Candidate Gene Association Study of Magnetic Resonance Imaging-based Hip Osteoarthritis (OA): Evidence for COL9A2 Gene as a Common Predisposing Factor for Hip OA and Lumbar Disc Degeneration

ANNU NÄKKI; TAPIO VIDEMAN; URHO M. KUJALA; MATTI SUHONEN; MINNA MÄNNIKKÖ; LEENA PELTONEN; MICHELE C. BATTIÉ; JAAKKO KAPRIO; JANNA SAARELA

doi:10.3899/jrheum.100080

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Figure 1.
Single-nucleotide polymorphisms in the amino acid Gln³²⁶.

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Table 1.

Subject characteristics by hip OA status (data are mean ± SD).

Disease Status	n (%)	Age, yrs	BMI	Smoking^†	Endurance Exercise^††	Resistance Exercise^††	Sport Exercise^††
Healthy^*	251 (72.8)	49.7 ± 7.4	25.8 ± 3.1	13.7 ± 16.7	1.94 ± 2.72	0.07 ± 0.32	2.54 ± 2.83
Affected^**	94 (26.4)	51.2 ± 7.3	25.8 ± 3.3	12.8 ± 16.6	1.73 ± 2.04	0.05 ± 0.35	2.34 ± 2.28
Total	345 (100)	50.1 ± 7.4	25.8 ± 3.2	13.4 ± 16.6	1.88 ± 2.55	0.06 ± 0.32	2.48 ± 2.68

↵* MRI images in both hips normal (grade 0).
↵** At least 1 hip graded as 1–4: 1 = small local osteophytes in caput or acetabulum; 2 = osteophytes in 2 or more locations and subchondral signal loss and/or individual subchondral changes; 3 = same as class 2 with incipient deformation of caput/acetabulum deformation, wider or several cysts; 4 = significant deformation of bone structure, malposition, and subchondral or paraarticular changes (increase in T2 signal intensity, loose bodies).
↵† Pack-years at baseline.
↵†† Mean weighted frequency per week of exercise after age 20 years. BMI: body mass index; MRI: magnetic resonance imaging.

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Table 2.

Association of the studied SNP with hip OA using the Pseudomarker program.

