lack of effective disease prevention strategies is due to our lack of understanding of the factors that cause disease. Previous studies have identified associations between environmental factors such as obesity, inflammation, and injury history. However, the complex interrelationships between these factors has created many challenges in differentiating between factors that cause OA from factors that are caused by OA. Mendelian randomization is a research design that uses genetic variation to understand independent causal relationship between risk factors and onset of disease. Mendelian Randomization (MR) works like a pseudo clinical trial to test for association between a modifiable risk factor and disease. We will use this design to understand the independent role of obesity, inflammation, and prior injury on the development of OA. The goal of this work is to identify risk factors that can be targeted in future studies to prevent the onset and progression of osteoarthritis.

We anticipate this project will take 12-18 months to complete. This project has important public health implications. OA is lifelong condition that results in substantial pain, limits mobility, and is associated with onset of chronic health conditions that can reduce an individual's life expectancy. Current treatment strategies are focused on managing symptoms. Total joint arthroplasty is an effective intervention strategy but is invasive and very costly. There is a strong need to identify modifiable risk factors that delay or prevent OA progression. This protocol aims to identify modifiable risk factors (inflammation and obesity) and furthermore, aims to identify high risk individuals (prior injury history) that can be targeted in follow-up studies aimed at preventing severe disease.

We propose the following changes to our aims. (1) In aims 2 and 3, in addition to inflammation and BMI, we will also test the following exposures: hip to waist ratio, fat mass, IL-6 receptor signaling, PTH receptor variation, and IGF1. All exposures will be defined based on prior GWAS. (2) We will perform a full GWAS to test whether prior lower limb injury modifies association between genetic variation and OA onset (SNP*prior injury), Aim 4. (3) We will perform a full GWAS to test whether BMI modifies the association between genetic variation and OA onset (SNP*BMI), Aim 5. BMI will be defined based on measured BMI as well as genetically predicted BMI. (4) We will test whether inflammation mediates the association between BMI and OA (BMI and inflammation will be defined using the genetic instruments). (5) In all aims, we will expand our outcome to also include hand OA. In summary, we have expanded our outcome to include hand OA and have expanded our list of exposures to include hip to waist ratio, fat mass, IL-6 receptor activity, PTH receptor activity, and IGF1. The proposed changes do not require a modification to the data that have already been released.