线粒体DNA U4b单倍群:中国塔吉克族高原原发性高血压的遗传易感因素

doi:10.12047/j.cjap.6038.2021.012

摘要/Abstract

摘要： 目的: 探讨线粒体DNA变异与中国塔吉克族高原原发性高血压的关系。方法: 在中国塔吉克族人群中,收集了53例高原原发性高血压病例和46例正常对照。通过PCR扩增线粒体DNA片段,经测序拼接获得线粒体全基因组,与剑桥序列比对以筛选线粒体DNA变异,分析在病例组与对照组中的分布差异,采用生物信息学工具预测阳性相关变异的功能。结果: 与对照组相比,U4b单倍群在病例组的频率显著升高(P=0.023,OR=7.062,CI(95%)=1.306-38.182),该单倍群内的8个变异位点也存在显著性差异(P均＜0.05)。其中,线粒体DNA 15693T＞C位点是位于线粒体细胞色素b基因编码区的唯一错义变异,使得第316位氨基酸由蛋氨酸改变为苏氨酸;生物信息学分析表明,该变异可能通过影响蛋白的二级结构发挥生物学功能。结论: 线粒体DNA U4b单倍群是中国塔吉克族人群高原原发性高血压的遗传易感因素,线粒体DNA 15693T＞C突变可能是高原原发性高血压的重要分子机制。

关键词: 高原, 高血压, 线粒体DNA, 塔吉克族

Abstract: Objective: To investigate the relationship between mitochondrial DNA (mtDNA) variation and high altitude essential hypertension(HAEH) in the Chinese Tajik population. Methods: Fifty-three patients with HAEH and 46 healthy subjects were enrolled from the Chinese Tajik population. The mtDNA fragments were amplificated by polymerase chain reaction, and products were sequenced to acquire full sequence of mtDNA. The mtDNA sequences of all subjects were compared to the Cambridge sequence to explore mtDNA variations and analyze difference between HAEH and healthy controls. Online softwares were applied to predict function changes caused by positive associated mtDNA variations. Results: Compared to the control group, the frequency of haplogroup U4b was significant higher in HAEH group(P=0.023,OR=7.062,CI(95%)=1.306-38.182), and the frequencies of 8 mutations from haplogroup U4b showed a significant difference between the HAEH group and control group (all with P values below 0.05). The mt DNA15693T＞C mutation was the only missense mutation, which affected amino acid 316 in mitochondrial cytochrome b (MTCYB) by changing it from methionine to threonine. Bioinformatics analysis indicated that the mutation in MTCYB may play a biological role through affecting the second structure of protein. Conclusion: MtDNA subhaplogroup U4b is a genetic factor for HAEH in the Chinese Tajik population, and mtDNA15693T＞C mutation may be an important molecular mechanism of HAEH.

Key words: high altitude, hypertension, mitochondrial DNA, Tajik

中图分类号:

R544.1

陈郁, 高亮, 龚亮, 陈兴书, 阳盛洪, 罗勇军. 线粒体DNA U4b单倍群:中国塔吉克族高原原发性高血压的遗传易感因素[J]. 中国应用生理学杂志, 2021, 37(3): 225-229.

CHEN Yu, GAO Liang, GONG Liang, CHEN Xing-shu, YANG Sheng-hong, LUO Yong-jun. MtDNA haplogroup U4b is a genetic susceptibility factor for high altitude essential hypertension in the Chinese Tajik population[J]. CJAP, 2021, 37(3): 225-229.

