对家族聚集性膝骨关节炎家系的基因测序及在普通人群中的初步验证

doi:10.3877/cma.j.issn.1674-0785.2025.05.002

目的

膝骨关节炎是一种常见的、主要由软骨损伤引起的退行性关节疾病，其发病的确切机制不详，但目前已知的危险因素包括年龄、肥胖、炎症、创伤和遗传因素等。本研究拟通过对膝骨关节炎高发家系进行全基因组测序，寻找与膝骨关节炎（KOA）相关的致病基因。并且在一般人群中进行初步验证。

方法

招募一个3代18例的膝骨关节炎高发家系中的6例成员，其中4例患有膝骨关节炎，2例不患膝骨关节炎；对这6例家系成员进行全基因组测序，并通过SIFT4G_Pred、Polyphen2_HDIV_Pred及Polyphen2_HVAR_Pred这三种有害性预测模型进行预测并筛选单核苷酸多态性（SNP）；再招募49例一般人群，其中膝骨关节炎患者27例，健康对照组22例。对这49例一般人群进行MassArray基因分型。

结果

对膝骨关节炎高发家系成员进行了全基因组测序，对测序结果使用了三种有害性预测模型，再经过筛选后，筛选出了33个可能与膝骨关节炎有相关性的SNP位点。以这33个筛选出SNP位点和54个来自文献检索的SNP位点为基础，在招募的一般人群中进行了初步验证，结果得到有4个SNP可能与KOA有相关性，包括rs10843013、rs12119908、rs2075164及rs7953280。其中rs10843013和rs7953280来自于文献报道。

结论

本研究表明膝骨关节炎的发生发展与SNP密切相关，并且当一些SNP聚集在一个家系中时，会导致该家系患膝骨关节炎的概率大幅上升。且这些SNP位点在一般人群中，也是影响膝骨关节炎发生发展的重要因素。

关键词: 骨关节炎, 膝骨关节炎, 单核苷酸多态性, 基因测序, 家系研究

Objective

Knee osteoarthritis (KOA) is a common degenerative joint disease primarily caused by cartilage damage. The exact mechanism of its pathogenesis remains unclear, but known risk factors include age, obesity, inflammation, trauma, and genetic factors. This study aimed to identify disease-associated genes related to KOA by conducting whole-genome sequencing on a high-incidence KOA family and performing preliminary validation in the general population.

Methods

Six members from a three-generation, 18-member high-incidence KOA family were recruited, including four with KOA and two without. Whole-genome sequencing was performed on these six family members, and single nucleotide polymorphisms (SNPs) were screened using three deleteriousness prediction models: SIFT4G_Pred, Polyphen2_HDIV_Pred, and Polyphen2_HVAR_Pred. Additionally, 49 individuals from the general population were recruited, including 27 KOA patients and 22 healthy controls. MassArray SNP genotyping was conducted on these 49 individuals.

Results

Whole-genome sequencing on the high-incidence KOA family members, combined with the three deleteriousness prediction models, identified 33 SNPs potentially associated with KOA. Based on these 33 SNPs and an additional 54 SNPs retrieved from the literature, preliminary validation was performed in the general population. The results revealed four SNPs that may be associated with KOA: rs10843013, rs12119908, rs2075164, and rs7953280. Among these, rs10843013 and rs7953280 were previously reported in the literature.

Conclusion

This study demonstrates that the development and progression of KOA are closely related to SNPs. When certain SNPs cluster within a family, the probability of KOA occurrence significantly increases. Moreover, these SNP loci also play an important role in influencing KOA susceptibility in the general population.

Key words: Osteoarthritis, Knee osteoarthritis, SNP, Gene sequencing, Family study

图1 图中黑色代表KOA患者，白色代表经问卷调查排除KOA的健康对照个体。先证者为Ⅱ2，纳入研究的家系成员包括Ⅱ-2、Ⅱ-6、Ⅱ-8、Ⅱ-10、Ⅲ-1和Ⅲ-2

表1 编码区的SNP的功能分类统计

样本	平均值	Ⅱ2	Ⅱ6	Ⅱ8	Ⅱ10	Ⅲ1	Ⅲ2
Synonymous	33369	33482	33478	33511	33785	33065	32895
Missense	26474	27093	26457	26688	26096	26315	26197
Stopgain	173	185	171	175	171	167	173
Stoploss	32	36	29	27	33	32	38
Startloss	51	53	54	53	52	52	46
Splicing	13396	13583	13314	13310	13513	13056	13604
Ti/Tv	2.99	2.96	3.03	2.96	2.98	3.05	2.99

