Biomarker potential of <i>hsa-miR-145-5p</i> in peripheral whole blood of manic bipolar I patients

Tekin, Sevinç Sürer; Erdal, Mehmet Emin; Asoğlu, Mehmet; Ay, Özlem İzci; Ay, Mustafa Ertan; Yılmaz, Şenay Görücü

doi:10.47626/1516-4446-2021-2260

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Brazilian Journal of Psychiatry

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Sumário

ORIGINAL ARTICLE • Braz J Psychiatry 44 (4) • Jul-Aug 2022 • https://doi.org/10.47626/1516-4446-2021-2260 copy

Biomarker potential of hsa-miR-145-5p in peripheral whole blood of manic bipolar I patients

Authorship SCIMAGO INSTITUTIONS RANKINGS

Objective:

Bipolar I disorder (BD-I) is a type of bipolar spectrum disorder characterized by manic or mixed episodes. Detecting microRNA regulations as epigenetic actors in BD-I is important to elucidate the pathogenesis of the disease and reveal the potential of microRNAs (miRNAs) as biomarkers.

Methods:

We evaluated the expression profile of six candidate miRNAs (hsa-miR-145-5p, hsa-miR-376a-3p, hsa-miR-3680-5p, hsa-miR-4253-5p, hsa-miR-4482-3p, and hsa-miR-4725) in patients with BD-I and in healthy controls (aged 11-50 years). We also determined the potential target genes of these miRNAs through in silico analysis. The diagnostic values of the miRNAs were calculated through receiver operating characteristic curve analysis.

Results:

Four miRNAs were upregulated (hsa-miR-376a-3p, hsa-miR-3680-5p, hsa-miR-4253-5p, hsa-miR-4482-3p) and hsa-miR-145-5p was downregulated in patients (p < 0.001). The target gene analyses showed that hsa-miR-145-5p specifically targets the dopamine decarboxylase (DDC) gene. The area under the curve of hsa-miR-145-5p was 0.987.

Conclusion:

Differential expression of five miRNAs in peripheral blood may be associated with the pathogenesis of BD-I, and hsa-miR-145-5p has potential as a BD-I biomarker. This miRNA can be used in dopamine-serotonin regulation and dose adjustment in drug therapy via the DDC gene.

Manic; bipolar I disorder; biomarker; miR-145

miRNAs	miRNA ID^† † www.ncbi.nlm.nih.gov/gene.	Nucleotide sequence^‡ ‡ http://www.ncbi.nlm.nih.gov.	Primer-probe sequences
hsa-miR-26b-5p	407017	NR_029500.1	RT-5′-GTCGTATGCAGTGCAGGGTCCGAGGTATTCGCACTGCATACGACACCTAT-3′
			F-5′-GCCGCTTCAAGTAATTCAGG-3′
			PR-FAM-5′-TG(pdC)ATA(pdC)GA(pdC)A(pdC)CTATCC-ZNA4-BHQ-1-3′
hsa-miR-145-5p	406937	NR_029686	RT-5′-GTCGTATGCAGTGCAGGGTCCGAGGTATTCGCACTGCATACGACAGGGAT-3′
			F-5′-GCCGCGTCCAGTTTTCC-3′
			PR-FAM-5′-TG(pdC)ATA(pdC)GA(pdC) AGGGAT-ZNA4-BHQ-1-3′
hsa-miR-4725-3p	100616449	NR_039878	RT-5′-GTCGTATGCAGTGCAGGGTCCGAGGTATTCGCACTGCATACGACCCCGAC-3′
			F-5′-GCCGCTGGGGAAGGC-3′
			PR-FAM-5′-TG(pdC)ATA(pdC)GAC CCCGAC-ZNA4-BHQ-1-3′
hsa-miR-376a-5p	494325	NR_029868	RT-5′-GTCGTATGCAGTGCAGGGTCCGAGGTATTCGCACTGCATACGACTACTCA-3′
			F-5′-GCCGCGTAGATTCTCCTTCTA-3′
			PR-FAM-5′-TG(pdC)ATA(pdC)GA(pdC) TA(pdC)T(pdC)A-ZNA4-BHQ-1-3′
hsa-miR-4482-3p	100616323	NR_039702	RT-5′-GTCGTATGCAGTGCAGGGTCCGAGGTATTCGCACTGCATACGACGAGCCC-3′
			F-5′-GCCGCTTTCTATTTCTCAGTGG-3′
			PR-FAM-5′-TG(pdC)ATA(pdC)GACGAGCCC-ZNA4-BHQ-1-3′
hsa-miR-4253	100422914	NR_036214	RT-5′-GTCGTATGCAGTGCAGGGTCCGAGGTATTCGCACTGCATACGACACCCCC-3′
			F-5-GCCGCAGGGCATGTCCA-3′
			PR-FAM-5′-TG(pdC)ATA(pdC)GACACCCCCT-ZNA4-BHQ-1-3′
hsa-miR-3680-3p	100500917	NR_037451	RT-5′-GTCGTATGCAGTGCAGGGTCCGAGGTATTCGCACTGCATACGACCCTACT-3′
			F-5′-GCCGCTTTTGCATGACCC-3′
			PR-FAM-5′-TG(pdC)ATA(pdC)GA(pdC) C(pdC)TA(pdC)T-ZNA4-BHQ-1-3′
Universal R primer			R-5′-GTGCAGGGTCCGAGGTAT-3′

