基于肥胖基因多效性识别缺血性脑卒中遗传风险位点的同胞对研究

doi:10.19723/j.issn.1671-167X.2025.03.007

摘要/Abstract

摘要：

目的: 基于肥胖相关基因遗传多效性识别缺血性脑卒中(ischemic stroke，IS)遗传风险位点，为理解IS遗传病因提供科学依据。方法: 利用“北方农村地区居民常见慢性非传染性疾病家系队列研究”所收集的资料，采用表型不一致同胞对设计，通过多基因传递不平衡检验(polygenic transmission disequilibrium test，pTDT)，比较患IS同胞的实际体重指数(body mass index，BMI)遗传风险与其期望风险，分析BMI多基因风险与IS的关联关系，确定与BMI和IS存在遗传多效性的遗传变异集合，然后将该集合作为候选分析基因集，通过传递不平衡检验进一步识别与IS相关的风险位点并进行验证，最后探索相关位点的功能。结果: 共纳入541例研究对象，组成326对IS表型不一致的同胞对。研究对象的平均年龄为(58.4±8.1)岁，男性占57.3%。利用不同P值筛选的基因集度量的BMI多基因风险评分(polygenic risk score, PRS)进行分析，IS同胞的BMI实际遗传风险均高于其预期风险，提示与高BMI水平相关的遗传风险与IS患病状态存在共同传递的倾向，其中，P值小于5×10^-4构建PRS得分的pTDT检验显著性水平最优，对应的单核苷酸多态性位点(single nucleotide polymorphism, SNP)集合对IS的遗传度解释最大，该集合与BMI和IS存在遗传多效性。该集合中有45个SNP与IS存在连锁和关联，它们定位于43个独立基因座，映射在40个基因上，这些基因在脂质代谢通路中显著富集，其中关联验证通过多重检验校正的rs2232852位点映射于CYB5R1和ADIPOR1基因，与脂质代谢、铁死亡通路有关。结论: BMI相关基因和IS存在遗传多效性，在多效性基因集中发现了45个IS相关位点，映射到40个基因上，其功能富集于脂质代谢通路。关联验证分析通过多重检验校正的rs2232852位点映射于CYB5R1和ADIPOR1基因，与脂质代谢、铁死亡通路有关，提示脂质和铁死亡代谢通路可能在IS的发生发展中发挥一定作用。

关键词: 遗传关联研究, 同胞, 缺血性卒中, 体重指数, 遗传多效性

Abstract:

Objective: To identify genetic etiology of ischemic stroke (IS) based on pleiotropy of obesity related genes. Methods: A discordant sib-pair study was designed based on the Fangshan family cohort in Beijing. Body mass index (BMI) polygenic risk score (PRS) was first constructed under different P values. Using the polygenic transmission disequilibrium test (pTDT), we then compared the actual BMI genetic risk of siblings with IS to their expected risk, to analyze whether higher BMI was over-transmitted to siblings with IS. The single nucleotide polymorphism (SNP) that comprised the PRS over-transmitted with IS and that corresponded to the highest heritability of IS were identified as a pleiotropy SNPs set between BMI and IS. This set was then utilized as a candidate set to identify and verify risk SNPs asso-ciated IS by transmission disequilibrium test. Finally, we identified independent genomic risk loci and mapped to genes, we then explored the biological function of the identified risk loci and genes by functional annotation and pathway enrichment. Results: A total of 541 participants were enrolled, with an average age of (58.4±8.1) years, including 326 discordant sib pairs of ischemic stroke. Compared with non-IS participants, IS participants with males, education level below junior high school, hypertension and hyperlipidemia accounted for a higher proportion (P < 0.05). For all the BMI PRS, we found that the actual genetic risk of BMI in siblings with IS was higher than their expectation, suggesting that genetic risk associated with high BMI was over-transmitted with IS. Compared with other SNP sets, the set (P < 5×10^-4) corresponded to the best analytical statistics of pTDT and the highest heritability of IS and was identified as the pleiotropy SNP set between BMI and IS. Within this set, there were 45 SNPs having linkage and association with IS, which were located in 43 independent genomic risk loci and mapped to 40 genes. These genes were significantly enriched in the lipid metabolism pathway. The rs2232852 corrected by multiple tests was mapped to CYB5R1 and ADIPOR1, which were related to lipid metabolism and the ferroptosis pathway. Conclusion: Pleiotropy between BMI-related genes and IS was observed. Forty-five SNPs were found with linkage and association with IS in the pleiotropy gene set and mapped to 40 genes, which were functionally enriched in lipid metabolic pathways. The rs2232852 corrected by multiple tests during association analysis validation was mapped to CYB5R1 and ADIPOR1, which were related to lipid metabolism and the ferroptosis pathway, suggesting that lipid metabolism and ferroptosis played an important role in the development of IS.

Key words: Genetic association studies, Siblings, Ischemic stroke, Body mass index, Pleiotropy

中图分类号:

R181.33

王坤, 王淮蓉, 于欢, 杨若彤, 郑柳燕, 吴婧娴, 秦雪英, 吴涛, 陈大方, 武轶群, 胡永华. 基于肥胖基因多效性识别缺血性脑卒中遗传风险位点的同胞对研究[J]. 北京大学学报（医学版）, 2025, 57(3): 448-455.

Kun WANG, Huairong WANG, Huan YU, Ruotong YANG, Liuyan ZHENG, Jingxian WU, Xueying QIN, Tao WU, Dafang CHEN, Yiqun WU, Yonghua HU. Identifying genetic etiology of ischemic stroke based on pleiotropy of obesity related genes: A sibling study[J]. Journal of Peking University (Health Sciences), 2025, 57(3): 448-455.