表1 编码区的SNP的功能分类统计

样本	平均值	Ⅱ2	Ⅱ6	Ⅱ8	Ⅱ10	Ⅲ1	Ⅲ2
Synonymous	33369	33482	33478	33511	33785	33065	32895
Missense	26474	27093	26457	26688	26096	26315	26197
Stopgain	173	185	171	175	171	167	173
Stoploss	32	36	29	27	33	32	38
Startloss	51	53	54	53	52	52	46
Splicing	13396	13583	13314	13310	13513	13056	13604
Ti/Tv	2.99	2.96	3.03	2.96	2.98	3.05	2.99

表2 SNP筛选结果

CHROM	POS	REF	ALT	rsID	SIFT4G_Pred	HDIV_Pred	HVAR_Pred	基因频率
chr11	125899459	T	C	667782	D	P	P	0.269
chr15	73927205	G	T	1048661	D	P	B	0.285
chr10	48180973	T	C	1346694	D	B	B	0.461
chr18	61507526	C	A	1943330	T	D	D	0.096
chr17	63918770	T	C	2001345	D	B	B	0.035
chr1	20354225	G	A	2072751	T	D	P	0.228
chr1	156175180	G	A	2075164	T	P	B	0.075
chr18	52906232	C	G	2229080	T	P	P	0.387
chr15	78098072	T	C	2289524	D	B	B	0.446
chr11	65641466	C	T	3741378	D	B	B	0.173
chr1	159943109	C	T	3747617	D	D	D	0.054
chr7	88184320	C	T	3789240	D	/	/	0.116
chr1	24095460	C	G	4319261	T	D	P	0.472
chr10	48605	C	T	10904047	D	/	/	0.773
chr15	78149427	T	C	11555541	D	/	/	0.547
chr1	20345468	G	A	11582960	D	D	D	0.312
chr5	157671748	G	T	11740603	D	P	P	0.172
chr1	156932430	G	A	12119908	D	D	B	0.177
chr1	247896174	A	C	12139390	T	D	D	0.651
chr4	151291334	C	T	13126069	D	B	P	0.361
chr1	152515670	G	A	16834168	D	D	D	0.044
chr4	151279901	G	A	36097019	D	D	D	0.361
chr15	74268435	G	T	56107695	D	D	P	0.077
chr7	100952651	C	A	71540917	D	/	/	0.176
chr1	152303983	C	T	75448155	/	D	D	0.06
chr9	41964577	A	C	76032838	D	/	/	0.426
chr17	21415757	G	A	76265595	D	D	D	0.5
chr17	21416127	T	G	76684759	D	D	D	0.5
chr17	21416124	G	A	77270326	D	D	D	0.5
chr1	16058547	G	A	77667563	T	D	P	0.369
chr12	52949223	G	A	79476176	D	D	P	0.32
chr1	39788196	C	T	191429577	T	P	P	0.027
chr7	100951900	A	C	745478294	D	/	/	0.500

表2 SNP筛选结果

CHROM	POS	REF	ALT	rsID	SIFT4G_Pred	HDIV_Pred	HVAR_Pred	基因频率
chr11	125899459	T	C	667782	D	P	P	0.269
chr15	73927205	G	T	1048661	D	P	B	0.285
chr10	48180973	T	C	1346694	D	B	B	0.461
chr18	61507526	C	A	1943330	T	D	D	0.096
chr17	63918770	T	C	2001345	D	B	B	0.035
chr1	20354225	G	A	2072751	T	D	P	0.228
chr1	156175180	G	A	2075164	T	P	B	0.075
chr18	52906232	C	G	2229080	T	P	P	0.387
chr15	78098072	T	C	2289524	D	B	B	0.446
chr11	65641466	C	T	3741378	D	B	B	0.173
chr1	159943109	C	T	3747617	D	D	D	0.054
chr7	88184320	C	T	3789240	D	/	/	0.116
chr1	24095460	C	G	4319261	T	D	P	0.472
chr10	48605	C	T	10904047	D	/	/	0.773
chr15	78149427	T	C	11555541	D	/	/	0.547
chr1	20345468	G	A	11582960	D	D	D	0.312
chr5	157671748	G	T	11740603	D	P	P	0.172
chr1	156932430	G	A	12119908	D	D	B	0.177
chr1	247896174	A	C	12139390	T	D	D	0.651
chr4	151291334	C	T	13126069	D	B	P	0.361
chr1	152515670	G	A	16834168	D	D	D	0.044
chr4	151279901	G	A	36097019	D	D	D	0.361
chr15	74268435	G	T	56107695	D	D	P	0.077
chr7	100952651	C	A	71540917	D	/	/	0.176
chr1	152303983	C	T	75448155	/	D	D	0.06
chr9	41964577	A	C	76032838	D	/	/	0.426
chr17	21415757	G	A	76265595	D	D	D	0.5
chr17	21416127	T	G	76684759	D	D	D	0.5
chr17	21416124	G	A	77270326	D	D	D	0.5
chr1	16058547	G	A	77667563	T	D	P	0.369
chr12	52949223	G	A	79476176	D	D	P	0.32
chr1	39788196	C	T	191429577	T	P	P	0.027
chr7	100951900	A	C	745478294	D	/	/	0.500