Characteristics	Control	Patient	p-value	hsa-miR-145-5p	hsa-miR-376a-3p	hsa-miR-3680-3p	hsa-miR-4253	hsa-miR-4482-3p	hsa-miR-4725-3p
Sex, n (%)			0.413	0.952	0.856	0.789	0.855	0.698	0.764
Female	26 (25)	25 (22.4)
Male	26 (25)	31 (27.6)
Age, mean ± SD			> 0.05	0.546	0.995	0.498	0.852	0.779	0.598
Female	29.4±14.4	31.3±10.4
Male	31.5±11.2	30.2±18.3

	Control (n=52)			Patient (n=56)
miRNA	Median ± SD	SE	[25th-75th]	Median ± SD	SE	[25th-75th]	p-value
hsa-miR-145-5p	527.291±9,893.657	1,428.026	[51.596-3,774.886]	0.138±0.821	0.107	[0.043-0.329]	< 0.001^* * p < 0.05 = statistically significant.
hsa-miR-376a-3p	1.466±29.662	4.471	[0.061-5.819]	17.208±8.659	1.167	[1.379-77.273]	< 0.001^* * p < 0.05 = statistically significant.
hsa-miR-3680-3p	1.403±1.908	275.535	[0.002-52.811]	205.746±3.285	4.390	[29.829-1811.22]	< 0.001^* * p < 0.05 = statistically significant.
hsa-miR-4253	13.019±7,976.664	1,151.332	[0.192-510.354]	248.247±2.454	3.251	[23.356-4150.996]	0.001^* * p < 0.05 = statistically significant.
hsa-miR-4482-3p	13.640±3,044.813	422.239	[0.357-129.498]	227.821±1.166	1.519	[61.313-14038.632]	< 0.001^* * p < 0.05 = statistically significant.
hsa-miR-4725-3p	46.642±5,249.445	765.710	[0.997-799.596]	117.586±3.506	4.603	[9.694-863.455]	0.209

miRNAs	AUC	95%CI	SE	p-value	Specificity (%)	Sensitivity (%)	Criterion
hsa-miR-145-5p	0.987	0.943-0.999	0.011	< 0.001	97.92	96.55	≤ 1.937
hsa-miR-376a-5p	0.730	0.632-0.815	0.050	< 0.001	77.27	67.27	> 140.396
hsa-miR-3680-3p	0.834	0.748-0.900	0.039	< 0.001	93.75	48.21	> 13.424
hsa-miR-4253	0.695	0.597-0.781	0.051	< 0.001	52.08	84.21	> 14.048
hsa-miR-4482-3p	0.811	0.726-0.879	0.038	< 0.001	65.38	79.66	> 49.013

