Associations of single nucleotide polymorphisms of HDAC9 and PPP3CA genes with frailty in the Chinese elderly people
YANG Pei and ZHANG Yu-jie contributed equally to the work
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摘要:
目的 探讨组蛋白去乙酰化酶9(histone deacetylase 9, HDAC9) rs2074633及钙调神经磷酸酶催化亚基A(calcineurin catalytic subunit A, PPP3CA) rs17030795的多态性与中国老年人衰弱发生的关联。 方法 本研究纳入衰弱组665例，对照组3 388例。基于基因型频率及五种遗传模型(共显性、加性、显性、隐性和超显性)，评估rs2074633及rs17030795多态性与衰弱之间的关联。 结果 在共显性模型中，与携带rs2074633 TT基因型相比，携带TC型(OR=1.99，95% CI: 1.36~2.90)、CC型(OR=2.15，95% CI: 1.48~3.13)的个体发生衰弱的风险增加；在加性(OR=1.28，95% CI: 1.11~1.47)、显性(OR=2.07，95% CI: 1.44~2.98)及隐形模型(OR=1.21，95% CI: 1.01~1.45)中rs2074633多态性均增加衰弱的发生风险；在共显性模型中，与携带rs17030795 AA基因型相比，携带AG(OR=1.72，95% CI: 1.19~2.51)、GG(OR=1.98，95% CI: 1.37~2.87)型的个体发生衰弱的风险增加；在加性(OR=1.28，95% CI: 1.11~1.48)、显性(OR=1.85，95% CI: 1.29~2.66)及隐性(OR=1.25，95% CI: 1.04~1.50)中rs17030795多态性均增加衰弱的发生风险。 结论 HDAC9 rs2074633及PPP3CA rs17030795多态性与中国老年人衰弱发生风险有关。 Abstract:Objective To explore the associations between the single nucleotide polymorphism (SNP) of histone deacetylase 9 (HDAC9) and calcineurin catalytic subunit A (PPP3CA) and frailty in the Chinese elderly people. Methods Our study included 665 participants in the frailty group and 3 388 participants in the control group. Associations between rs2074633 and rs17030795 gene polymorphisms and frailty were evaluated based on genotype frequencies, and five genetic models (co-dominance, additive, dominance, recessive and over-dominance models). Results In co-dominance model, individuals carrying HDAC9 rs2074633 TC genotype (OR=1.99, 95% CI: 1.36-2.90) and CC genotype (OR=2.15, 95% CI: 1.48-3.13) were more likely to develop frailty, compared with those carrying TT genotype3. The rs2074633 polymorphisms increased the risk of frailty in both additive model (OR=1.28, 95% CI: 1.11-1.47), dominant model (OR=2.07, 95% CI: 1.44-2.98) and recessive model (OR=1.21, 95% CI: 1.01-1.45). In co-dominance model, individuals carrying PPP3CA rs17030795 AG (OR=1.72, 95% CI: 1.19-2.51) genotype and GG (OR=1.98, 95% CI: 1.37-2.87) genotype were more likely to develop frailty, compared with those carrying AA genotype. The rs17030795 polymorphisms increased the risk of frailty in both additive model (OR=1.28, 95% CI: 1.11-1.48), dominant model (OR=1.85, 95% CI: 1.29-2.66) and recessive model (OR=1.25, 95% CI: 1.04-1.50). Conclusions The rs2074633and rs17030795 polymorphisms are associated with the increased risk of frailty. -
Key words:
- Frailty /
- Gene polymorphism /
- Histone deacetylase 9 /
- Calcineurin catalytic subunit A
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表 1 总人群及不同代谢状况与体重分组基本情况[n(%)]
Table 1. Basic information of the whole population and different metabolical and weight groups [n(%)]