表3 来自GWAS的SNP

rs10038860	rs12914479	rs2163832	rs4548913	rs74676797
rs10831476	rs13107325	rs2605098	rs4775006	rs753350451
rs10842226	rs1426371	rs2622873	rs551471509	rs7581446
rs10842226	rs143384	rs2791549	rs571734653	rs7581446
rs10843013	rs143384	rs2856821	rs58973023	rs7680647
rs10974438	rs1517572	rs34195470	rs59163323	rs7953280
rs10974438	rs1546737	rs3755381	rs6500609	rs7967762
rs1149620	rs1631174	rs3884606	rs66906321	rs80308593
rs11705555	rs17615906	rs4380013	rs72760655	rs9908159
rs12193102	rs1913707	rs4380013	rs72760655	rs9940278
rs12901372	rs2066928	rs4548913	rs72979233

表3 来自GWAS的SNP

rs10038860	rs12914479	rs2163832	rs4548913	rs74676797
rs10831476	rs13107325	rs2605098	rs4775006	rs753350451
rs10842226	rs1426371	rs2622873	rs551471509	rs7581446
rs10842226	rs143384	rs2791549	rs571734653	rs7581446
rs10843013	rs143384	rs2856821	rs58973023	rs7680647
rs10974438	rs1517572	rs34195470	rs59163323	rs7953280
rs10974438	rs1546737	rs3755381	rs6500609	rs7967762
rs1149620	rs1631174	rs3884606	rs66906321	rs80308593
rs11705555	rs17615906	rs4380013	rs72760655	rs9908159
rs12193102	rs1913707	rs4380013	rs72760655	rs9940278
rs12901372	rs2066928	rs4548913	rs72979233

表4 部分统计结果

RSid	基因频率（全球例口）	基因频率（OA组）	基因频率（对照组）	KOA组			对照		P值	FDR阈值	q值
rs10843013	A=0.810	A=0.815	A=0.786	AA	CA	CC	AA	CA
rs10843013	C=0.190	C=0.185	C=0.214	AA	CA	CC	AA	CA
				20	4	3	12	9	0.043	0.002	0.946
rs12119908	G=0.823	G=0.741	G=0.955	GG	GA	AA	GG	GA
rs12119908	A=0.177	A=0.259	A=0.045	GG	GA	AA	GG	GA
				16	8	3	20	2	0.036	0.001	1.000
rs2075164	G=0.925	G=0.833	G=0.955	GG	AG		GG	AG
rs2075164	A=0.075	A=0.167	A=0.045	GG	AG		GG	AG
				18	9		20	2	0.043	0.002	1.000
rs7953280	G=0.458	G=0.250	G=0.023	CC	CG	GG	CC	CG
rs7953280	C=0.541	G=0.750	0.977	CC	CG	GG	CC	CG
				16	7	3	21	1	0.019	0.001	1.000

表4 部分统计结果

RSid	基因频率（全球例口）	基因频率（OA组）	基因频率（对照组）	KOA组			对照		P值	FDR阈值	q值
rs10843013	A=0.810	A=0.815	A=0.786	AA	CA	CC	AA	CA
rs10843013	C=0.190	C=0.185	C=0.214	AA	CA	CC	AA	CA
				20	4	3	12	9	0.043	0.002	0.946
rs12119908	G=0.823	G=0.741	G=0.955	GG	GA	AA	GG	GA
rs12119908	A=0.177	A=0.259	A=0.045	GG	GA	AA	GG	GA
				16	8	3	20	2	0.036	0.001	1.000
rs2075164	G=0.925	G=0.833	G=0.955	GG	AG		GG	AG
rs2075164	A=0.075	A=0.167	A=0.045	GG	AG		GG	AG
				18	9		20	2	0.043	0.002	1.000
rs7953280	G=0.458	G=0.250	G=0.023	CC	CG	GG	CC	CG
rs7953280	C=0.541	G=0.750	0.977	CC	CG	GG	CC	CG
				16	7	3	21	1	0.019	0.001	1.000

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Gene sequencing of a family with knee osteoarthritis and preliminary verification in the general population

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Gene sequencing of a family with knee osteoarthritis and preliminary verification in the general population