miRNA	AUC for multiple logistic regression	95%CI	Standard error	p-value	R²
hsa-miR-145-5p+hsa-miR-376a-5p	0.988	0.966-1.000	0.011	< 0.0001*	0.687
hsa-miR-145-5p+hsa-miR-3680-3p	0.987	0.966-1.000	0.011	< 0.0001*	0.683
hsa-miR-145-5p+hsa-miR-4253	0.987	0.967-1.000	0.010	< 0.0001*	0.685
hsa-miR-145-5p+hsa-miR-4482-3p	0.989	0.970-1.000	0.010	< 0.0001*	0.688
hsa-miR-145-5p+hsa-miR-4725-3p	0.988	0.994-1.000	0.002	< 0.0001*	0.705
hsa-miR-376a-5p+hsa-miR-3680-3p	0.845	0.763-0.926	0.041	< 0.0001*	0.076
hsa-miR-376a-5p+hsa-miR-4253	0.744	0.645-0.844	0.051	< 0.0001*	0.097
hsa-miR-376a-5p+hsa-miR-4482-3p	0.821	0.739-0.903	0.042	< 0.0001*	0.098
hsa-miR-376a-5p+hsa-miR-4725-3p	0.606	0.491-0.721	0.059	0.081	0.082
hsa-miR-3680-3p+hsa-miR-4253	0.593	0.480-0.706	0.058	0.111	0.088
hsa-miR-3680-3p+hsa-miR-4482-3p	0.794	0.709-0.879	0.043	< 0.0001*	0.083
hsa-miR-3680-3p+hsa-miR-4725-3p	0.764	0.668-0.860	0.049	< 0.0001*	0.085
hsa-miR-4253+hsa-miR-4482-3p	0.789	0.703-0.875	0.044	< 0.0001*	0.095
hsa-miR-4253 + hsa-miR-4725-3p	0.699	0.597-0.802	0.052	0.001*	0.096
hsa-miR-4482-3p+hsa-miR-4725-3p	0.735	0.639-0.831	0.049	< 0.0001*	0.093
hsa-miR-145+hsa-miR-376a-5p+hsa-miR-3680-3p	0.986	0.963-1.000	0.012	< 0.0001*	0.682
hsa-miR-145+hsa-miR-376a-5p+hsa-miR-4253	0.987	0.965-1.000	0.011	< 0.0001*	0.683
hsa-miR-145+hsa-miR-376a-5p+hsa-miR-4482-3p	0.988	0.968-1.000	0.010	< 0.0001*	0.689
hsa-miR-145+hsa-miR-376a-5p+hsa-miR-4725-3p	0.998	0.994-1.000	0.002	< 0.0001*	0.705
hsa-miR-145+hsa-miR-3680-3p+hsa-miR-4253	0.987	0.966-1.000	0.011	< 0.0001*	0.683
hsa-miR-145+hsa-miR-3680-3p+hsa-miR-4482-3p	0.987	0.966-1.000	0.011	< 0.0001*	0.683
hsa-miR-145+ hsa-miR-3680-3p+hsa-miR-4725-3p	0.998	0.993-1.000	0.002	< 0.0001*	0.703
hsa-miR-145-5p+hsa-miR-4253+hsa-4482-3p	0.998	0.968-1.000	0.010	< 0.0001*	0.686
hsa-miR-145-5p+hsa-miR-4253+hsa-4725-3p	0.998	0.993-1.000	0.002	< 0.0001*	0.705
hsa-miR-145-5p+hsa-miR-4482-3p+hsa-4725-3p	0.998	0.994-1.000	0.002	< 0.0001*	0.706
hsa-miR-376a-5p+hsa-miR-3680-3p+hsa-miR-4253	0.650	0.533-0.767	0.060	0.017*	0.079
hsa-miR-376a-5p+hsa-miR-3680-3p+hsa-miR-4482-3p	0.842	0.761-0.923	0.041	< 0.0001*	0.077