Gene	rs Number	MAF	Disc Degeneration	p values (hip OA)^*		Gene	rs Number	MAF	Disc Degeneration	p values (hip OA)^*
Gene	rs Number	MAF	Disc Degeneration	Dominant	Recessive	Gene	rs Number	MAF	Disc Degeneration	Dominant	Recessive
AGC1	rs939587	0.280	X	0.888	0.920	COL11A1	rs1415359	0.400		0.374	0.332
	rs4932424	0.280	X	0.480	0.488		rs1337185	0.180	X	0.439	0.362
	rs3825996	0.490	X	1.000	1.000		rs1463035	0.180	X	0.258	0.230
	rs1042631	0.230	X	0.498	1.000		rs3753841	0.320		0.597	0.498
	rs1516797	0.340	X	0.115	0.082	COL11A2	rs2072915	0.240	X	0.124	0.106
COL1A1	rs1800012	0.120		0.171	0.168		rs9277933	0.240	X	0.308	0.277
	rs2075555	0.130	X	0.202	0.229		rs2076311	0.240	X	0.237	0.207
	rs1007086	0.270	X	0.888	0.888		rs2855432	0.300		0.399	0.299
	rs909102	0.140		0.037	0.032		rs2257126	0.360		0.862	0.806
COL1A2	rs3763468	0.050		0.078	0.091		rs734181	0.180		0.191	0.142
	rs388625	0.400		0.920	0.920	ILA	rs2071375	0.350	X	0.916	0.923
	rs412777	0.420		0.045	0.048	ILB	rs1143634	0.260		0.071	0.068
	rs400218	0.350		0.383	0.351	IL1R1	rs1465325	0.200		0.512	0.617
	rs1034620	0.200		0.777	0.841		rs956730	0.280		1.000	0.920
OL2A1	rs1859443	0.180		0.365	0.390		rs3917225	0.410		0.517	0.502
	rs1635529	0.200		0.303	0.299		rs2287047	0.250		0.538	0.532
	rs2276453	0.390		0.920	0.920		rs3771200	0.430		0.036	0.033
	rs917055	0.200		0.354	0.330	IL1R2	rs740044	0.160		0.718	0.791
	rs2276458	0.360		0.431	0.396		rs4141134	0.260		0.450	0.450
	rs6823	0.470		0.371	0.340		rs719250	0.190		0.284	0.299
COL3A1	rs1878199	0.290		0.823	1.000		rs3218984	0.410		0.269	0.245
	rs2056156	0.470		0.663	0.603		rs1008394	0.410		0.269	0.265
	rs2203601	0.470		0.450	0.446	IL1RL1	rs1420089	0.130		0.054	0.040
	rs1800255	0.230		0.383	0.488		rs1997466	0.490		1.000	1.000
COL5A1	rs4842138	0.120		0.233	0.271		rs1041973	0.240		0.142	0.142
	rs4341231	0.490		0.180	0.221		rs12905	0.270		0.242	0.194
	rs3128619	0.480		0.498	0.498	IL1RL2	rs2241132	0.130		0.157	0.080
	rs10858281	0.450		0.273	0.368		rs870684	0.400		0.095	0.062
	rs7357740	0.490		0.127	0.177		rs1922290	0.400		0.067	0.049
COL5A2	rs1983318	0.110		0.578	0.560		rs1922295	0.400		0.069	0.051
	rs13005821	0.340		0.920	0.920		rs1997502	0.350		0.232	0.216
	rs2138374	0.310		0.740	1.000		rs2302612	0.140		0.572	0.590
	rs12693527	0.200		0.888	0.888		rs1558626	0.460		0.888	0.888
	rs1131518			0.663	0.680	IL18R1	rs2287037	0.390		0.752	0.920
COL9A1	rs696990	0.160	X	0.322	0.406		rs2270298	0.270		0.202	0.148
	rs564031	0.400		0.192	0.192		rs1035130	0.270		0.320	0.294
	rs592121	0.320		0.327	0.359		rs1420096	0.480		0.084	0.053
	rs2076816	0.400		0.213	0.187	IL18RAP	rs1420106	0.210	X	0.240	0.245
	rs1200564	0.070		1.000	1.000		rs1420100	0.480	X	0.110	0.068
	rs997953	0.380		1.000	1.000		rs917997	0.200	X	0.191	0.244
COL9A2	rs449541	0.340		0.158	0.196	MMP3	rs645419	0.390		0.192	0.238
	rs364281	0.370		0.920	0.888		rs646910	0.250		0.322	0.380
	rs7533552	0.175	X	0.0033	0.0025	MMP8	rs1940475	0.470		0.791	1.000
COL9A3	rs3891033	0.450		0.127	0.134		rs2509013	0.380		1.000	1.000
	rs1046789	0.270		1.000	1.000		rs1276283	0.330		0.777	0.764
COL10A1	rs549332	0.470		0.178	0.125	MMP9	rs3918241	0.170		0.152	0.081
	rs1064583	0.340		0.030	0.025		rs2664538	0.380		0.271	0.322
	rs3812111	0.340		0.024	0.011		rs20544	0.490		0.087	0.091
	rs568725	0.320		0.002	0.004	MMP13	rs2252070	0.400		0.028	0.063
	rs568725	0.320		0.002	0.004		rs3819089	0.110		0.192	0.227

↵* Noncorrected (significance threshold = 0.00073). Disc degeneration: X denotes SNP associated with any of the disc degeneration phenotypes in our previous study⁴ (p < 0.05 after 1000 permutations). Dominant, Recessive: Dominant and recessive mode of inheritances in the association analysis using the Pseudomarker program. MAF: minor allele frequency in Finnish population; SNP: single-nucleotide polymorphism; OA: osteoarthritis.

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Table 3.

Amino acid combinations for variants in Gln³²⁶ codon in unrelated individuals.

	SNP Combination			Corresponding Amino Acid	Function	Unrelated Carriers^*
	1st base: rs12077871	2nd base: rs7533552	3rd base: monomorphic	Corresponding Amino Acid	Function	Controls, n (%)	Hip OA, n (%)
	C	A	G	Gln	WT	96 (67.1)	36 (49.3)
	C	A	G	Gln	WT	96 (67.1)	36 (49.3)
	C	A	G	Gln	WT	41 (28.7)	28 (38.4)
	C	G	G	Arg	P	41 (28.7)	28 (38.4)
	C	A	G	Gln	WT	3 (2.1)	1 (1.4)
	T	G	G	Trp	P	3 (2.1)	1 (1.4)
	C	G	G	Arg	P	3 (2.1)	7 (9.6)
	C	G	G	Arg	P	3 (2.1)	7 (9.6)
	C	G	G	Arg	P	0 (0.0)	1 (1.4)
	T	G	G	Trp	P	0 (0.0)	1 (1.4)
Total						143 (100)	73 (100)

↵* Unrelated individuals used in chi-square test: one twin of each monozygotic twin pair was randomly selected for genotyping. From dizygotic pairs, affected individual from discordant pairs and random individual from concordant pairs were selected. SNP: single-nucleotide polymorphism; OA: osteoarthritis; WT: wild-type allele; P: predisposing allele; Gln: glutamine; Arg: arginine; Trp: tryptophan.