Genome-wide association study of mitochondrial DNA in Chinese men identifies seven new susceptibility loci for high-altitude pulmonary oedema

Caizhi Tang; Yu Chen; Xinyuan Liu; Zhuang Ran; Yongjun Luo

doi:10.2298/VSP191027063T

Caizhi Tang Army Medical University, Army Medical Service Training Base, Department of Military Medical Geography, Chongqing, China
Yu Chen Army Medical University, Army Medical Service Training Base, Department of Military Medical Geography, Chongqing, China
Xinyuan Liu Army Medical University, Army Medical Service Training Base, Department of Military Medical Geography, Chongqing, China
Zhuang Ran Army Medical University, Army Medical Service Training Base, Department of Military Medical Geography, Chongqing, China Army Medical Service Training Base, Amy Medical University, Chongqing 400038, China
Yongjun Luo Army Medical University, Army Medical Service Training Base, Department of Military Medical Geography, Chongqing, China

DOI: https://doi.org/10.2298/VSP191027063T

Keywords: genetic techniques;, genome;, hypoxia;, polymorphism, genetic;, pulmonary oedema;, pulmonaty edema of mountaineers

Abstract

Background/Aim. High-altitude pulmonary oedema (HAPE), which normally occurs at altitudes higher than 3,000 m, is a potentially fatal disease due to hypoxia. The role of mitochondrial genomes in determining an individual's susceptibility to HAPE has not been determined yet. However, a number of genetic polymorphisms have recently been found to be overrepresented in HAPE patients. The majority of published genome-wide association studies have investigated only a small number of top-ranking single-nucleotide polymorphisms (SNPs)/genes by the overview of nuclear DNA and considered each of the identified SNPs/genes independently. Little research has been conducted on mitochondrial genomes in relapsing HAPE patients by genome-wide association studies. Methods. To identify biological pathways important to HAPE occurrence, we examined approximately 500,000 SNPs genome-wide from 10 unrelated cases of relapsing HAPE and we compared the SNPs in these cases with those in the Chinese in Beijing, China population (45 controls) to discover the association between genotypes and HAPE susceptibility among the mitochondrial function-related genes. We used the FUMA platform to expand those SNPs to selected candidate SNPs. Results. A total of 369 candidate SNPs, 4 lead SNPs, 4 genomic risk loci and 5 mapped genes were obtained. The 7 mapped genes were ADAMTS9-AS2, NEK1, CLCN3, C4orf27(HPF1), RP11-219J21.2, ANKRD26 and YME1L1. Conclusion. This study confirms the association of ADAMTS9-AS2, NEK1, CLCN3, C4orf27(HPF1), RP11-219J21.2, ANKRD26 and YME1L1 with HAPE, which may provide future targets for the treatment of this disease.

References

Menon ND. High-Altitude Pulmonary Edema: A Clinical Study. N Engl J Med 1965; 273: 66‒3.

Peacock AJ. High altitude pulmonary oedema: who gets it and why? Eur Respir J 1995; 8(11): 1819‒21.

Sartori C, Trueb L, Scherrer U. High-altitude pulmonary edema. Mechanisms and management. Cardiologia 1997; 42(6): 559‒67.

Schoene RB. High-altitude pulmonary edema: more lessons from the master. Wilderness Environ Med 1997; 8(4): 202‒3.

Mortimer H, Patel S, Peacock AJ. The genetic basis of high-altitude pulmonary oedema. Pharmacol Ther 2004; 101(2): 183‒92.

Ahsan A, Mohd G, Norboo T, Baig MA, Pasha MA. Heterozy-gotes of NOS3 polymorphisms contribute to reduced nitrogen oxides in high-altitude pulmonary edema. Chest. 2006; 130(5): 1511‒9.

Luo Y, Gao W, Chen Y, Liu F, Gao Y. Rare mitochondrial DNA polymorphisms are associated with high altitude pulmo-nary edema (HAPE) susceptibility in Han Chinese. Wilderness Environ Med 2012; 23(2): 128‒32.

Charu R, Stobdan T, Ram RB, Khan AP, Qadar Pasha MA, Nor-boo T, et al. Susceptibility to high altitude pulmonary oedema: role of ACE and ET-1 polymorphisms. Thorax. 2006; 61(11): 1011‒2.

Wang Y, Liu VW, Xue WC, Tsang PC, Cheung AN, Ngan HY. The increase of mitochondrial DNA content in endometrial adenocarcinoma cells: a quantitative study using laser-captured microdissected tissues. Gynecol Oncol 2005; 98(1): 104‒10.

Xing J, Chen M, Wood CG, Lin J, Spitz MR, Ma J, et al. Mito-chondrial DNA content: its genetic heritability and association with renal cell carcinoma. J Nat Cancer Inst 2008; 100(15): 1104‒12.

Lewis W, Day BJ, Kohler JJ, Hosseini SH, Chan SS, Green EC, et al. Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant poly-merase gamma. Lab Invest 2007; 87(4): 326‒35.

Morten KJ, Ashley N, Wijburg F, Hadzic N, Parr J, Jayawant S, et al. Liver mtDNA content increases during development: a comparison of methods and the importance of age- and tissue-specific controls for the diagnosis of mtDNA depletion. Mito-chondrion 2007; 7(6): 386‒95.