变量 对照组(n=3 388) 衰弱组(n=665) Z/χ2值 P值 变量 对照组(n=3 388) 衰弱组(n=665) Z/χ2值 P值 年龄(岁) 76.00(70.00，84.00) 88.00(82.00，93.00) -23.401 < 0.001 当前吸烟状态 39.917 < 0.001 性别 34.889 < 0.001 否 2 487(73.41) 565(84.96) 男 1 810(53.42) 272(40.90) 是 901(26.59) 100(15.04) 女 1 578(46.58) 393(59.10) 当前饮酒状态 18.265 < 0.001 受教育程度(年) 83.536 < 0.001 否 2 558(75.50) 553(83.16) 0 1 585(46.78) 440(66.17) 是 830(24.50) 112(16.84) ≥1 1 803(53.22) 225(33.83) 经常锻炼身体 2.309 0.129 独居情况 0.347 0.556 否 2 593(76.53) 527(79.25) 否 2 832(83.59) 562(84.51) 是 795(23.47) 138(20.75) 是 556(16.41) 103(15.49) 共病情况 990(29.22) 202(30.38) 0.357 0.55 BMI(kg/m2) 20.83(18.75，23.44) 19.98(17.86，22.37) -6.565 < 0.001 注：年龄、BMI表示为[M(P25，P75)]。 
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表 2 不同遗传模型下rs2074633和rs17030795多态性与衰弱的关联[n(%)]
Table 2. Associations between rs2074633 and rs17030795 polymorphisms and frailty in different genetic models [n(%)]
遗传模型 rs2074633 遗传模型 rs17030795 对照组 病例组 OR(95% CI)值 P值 对照组 病例组 OR(95% CI)值 P值 共显性模型 共显性 TT 380(11.22) 39(5.86) 1.00 AA 351(10.36) 40(6.01) 1.00 TC 1 465(43.24) 289(43.46) 1.99(1.36~2.90) < 0.001 AG 1 501(44.30) 287(43.16) 1.72(1.19~2.51) 0.004 CC 1 543(45.54) 337(50.68) 2.15(1.48~3.13) < 0.001 GG 1 536(45.34) 338(50.83) 1.98(1.37~2.87) < 0.001 加性模型 1.28(1.11~1.47) 0.001 加性模型 1.28(1.11~1.48) 0.001 显性模型 显性模型 TT 380(11.22) 39(5.86) 1.00 AA 351(10.36) 40(6.02) 1.00 TC+CC 3 008(88.78) 626(94.14) 2.07(1.44~2.98) < 0.001 AG+GG 3 037(89.64) 625(93.98) 1.85(1.29~2.66) 0.001 隐性模型 隐性模型 TT+TC 1 845(54.46) 328(49.32) 1.00 AA+AG 1 852(54.66) 327(49.17) 1.00 CC 1 543(45.54) 337(50.68) 1.21(1.01~1.45) 0.041 GG 1 536(45.34) 338(50.83) 1.25(1.04~1.50) 0.016 超显性模型 超显性模型 TT+CC 1 923(56.76) 376(56.54) 1.00 AA+GG 1 887(55.70) 378(56.84) 1.00 TC 1 465(43.24) 289(43.46) 1.03(0.86~1.24) 0.724 AG 1 501(44.30) 287(43.16) 0.96(0.80~1.16) 0.681 注：logistic回归分析模型调整因素为：年龄、性别、当前吸烟状态、当前饮酒状态、受教育年限、是否独居、BMI、经常锻炼身体、共病情况。
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表 3 突变总和与衰弱的logistic回归分析模型
Table 3. Multivariate logistic regression analysis between sum of SNPs mutations and frailty
等位基因突变个数 病例/总数 完全调整模型 OR(95% CI)值 P值 P趋势 0~2 200/1 536 1.00 - - 3~4 465/2 517 1.57(1.29~1.91) < 0.001 < 0.001 注：完全模型调整因素为：年龄、性别、当前吸烟状态、当前饮酒状态、受教育年限、是否独居、BMI、经常锻炼身体、共病情况。
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表 4 rs2074633及rs17030795与衰弱的分层分析
Table 4. Stratified analysis on the association of rs2074633, and rs17030795 with frailty
变量 rs2074633 rs17030795 OR(95% CI)值 P值 P交互值 OR(95% CI)值 P值 P交互值 年龄组(岁) 0.051 0.004 < 80 1.19(0.89~1.59) 0.246 0.98(0.74~1.30) 0.885 ≥80 1.31(1.11~1.54) 0.001 1.40(1.19~1.65) < 0.001 性别 0.768 0.717 男 1.31(1.05~1.63) 0.015 1.33(1.07~1.66) 0.010 女 1.26(1.04~1.53) 0.018 1.26(1.04~1.53) 0.020 BMI(kg/m2) 0.301 0.329 < 24.0 1.32(1.13~1.55) < 0.001 1.32(1.13~1.54) 0.001 ≥24.0 1.07(0.73~1.57) 0.714 1.11(0.76~1.64) 0.581 受教育程度(年) 0.986 0.428 0 1.24(1.04~1.48) 0.017 1.35(1.13~1.63) 0.001 ≥1 1.35(1.05~1.72) 0.017 1.18(0.93~1.49) 0.171 当前吸烟状态 0.815 0.768 否 1.29(1.10~1.50) 0.002 1.29(1.10~1.52) 0.001 是 1.16(0.82~1.65) 0.393 1.24(0.87~1.78) 0.238 当前饮酒状态 0.827 0.708 否 1.29(1.10~1.51) 0.002 1.30(1.11~1.53) 0.001 是 1.23(0.87~1.73) 0.244 1.25(0.88~1.77) 0.217