图/表 4

表1

表2

表3

与IS同时存在连锁与关联的SNP对应的基因座及其映射基因"

SNP	Cytogenetic band	Genomic risk loci (chromosome: start position-end position)	Gene
rs118074101	1p13.3	1:110750031-110750031	KCNC4, SLC6A7
rs12093350	1q22	1: 155468732-155793969	ASH1L, MSTO1, YY1AP1, DAP3, GON4L
rs2232852	1q32.1	1:202924936-202938778	ADIPOR1, CYB5R1
rs34378983	1q32.3	1:214331416-214404556
rs75747776	2p24.1	2:20409638-20502198	SDC1, PUM2
rs12612799	2p16.1	2:56316415-56385145
rs147755783	2q24.1	2:158031410-158031410
rs1460669	2q24.3	2:164613829-164653060
rs141123347	2q24.3	2:169174780-169174780
rs17053757	3p21.1	3:54169266-54171774	CACNA2D3
rs10025110	4p12	4:44901237-45014151
rs59257388	4q21.22	4:83203517-83270007	HNRNPD
rs3811801	4q23	4:100244319-100336102	ADH1B, ADH1C, ADH7
rs76339045	4q32.3	4:167710607-167710607	SPOCK3
rs13177532	5p13.2	5:36728340-36783545
rs12656015	5q11.2	5:53089622-53160978
rs7723244	5q22.1	5:111261184-111443109	NREP
rs2043478	5q31.2	5:136498493-136498493	SPOCK1
rs181895	5q31.3	5:141769375-141822539
rs2062536	5q34	5:165795362-165795362
rs368399960	6p21.32	6:32300809-32331002	C6orf10
rs13202872	6p12.3	6:51189632-51264082
rs6947395	7q11.22	7:69403462-69406661	AUTS2
rs10268638	7q33	7:137100832-137129484	DKGI
rs6999964	8q24.22	8:132862920-132862920
rs10961656	9p22.3	9:14639666-14694602	ZDHHC21
rs12343952	9q33.1	9:122445599-122497319
rs74829026	10p15.3	10:2298746-2298746
rs117023276	10p12.31	10:21246955-21291331	NEBL
rs138468034	10q22.2	10:77321693-77366416	C10orf11
rs664706	10q23.31	10:89773567-89777068
rs192881652	11p15.1	11:18034532-18034532	TPH1, SERGEF
rs308754	11q14.2	11:88161676-88172516
rs1820460	12q23.3	12:107704705-107704705	BTBD11
rs4477562 rs2785821	13q14.3	13:54091759-54272104
rs11631335	15q15.1	15:40395604-40421006	BMF
rs9646281	16q12.1	16:52264631-52264631
rs75659809	16q23.1	16:77018698-77018698
rs11877418	18q11.2	18:20748733-20787099	CABLES1, TMEM241
rs77247480 rs56080693	18q12.1	18:27163063-27426754
rs148990504	18q21.31	18:54255607-54255607	TXNL1
rs769449	19q13.32	19:45410002-45428234	TOMM40, APOE, APOC1
rs117988645	22q11.21	22:20093967-20174270	DGCR8, TRMT2A, RANBP1, ZDHHC8, AC006547.14

表3

表4

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Items	Total (n=541)	Participants with IS (n=276)	Participants without IS (n=265)	P value
Age/years, ${\bar x}$±s	58.4±8.1	60.1±7.4	56.6±8.5	< 0.001
Male, n (%)	310 (57.3)	171 (62.0)	139 (52.5)	0.032
Married, n (%)	468 (86.5)	236 (85.5)	232 (87.5)	0.872
Junior high school education or above, n (%)	290 (53.6)	136 (49.3)	154 (58.1)	0.048
Smoker, n (%)	287 (53.1)	147 (53.3)	140 (52.8)	0.957
Drinker, n (%)	243 (44.9)	131 (47.5)	112 (42.3)	0.227
Adequate exercise, n (%)	159 (29.4)	86 (31.2)	73 (27.5)	0.193
BMI/(kg/m²), ${\bar x}$±s	26.2±3.4	26.2±3.3	26.3±3.6	0.637
Diabetes, n (%)	172 (31.8)	94 (34.1)	78 (29.4)	0.288
Hypertension, n (%)	276 (51.0)	158 (57.2)	118 (44.5)	0.004
Hyperlipidemia, n (%)	179 (33.1)	114 (41.3)	65 (24.5)	< 0.001
BMI-PRS, ${\bar x}$±s	0.040±0.162	0.047±0.157	0.032±0.166	0.284

P	SNPn	DEV (mean)	P_pTDT	h_SNPn²	R²
5×10^-7	399	0.081	0.126	1×10^-6	6.99×10^-4
5×10^-6	644	0.088	0.095	1×10^-6	6.91×10^-4
5×10^-5	1 244	0.052	0.242	1×10^-6	2.06×10^-4
5×10^-4	3 031	0.080	0.072	2×10^-6	1.20×10^-3
5×10^-3	9 172	0.045	0.314	2×10^-6	3.89×10^-4

SNP	Effect allele	MAF	OR(95%CI)	P
rs2232852	C	0.387	1.53 (1.21-1.94)	4.582×10^-5
rs1460669	T	0.415	1.37 (1.08-1.73)	0.010
rs12343952	T	0.247	1.42 (1.07-1.90)	0.017
rs75659809	T	0.009	0.25 (0.07-0.85)	0.026
rs141123347	G	0.013	0.32 (0.12-0.88)	0.027
rs11631335	G	0.236	0.77 (0.60-1.00)	0.049

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