Luo Y, Liao W, Chen Y, Cui J, Liu F, Jiang C, et al. Altitude can alter the mtDNA copy number and nDNA integrity in sperm. J Assist Reprod Genet 2011; 28(10): 951‒6.

Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005; 6(2): 95‒108.

Yang YZ, Wang YP, Ma L, Du Y, Ge RL. Genome-wide asso-ciation study of high-altitude pulmonary edema in Han Chi-nese. Yi Chuan 2013; 35(11): 1291‒9. (Chinese)

Hultgren HN, Marticorena EA. High altitude pulmonary edema. Epidemiologic observations in Peru. Chest 1978; 74(4): 372‒6.

Watanabe K, Taskesen E, van Bochoven A, Posthuma D. Function-al mapping and annotation of genetic associations with FU-MA. Nat Commun 2017; 8(1): 1826.

Cal S, Obaya AJ, Llamazares M, Garabaya C, Quesada V, Lopez-Otin C. Cloning, expression analysis, and structural characteri-zation of seven novel human ADAMTSs, a family of metallo-proteinases with disintegrin and thrombospondin-1 domains. Gene 2002; 283(1‒2): 49‒62.

Apte SS. A disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motifs: the ADAMTS family. Int J Biochem Cell Biol 2004; 36(6): 981‒5.

Hotta J, Hanaoka M, Droma Y, Katsuyama Y, Ota M, Kobayashi T. Polymorphisms of renin-angiotensin system genes with high-altitude pulmonary edema in Japanese subjects. Chest 2004; 126(3): 825‒30.

Loffek S, Schilling O, Franzke CW. Series "matrix metallopro-teinases in lung health and disease": Biological role of matrix metalloproteinases: a critical balance. Eur Respir J 2011; 38(1): 191‒208.

Churg A, Zhou S, Wright JL. Series "matrix metalloproteinases in lung health and disease": Matrix metalloproteinases in COPD. Eur Respir J 2012; 39(1): 197‒209.

Cui N, Hu M, Khalil RA. Biochemical and Biological Attrib-utes of Matrix Metalloproteinases. Prog Mol Biol Transl Sci 2017; 147: 1‒73.

Jentsch TJ, Pusch M. CLC Chloride Channels and Transporters: Structure, Function, Physiology, and Disease. Physiol Rev 2018; 98(3): 1493‒590.

Guan YY, Wang GL, Zhou JG. The ClC-3 Cl- channel in cell volume regulation, proliferation and apoptosis in vascular smooth muscle cells. Trends Pharmacol Sci 2006; 27(6): 290‒6.

Dai YP, Bongalon S, Hatton WJ, Hume JR, Yamboliev IA. ClC-3 chloride channel is upregulated by hypertrophy and inflamma-tion in rat and canine pulmonary artery. Br J Pharmacol 2005; 145(1): 5‒14.

Guison J, Blaison G, Stoica O, Hurstel R, Favier M, Favier R. Idi-opathic Pulmonary Embolism in a case of Severe Family ANKRD26 Thrombocytopenia. Mediterr J Hematol Infect Dis 2017; 9(1): e2017038.

Chen Y, Gaczynska M, Osmulski P, Polci R, Riley DJ. Phos-phorylation by Nek1 regulates opening and closing of voltage dependent anion channel 1. Biochem Biophys Res Commun 2010; 394(3): 798‒803.

El-Hattab AW, Suleiman J, Almannai M, Scaglia F. Mitochon-drial dynamics: Biological roles, molecular machinery, and re-lated diseases. Mol Genet Metab 2018; 125(4): 315‒21.

Quiros PM, Langer T, Lopez-Otin C. New roles for mitochon-drial proteases in health, ageing and disease. Nat Rev Mol Cell Biol. 2015; 16(6): 345‒59.

Rainbolt TK, Lebeau J, Puchades C, Wiseman RL. Reciprocal Degradation of YME1L and OMA1 Adapts Mitochondrial Proteolytic Activity during Stress. Cell Rep 2016; 14(9): 2041‒9.

Guillery O, Malka F, Landes T, Guillou E, Blackstone C, Lombes A, et al. Metalloprotease-mediated OPA1 processing is modu-lated by the mitochondrial membrane potential. Biol Cell 2008; 100(5): 315‒25.

Hartmann B, Wai T, Hu H, MacVicar T, Musante L, Fischer-Zirnsak B, et al. Homozygous YME1L1 mutation causes mito-chondriopathy with optic atrophy and mitochondrial network fragmentation. Elife 2016; 5: pii: e16078.

Bartlett E, Bonfiglio JJ, Prokhorova E, Colby T, Zobel F, Ahel I, et al. Interplay of Histone Marks with Serine ADP-Ribosylation. Cell Rep 2018; 24(13): 3488‒502. e5.

Langelier MF, Eisemann T, Riccio AA, Pascal JM. PARP family enzymes: regulation and catalysis of the poly(ADP-ribose) posttranslational modification. Curr Opin Struct Biol 2018; 53: 187‒98.