hsa-miR-376a-5p+hsa-miR-3680-3p+hsa-miR-4725-3p	0.704	0.591-0.818	0.058	0.001	0.064
hsa-miR-376a-5p+hsa-miR-4253+hsa-miR-4482-3p	0.735	0.632-0.837	0.052	< 0.0001*	0.100
hsa-miR-376a-5p+hsa-miR-4253+hsa-miR-4725-3p	0.662	0.549-0.776	0.058	0.009*	0.098
hsa-miR-3680-3p+hsa-miR-4253+hsa-miR-4482-3p	0.772	0.678-0.876	0.048	< 0.0001*	0.088
hsa-miR-3680-3p+hsa-miR-4253+hsa-miR-4725-3p	0.593	0.477-0.709	0.059	0.119	0.092
hsa-miR-3680-3p+hsa-miR4482-3p+hsa-miR-4725-3p	0.723	0.621-0.825	0.052	< 0.0001*	0.085
hsa-miR-4253+hsa-miR-4482-3p+hsa-miR-4725-3p	0.669	0.563-0.774	0.054	0.004*	0.099
hsa-miR-145-5p+hsa-miR-376a-5p+hsa-miR-3680-3p+hsa-miR-4253	0.986	0.962-1.000	0.012	< 0.0001*	0.681
hsa-miR-145-5p+hsa-miR-376a-5p+hsa-miR-3680-3p+hsa-miR-4482-3p	0.986	0.963-1.000	0.012	< 0.0001*	0.682
hsa-miR-145-5p+hsa-miR-376a-5p+hsa-miR-3680-3p+hsa-miR-4725-3p	0.998	0.993-1.000	0.003	< 0.0001*	0.703
hsa-miR-145-5p+hsa-miR-376a-5p+hsa-miR-4253+hsa-4482-3p	0.987	0.966-1.000	0.011	< 0.0001*	0.684
hsa-miR-145-5p+hsa-miR-376a-5p+hsa-miR-4253+hsa-4725-3p	0.998	0.993-1.000	0.002	< 0.0001*	0.705
hsa-miR-145-5p+hsa-miR-3680-3p+hsa-miR-4253+hsa-miR-4482-3p	0.987	0.966-1.000	0.011	< 0.0001*	0.683
hsa-miR-145-5p+hsa-miR-3680-3p+hsa-miR-4253+hsa-miR-4725-3p	0.998	0.993-1.000	0.002	< 0.0001*	0.703
hsa-miR-145-5p+hsa-miR-4253+hsa-miR-4482-3p+hsa-miR-4725-3p	0.998	0.993-1.000	0.002	< 0.0001*	0.706
hsa-miR-3680-3p+hsa-miR-4253+hsa-miR-4482-3p+hsa-miR-4725-3p	0.688	0.581-0.795	0.055	0.002*	0.092
hsa-miR-145-5p+hsa-miR-376a-5p+hsa-miR-3680-3p+hsa-miR-4253+miR-4482-3p	0.986	0.962-1.000	0.012	< 0.0001*	0.681
hsa-miR-145-5p+hsa-miR-376a-5p+hsa-miR-3680-3p+hsa-miR-4253+hsa-miR-4725-3p	0.998	0.992-1.000	0.003	< 0.0001*	0.704
hsa-miR-376a-5p+hsa-miR-3680-3p+hsa-miR-4253+hsa-miR-4482-3p+miR-4725-3p	0.694	0.581-0.807	0.058	0.002*	0.080
hsa-miR-145-5p+hsa-miR-376a-5p+hsa-miR-3680-3p+hsa-miR-4253+hsa-miR-4482-3p+hsa-miR-4725	0.898	0.811-0.954	0.039	< 0.0001*	0.872

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[1] Correspondence: Şenay Görücü Yılmaz, Gaziantep University, Department of Nutrition and Dietetics, University Avenue, 27310 Sehitkami, Gaziantep, Turkey. E-mail: gorucu@gantep.edu.tr