参考文献 25

[1]	Fang L, Song J, Ma Z, et al. Prevalence and characteristics of hypertension in mainland Chinese adults over decades: a systematic review[J]. J Hum Hypertens, 2014, 28(11): 649-656.
[2]	Delles C, Mcbride MW, Graham D, et al. Genetics of hypertension: from experimental animals to humans[J]. Biochim Biophys Acta, 2010, 1802(12): 1299-1308.
[3]	Ahn SY, Gupta C. Genetic programming of hypertension[J]. Front Pediatr, 2017, 5: 285.
[4]	Morgado J, Sanches B, Anjos R, et al. Programming of essential hypertension: What pediatric cardiologists need to know[J]. Pediatr Cardiol, 2015, 36(7): 1327-1337.
[5]	Li Q, Lin K, Sun H, et al. Mitochondrial haplogroup M9a1a1c1b is associated with hypoxic adaptation in the Tibetans[J]. J Hum Genet, 2016, 61(12): 1021-1026.
[6]	Li Y, Huang W, Yu Q, et al. Lower mitochondrial DNA content relates to high-altitude adaptation in Tibetans[J]. Mitochondrial DNA A DNA Mapp Seq Anal, 2016, 27(1): 753-757.
[7]	Jiang C, Cui J, Liu F, et al. Mitochondrial DNA 10609T promotes hypoxia-induced increase of intracellular ROS and is a risk factor of high altitude polycythemia[J]. PLoS One, 2014, 9(1): e87775.
[8]	Yin SL, Lan C, Pei H, et al. Mitochondrial transfer RNA mutations and hypertension[J]. Genet Mol Res, 2015, 14(4): 17692-17698.
[9]	Yu SS, Du JM, Tang ZD, et al. Molecular characterization of mitochondrial transferRNAGln and transferRNAMet A4401G mutations in a Chinese family with hypertension[J]. Mol Med Rep, 2017, 15(4): 1832-1836.
[10]	Chen X, Zhang Y, Xu B, et al. The mitochondrial calcium uniporter is involved in mitochondrial calcium cycle dysfunction: Underlying mechanism of hypertension associated with mitochondrial tRNA(Ile) A4263G mutation[J]. Int J Biochem Cell Biol, 2016, 78: 307-314.
[11]	Liu JN, Dolikun M, Stambuk J, et al. The association between subclass-specific IgG Fc N-glycosylation profiles and hypertension in the Uygur, Kazak, Kirgiz, and Tajik populations[J]. J Hum Hypertens, 2018, 32(8-9): 555-563.
[12]	Chen Y, Jiang C, Luo Y, et al. Interaction of CARD14, SENP1 and VEGFA polymorphisms on susceptibility to high altitude polycythemia in the Han Chinese population at the Qinghai-Tibetan Plateau[J]. Blood Cells Mol Dis, 2016, 57: 13-22.
[13]	Bandelt HJ, Kloss-Brandstatter A, Richards MB, et al. The case for the continuing use of the revised cambridge reference sequence (rCRS) and the standardization of notation in human mitochondrial DNA studies[J]. J Hum Genet, 2014, 59(2): 66-77.
[14]	Mani B, Agarwal M, Katiyar-Agarwal S. Comprehensive expression profiling of rice Tetraspanin genes reveals diverse roles during development and abiotic stress[J]. Front Plant Sci, 2015, 6: 1088.
[15]	Bohlen CJ, Chesler AT, Sharif-Naeini R, et al. A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain[J]. Nature, 2011, 479(7373): 410-414.
[16]	Gur E, Sauer RT. Recognition of misfolded proteins by Lon, a AAA(+) protease[J]. Genes Dev, 2008, 22(16): 2267-2277.
[17]	刘祥. 绿脓杆菌外膜蛋白OprF的生物信息学分析[J]. 生物技术, 2015, 25(4): 343-348.
[18]	Mcguffin LJ, Bryson K, Jones DT. The PSIPRED protein structure prediction server[J]. Bioinformatics, 2000, 16(4): 404-405.
[19]	Yachdav G, Kloppmann E, Kajan L, et al. Predict protein-an open resource for online prediction of protein structural and functional features[J]. Nucleic Acids Res, 2014, 42(Web Server issue): W337-W343.
[20]	Biasini M, Bienert S, Waterhouse A, et al. SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information[J]. Nucleic Acids Res, 2014, 42(Web Server issue): W252-W258.
[21]	Tang S, Batra A, Zhang Y, et al. Left ventricular noncompaction is associated with mutations in the mitochondrial genome[J]. Mitochondrion, 2010, 10(4): 350-357.
[22]	Sinyov VV, Chicheva MM, Barinova VA, et al. The heteroplasmy level of some mutations in gene MT-CYB among women with asymptomatic atherosclerosis[J]. Genetika, 2016, 52(8): 951-957.
[23]	Sobenin I A, Chistiakov DA, Sazonova MA, et al. Association of the level of heteroplasmy of the 15059G>A mutation in the MT-CYB mitochondrial gene with essential hypertension[J]. World J Cardiol, 2013, 5(5): 132-140.
[24]	Machida T, Ohta M, Onoguchi A, et al. 5-Hydroxytryptamine induces cyclooxygenase-2 in rat vascular smooth muscle cells: Mechanisms involving Src, PKC and MAPK activation[J]. Eur J Pharmacol, 2011, 656(1-3): 19-26.
[25]	Gutierrez A, Contreras C, Sanchez A, et al. Role of phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) in calcium signaling pathways linked to the alpha1-adrenoceptor in resistance arteries[J]. Front Physiol, 2019, 10: 55.