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[1] Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype[J]. J Gerontol A Biol Sci Med Sci, 2001, 56(3): M146-M156. DOI: 10.1093/gerona/56.3.M146. [2] Clegg A, Young J, Iliffe S, et al. Frailty in elderly people[J]. Lancet, 2013, 381(9868): 752-762. DOI: 10.1016/S0140-6736(12)62167-9. [3] Hoogendijk EO, Afilalo J, Ensrud KE, et al. Frailty: implications for clinical practice and public health[J]. Lancet, 2019, 394(10206): 1365-1375. DOI: 10.1016/S0140-6736(19)31786-6. [4] Sathyan S, Verghese J. Genetics of frailty: a longevity perspective[J]. Transl Res, 2020, 221: 83-96. DOI: 10.1016/j.trsl.2020.03.005. [5] Inglés M, Mas-Bargues C, Gimeno-Mallench L, et al. Relation between genetic factors and frailty in older adults[J]. J Am Med Dir Assoc, 2019, 20(11): 1451-1457. DOI: 10.1016/j.jamda.2019.03.011. [6] Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis[J]. Age Ageing, 2019, 48(4): 601. DOI: 10.1093/ageing/afyz046. [7] Bycroft C, Freeman C, Petkova D, et al. The UK Biobank resource with deep phenotyping and genomic data[J]. Nature, 2018, 562(7726): 203-209. DOI: 10.1038/s41586-018-0579-z. [8] Zhang CL, McKinsey TA, Olson EN. Association of class Ⅱ histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation[J]. Mol Cell Biol, 2002, 22(20): 7302-7312. DOI: 10.1128/MCB.22.20.7302-7312.2002. [9] Tang H, Goldman D. Activity-dependent gene regulation in skeletal muscle is mediated by a histone deacetylase (HDAC)-dach2-myogenin signal transduction cascade[J]. Proc Natl Acad Sci USA, 2006, 103(45): 16977-16982. DOI: 10.1073/pnas.0601565103.Epub2006Oct30. [10] Chen HH, Tsai LK, Liao KY, et al. Muscle-restricted nuclear receptor interaction protein knockout causes motor neuron degeneration through down-regulation of myogenin at the neuromuscular junction[J]. J Cachexia Sarcopenia Muscle, 2018, 9(4): 771-785. DOI: 10.1002/jcsm.12299. [11] Cardoso AL, Fernandes A, Aguilar-Pimentel JA, et al. Towards frailty biomarkers: candidates from genes and pathways regulated in aging and age-related diseases[J]. Ageing Res Rev, 2018, 47: 214-277. DOI: 10.1016/j.arr.2018.07.004. [12] Bennett S, Song X, Mitnitski A, et al. A limit to frailty in very old, community-dwelling people: a secondary analysis of the Chinese longitudinal health and longevity study[J]. Age Ageing, 2013, 42(3): 372-377. DOI: 10.1093/ageing/afs180. [13] Gu D, Dupre ME, Sautter J, et al. Frailty and mortality among Chinese at advanced ages[J]. J Gerontol B Psychol Sci Soc Sci, 2009, 64(2): 279-289. DOI: 