Author:
Gill Robert,Liu Ming,Sun Guang,Furey Andrew,Spector Tim,Rahman Proton,Zhai Guangju
Abstract
Abstract
Background
Genomic heterozygosity has been shown to confer a health advantage in humans and play a protective role in complex diseases. Given osteoarthritis (OA) is a highly polygenic disease, we set out to determine if an association exists between OA and genomic heterozygosity.
Results
End-stage knee and hip OA patients and healthy controls were recruited from the Newfoundland and Labrador (NL) population. The Arthritis Research UK Osteoarthritis Genetics (arcOGEN) consortium database was utilized as a replication cohort. DNA was extracted from blood samples and genotyped. Individual rates of observed heterozygosity (HetRate) and heterozygosity excess (HetExcess) relative to the expected were mathematically derived, and standardized to a z-score. Logistic regression modeling was used to examine the association between OA and HetRate or HetExcess. A total of 559 knee and hip OA patients (mean age 66.5 years, body mass index (BMI) 33.7 kg/m2, and 55% females) and 118 healthy controls (mean age 56.4 years, BMI 29.5 kg/m2, and 59% female) were included in the NL cohort analysis. We found that OA had an inverse relationship with HetRate and HetExcess with odds ratios of 0.64 (95% CI: 0.45–0.91) and 0.65 (95% CI: 0.45–0.93) per standard deviation (SD), respectively. The arcOGEN data included 2,019 end-stage knee and hip OA patients and 2,029 healthy controls, validating our findings with HetRate and HetExcess odds ratios of 0.60 (95% CI: 0.56–0.64) and 0.44 (95% CI: 0.40–0.47) per SD, respectively.
Conclusions
Our results are the first to clearly show evidence, from two separate cohorts, that reduced genomic heterozygosity confers a risk for the future development of OA.
Funder
Canadian Institutes of Health Research
Arthritis Research UK
Wellcome Trust
Medical Research Council
Versus Arthritis
Horizon 2020
Chronic Disease Research Foundation
Zoe Ltd
National Institute for Health and Care Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre
The Research and Development Corporation of Newfoundland and Labrador
The Memorial University of Newfoundland Medical Research Fund
Publisher
Springer Science and Business Media LLC