Background/Purpose: Although the etiopathogenesis of osteoarthritis of the knee remains largely unknown, it is clear that genetic risks are contributory. Traditional family, twin, case control and GWAS designs have all contributed to the extensive knowledge in this area. Recently, groups have reported that mitochondrial genes are involved (1) and not-involved (2) in OA risk. The Utah Population Database (UPDB), a unique genealogic resource housed at the University of Utah has previously been used to study large founder pedigrees for evidence of many heritable diseases and we have used it to examine traditional Mendelian inheritance in OA of the knee. We hypothesized that these pedigrees could also be used to assess the potential role of non-Mendelian inheritance, specifically mitochondrial inheritance on the development of OA of the knee by comparing the statistical measures of mitochondrial models (MP) to autosomal models (AP) in these same founder families.

Methods: All OA cases who underwent TKA in Utah were selected based on billing codes in the International Classification of Diseases and data pulled from statewide hospital discharge data for a ten year period (1996-2007). Cases and controls matched for gender and age and their families were linked to the UPDB for analysis. The software kinship analysis tool (KAT) was used to analyze mitochondrial (MP) with autosomal (AP) by comparing familial standardized incidence ratio (FSIR) under each inheritance models. 

Results:

Over 18,000 OA patients who underwent TKA in Utah hospitals were linked to the UPDB and analysis performed for mitochondrial inheritance. The linkage resulted in 683 founder families with at least 5 affected members for analysis in comparison to randomly selected control families.

Pattern	FSIR	Extended Bayes FSIR	PAR
Autosomal Pattern	1	1.75 (1.61-1.91)	0.21 (0.18-0.24)
Mitochondrial Pattern	1.015	1.77 (1.61-1.96)	0.14 (0.12-0.15)

MP had a very low population-attributable risk, PAR value, 14, where AP has a higher value of 0.21. It suggested approximately *% of the population who have OA of the knee could be from mitochondrial inheritance, whereas 21 percent of OA of the knee resulting in TKA are familial.

Conclusion:

The UPDB is a resource that has confirmed a Mendelian heritable risk for OA of the knee with a PAR of 21%. Now, it has also been used to shown non-Mendelian, in particular mitochondrial inheritance is not likely responsible for a large fraction of the heritability of OA of the knee severe enough to result in TKA as its associated PAR is 14. 

1.              Rego-Perez I, Fernandez-Moreno M, Fernandez-Lopez C, Arenas J, Blanco FJ. Mitochondrial DNA haplogroups: role in the prevalence and severity of knee osteoarthritis. Arthritis Rheum. 2008;58(8):2387-96.

2.              Hudson G, Panoutsopoulou K, Wilson I, Southam L, Rayner NW, Arden N, et al. No evidence of an association between mitochondrial DNA variants and osteoarthritis in 7393 cases and 5122 controls. Ann Rheum Dis. 2013;72(1):136-9.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/is-there-a-role-for-non-mendelian-inheritance-in-severe-osteoarthritis-of-the-knee/