10.1093/geronb/gbn009. [14] Rockwood K, Andrew M, Mitnitski A. A comparison of two approaches to measuring frailty in elderly people[J]. J Gerontol a Biol Sci Med Sci, 2007, 62(7): 738-743. DOI: 10.1093/gerona/62.7.738. [15] Zeng Y, Nie C, Min J, et al. Novel loci and pathways significantly associated with longevity[J]. Sci Rep, 2016, 6: 21243. DOI: 10.1038/srep21243. [16] Li L, Xiong WC, Mei L. Neuromuscular junction formation, aging, and disorders[J]. Annu Rev Pysiol, 2018, 80: 159-188. DOI: 10.1146/annurev-physiol-022516-034255. [17] Zhou X, Marks PA, Rifkind RA, et al. Cloning and characterization of a histone deacetylase, HDAC9[J]. Proc Natl Acad Sci USA, 2001, 98(19): 10572-10577. DOI: 10.1073/pnas.191375098. [18] Wang M, Gu M, Li Z, et al. HDAC9 polymorphisms predict susceptibility, severity, and short-term outcome of large artery atherosclerotic stroke in Chinese ppulation[J]. J Mol Neurosci, 2019, 67(1): 165-171. DOI: 10.1007/s12031-018-1221-0. [19] Haberland M, Arnold MA, McAnally J, et al. Regulation of HDAC9 gene expression by MEF2 establishes a negative-feedback loop in the transcriptional circuitry of muscle differentiation[J]. Mol Cell Biol, 2007, 27(2): 518-525. DOI: 10.1128/MCB.01415-06. [20] Macpherson PCD, Farshi P, Goldman D. Dach2-HDAC9 signaling regulates reinnervation of muscle endplates[J]. Development, 2015, 142(23): 4038-4048. DOI: 10.1242/dev.125674. [21] Roy J, Cyert MS. Identifying new substrates and functions for an old enzyme: calcineurin[J]. Cold Spring Harb Perspect Biol, 2020, 12(3): a035436. DOI: 10.1101/cshperspect.a035436. [22] Li H, Rao A, Hogan PG. Interaction of calcineurin with substrates and targeting proteins[J]. Trends Cell Biol, 2011, 21(2): 91-103.1016/j.tcb.2010.09.011. doi: 1016/j.tcb.2010.09.011 [23] Myers CT, Stong N, Mountier EI, et al. De novo mutations in PPP3CA cause severe neurodevelopmental disease with seizures[J]. Am J Hum Genet, 2017, 101(4): 516-524. DOI: 10.1016/j.ajhg.2017.08.013. [24] Rydzanicz M, Wachowska M, Cook EC, et al. Novel calcineurin a (PPP3CA) variant associated with epilepsy, constitutive enzyme activation and downregulation of protein expression[J]. Eur J Hum Genet, 2019, 27(1): 61-69. DOI: 10.1038/s41431-018-0254-8. [25] 薛梦婷, 姜荣荣, 徐桂华, 等. 老年人衰弱的研究进展[J]. 中国老年学杂志, 2021, 41(8): 1761-1765. DOI: 10.3969/j.issn.1005-9202.2021.08.056.Xue MT, Jiang RR, Xu GH, et al. Research progress of frailty in the elderly[J]. Chin J Geriatr, 2021, 41(8): 1761-1765. DOI: 10.3969/j.issn.1005-9202.2021.08.056. [26] 周立远, 吴天清, 张旭东, 等. 不同年龄大鼠心血管组织中钙调神经磷酸酶活性的变化[J]. 中国医药指南, 2012, 10(17): 95-97. DOI: 10.3969/j.issn.1671-8194.2012.17.061.Zhou LY, Wu TQ, Zhang XD, et al. Changes of calcineurin activity in cardiovascular tissues of rats of different ages[J]. Guide of China Medicine, 2012, 10(17): 95-97. DOI: 10.3969/j.issn.1671-8194.2012.17.061. -
