Whole Mitochondrial Genomic Association Study Of Essential Hypertension In Chinese General Population

Background: Essential hypertension (EH), an established risk factor for stroke,coronary heart disease, congestive heart failure and renal dysfunction, remains one ofthe greatest public health issues world-widely. The morbidity of EH is increasingly high,however the etiology of hypertension is still not well understood due to multifactorialcauses such as environmental and genetic factors. It has been reported that maternalinheritance exerts much influence on blood pressure. Yet, the nuclear genome hasalways been the focus of study on genetic risk factors and only limited insights havebeen gained for the relationship between hypertension and the mitochondrial genome.Additionally, the fact thatthe detection of diseases associated genetic variants could notbe well replicated in different studies indicates the influence of clinical andenvironmental factors on genetic susceptibility to phynotype as well asgene-environmental interaction. However, the interaction between mitochondrialgenetic variants and those hypertension associated clinical and environmental factors isstill unclear and deserves further exploration.Part1.Screening for hypertension associated genetic variants inthe whole mitochondrial genomeObjective:To date, accumulated evidences supported the contribution of mitochondrialgenetic variants to essential hypertension. However, most of the associated variantswere tRNA variants detected in pedigree patients with maternally inherited hypertension.It is still uncertain whether the remaining parts of mitochondrial genome could attributeto the susceptibility of essential hypertension (EH). This study aimed to investigate therelationship between mitochondrial genetic variants and essential EH in Chinese general population.Methods: Demographic and clinical matched100hypertensive patients and100controls from Shanxi province (West of China) were recruited. Whole mitochondrialgenome was re-sequenced by Sanger method with DNA extracted from the peripheralwhole blood of each patient. The distribution of each mitochondrial genetic variant inhypertensive patients and controls was compared.Results: A total of537genetic variants were detected in mitochondrial genome with29variants in tRNA genes,45variants in rRNA genes,10variants in D-Loop functionalregions and453variants in protein-coding genes.No statistical difference could befound between EH patients and controls for the distribution of tRNA, rRNA and D-loopgenetic variants. Compared with controls, the occurrence of C5178A (rs28357984) ofND2gene in EH cases was significantly lower [18%(18in100) vs.31%(31in100), P=0.03]. Similarly, the occurrence of C8414T (rs28358884) of ATP8gene in EH caseswas significantly lower than that in controls [10%(10in100) vs.22%(22in100), P=0.02]. No other mitochondrial variant exhibited significantly different distributionbetween EH cases and controls.Conclusion: This study provides the evidence that mitochondrial genetic variants ofC5178A in ND2gene and C8414T in ATP8gene may exert protective role against EHin Chinese population. The present evidence may aid in the identification of the geneticbasis of EH and help identify high risk individuals. Part2.Validation for hypertension associated mitochondrialvariantsand the influence of gene-environment interactions onessential hypertensionObjective: This study aimed to evaluate the protective role of the mitochondrial geneticvariant ND2C5178A and ATP8C8414T as well as the related gene-environmentinteraction on essential hypertension (EH) in Chinese population. Methods: EH cases and controls were recruited consecutively from Institute ofGeriatric Cardiology and Health Examination Center in General Hospital of ChinesePeople’s Liberation Army from February2013to January2014. Demographic andclinical characteristics were recorded. Mitochondrial genetic variant ND2C5178A andATP8C8414T were genotyped with the method of SNaPshot for each participant. Theassociation between ND2C5178A, ATP8C8414T and EH, as well as the influence ofgene-environment interaction were analyzed.Results: A total of797EH cases and816controls were recruited. Genotyping analysisshowed that compared to ND25178C, ND25178A was associated with a lower risk forEH [24.59%(196in797) in EH vs.32.72%(267in816) in control; adjusted OR:0.618,95%CI:0.485-0.789, P<0.001]. Compared to ATP88414C, ATP88414T wasassociated with a lower risk for EH [17.69%(141in797) in EH vs.23.16%(189in816)in control; adjusted OR:0.677,95%CI:0.516-0.888, P=0.005]. Logistic regressionanalysis showed that smoking (OR:1.499,95%CI:1.103-2.035, P=0.01),triglyceride(OR:1.759,95%CI:1.252-2.472, P=0.001) and urea nitrogen (OR:1.183,95%CI:1.067-1.313, P=0.001) were independent risk factors for EH only in subjectswith ND25178Cbut not in those with5178A，and HDL-C (OR:0.357,95%CI:0.164-0.780, P=0.01) was the protective factor only in subjects with5178A but not inthose with5178C. Similarly, smoking (OR:1.434,95%CI:1.075-1.912, P=0.01),triglyceride (OR:1.678,95%CI:1.216-2.315, P=0.002) and urea nitrogen (OR:1.186,95%CI:1.073-1.311, P=0.001) were independent risk factors for EH only in subjectswith ATP88414Cbut not in those with8414T， and HDL-C (OR:0.321,95%CI:0.128-0.80, P=0.02) was the protective factor only in subjects with8414T butnot in those with8414C.Conclusion: Mitochondrial ND2C5178A and ATP8C8414T exert protective roleagainst EH in Chinese population. They interact with hypertension associatedenvironmental factors including smoking, triglyceride, urea nitrogen and high-densitylipoprotein cholesterol to influence the susceptibility of EH. The present study may guide for the individualized prevention st rategies for EH.