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Background-Essential hypertension has been recognized as a disease resulting from a combination of environmental and genetic factors. Recent studies demonstrated that microRNAs (miRNAs) are involved in cardiac hypertrophy and heart failure. However, little is known about the roles of miRNAs in essential hypertension. Methods and Results-Using microarray-based miRNA expression profiling, we compared the miRNA expressions in plasma samples from 13 hypertensive patients and 5 healthy control subjects. Twenty-seven miRNAs were found to be differentially expressed. The expressions of selected miRNAs (miR-296 -5p, let-7e, and a human cytomegalovirus [HCMV]-encoded miRNA, hcmv-miR-UL112) were validated independently in plasma samples from 24 hypertensive patients and 22 control subjects. The absolute expression levels of hcmv-miR-UL112, miR-296 -5p, and let-7e were further determined in 127 patients and 67 control subjects (fold changes are 2.5, 0.5, and 1.7 respectively; all PϽ0.0001). Additionally, we demonstrated that interferon regulatory factor 1 is a direct target of hcmv-miR-UL112.Increased HCMV seropositivity and quantitative titers were found in the hypertension group compared with the control group (52.7% versus 30.9%, Pϭ0.0005; 1870 versus 54 copies per 1 mL plasma, PϽ0.0001). Seropositivity, log-transformed copies of HCMV, and hcmv-miR-UL112 were independently associated with an increased risk of hypertension (odds ratio, 2.48; 95% confidence interval, 1.48 to 4.15; Pϭ0.0005; odds ratio, 1.97; 95% confidence interval, 1.58 to 2.46; PϽ0.0001; and odds ratio, 2.55; 95% confidence interval, 1.98 to 3.27; PϽ0.0001, respectively). Conclusions-We report for the first time a circulating miRNA profile for hypertensive patients and demonstrate a novel link between HCMV infection and essential hypertension. These findings may reveal important insights into the pathogenesis of essential hypertension. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00420784. Key Words: cytomegalovirus Ⅲ hypertension Ⅲ interferon regulatory factor-1 Ⅲ microRNAs E ssential hypertension is a predisposing risk factor for stroke, myocardial infarction, congestive heart failure, and arterial aneurysm; it is also the leading cause of chronic renal failure. 1 Approximately 90% to 95% of hypertension, affecting Ͼ1 billion adults worldwide, is the essential hypertension subtype. 2 Discernment between essential and secondary hypertension is critical because the former has no precise cause and the latter has a clear cause usually remediable by a Clinical Perspective on p 184 microRNAs (miRNAs) are short, endogenous, noncoding RNAs that regulate gene expression at the posttranscriptional level by binding to the 3Ј untranslated regions (UTRs) of their target mRNAs. 7 Although dysregulation of miRNA expression is a feature of malignancies, 8 -10 research into miRNAs in biological processes reveals their regulation of immune cell development, 11 involvement in inflammatory response, 12 and critical participation...