Table 1.

Human genetic studies for association with hip and knee osteoarthritis

Gene	Study design, population	Protein	Function	Mechanism	Study outcome	Comment
ASPN [81, 86]	Asians	Asporin	Extracellular matrix macromolecule from proteoglycan protein family	Asporin may inhibit TGFß	ASPN is associated with DDH in Chinese	Effects shown in Asian populations
DIO2 [56, 103]	Genomewide linkage Europeans Hip OA	Deiodinase 2 (D2)	DIO2 encodes enzyme D2	D2 regulates availability of active thyroid hormone T3, important for long bone formation	DIO2 relates to both morphotype and cartilotype of the hip	First to relate gene to form to OA; SSM not related to cam/pincer?
GDF5 [57, 100]	Candidate gene Asian European	GDF5 (from TGFß superfamily and related to BMP)	GDF5 is regulator of cell growth and differentiation in both embryonic and adult tissues	GDF5 is involved in bone and joint formation and also expressed in soft tissue joint structures	Decreased GDF5 expression may lead to increased OA susceptibility [57, 76] GDF5 is associated with 17% risk increase of knee OA (OR, 1.17; 95% CI, 1.12–1.23)	GDF5 insufficient mice develop OA [16]
FRZB [5]	White women ≥ 65 years	sFRP3	Encodes sFRP3, and inhibits WNT signaling in both embryos and adults	WNT signaling in chondrocytes and osteoblasts is important in cartilage and bone homeostasis and during skeletal patterning in embryogenesis	FRZB influences both morphotype and cartilotype of the hip	FRZB knockout mice develop OA [52] Shape Mode 2 relates to lack of head-neck offset? [5]
SMAD3 [102]	European	SMAD3 protein, member of TGFß superfamily	Smad3 is a key intracellular messenger in TGF signaling pathway	TGFß/Smad3 signaling has been shown to be essential for maintaining articular cartilage	Genetic variation in the SMAD3 gene has a role in the risk of large-joint OA OA hip OR, 1.22 OA knee OR, 1.12

OA = osteoarthritis; TGF = tumor growth factor; BMP = bone morphogenic protein; DDH = developmental dysplasia of the hip; OR = odds ratio.