RESUMO
BACKGROUND: African Americans (AA) remain underrepresented in Alzheimer's disease (AD) research, despite the prevalence of AD being double in AA compared to non-Hispanic whites. To address this disparity, our group has established the Florida Consortium for African American Alzheimer's Disease Studies (FCA3DS), focusing on the identification of genetic risk factors and novel plasma biomarkers. METHOD: Utilizing FCA3DS whole exome sequence (WES) and plasma RNA samples from AD cases (n=151) and cognitively unimpaired (CU) elderly controls (n=269), we have performed differential gene expression (DGE) and expression quantitative trait locus (eQTL) analyses on 50 transcripts measured with a custom nanoString® panel. We designed this panel to measure, in plasma, cell-free mRNA (cf-mRNA) levels of AD-relevant genes. FINDINGS: Association with higher plasma CLU in CU vs. AD remained significant after Bonferroni correction. Study-wide significant eQTL associations were observed with 105 WES variants in cis with 22 genes, including variants in genes previously associated with AD risk in AA such as ABCA7 and AKAP9. Results from this plasma eQTL analysis identified AD-risk variants in ABCA7 and AKAP9 that are significantly associated with lower and higher plasma mRNA levels of these genes, respectively. Receiver operating characteristic analysis of age, sex APOE-ε4 dosage, CLU, APP, CD14, ABCA7, AKAP9 and APOE mRNA levels, and ABCA7 and AKAP9 eQTLs, achieved 77% area under the curve to discriminate AD vs. CU, an 8% improvement over a model that only included age, sex and APOE-ε4 dosage. INTERPRETATION: Incorporating plasma mRNA levels could contribute to improved predictive value of AD biomarker panels. FUNDING: This work was supported by the National Institute on Aging [RF AG051504, U01 AG046139, R01 AG061796 to NET; P30 AG062677 to JAL and NGR]; Florida Health Ed and Ethel Moore Alzheimer's Disease grants [5AZ03 and 7AZ17 to NET; 7AZ07 to MMC; 8AZ08 to JAL].
Assuntos
Doença de Alzheimer , Negro ou Afro-Americano , Transportadores de Cassetes de Ligação de ATP/genética , Negro ou Afro-Americano/genética , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Biomarcadores/sangue , Humanos , RNA Mensageiro/genéticaRESUMO
Male infertility is a devastating problem that affects many couples worldwide. However, the molecular mechanisms and causes of idiopathic male infertility remain unclear. Circulating cell-free nucleic acids have an important role in human physiology and emerging evidence suggests that they play a role in male infertility. This review summarizes recent results on cell-free and intracellular nucleic acids in male infertility and discusses their potential use as biomarkers of male infertility in the clinical practice.
L'infertilité masculine est un problème qui touche de nombreux couples. Cependant, aujourd'hui les mécanismes moléculaires et les causes de l'infertilité masculine idiopathique ne sont pas élucidés. Les acides nucléiques circulant ont un rôle important dans la physiologie et des évidences suggèrent qu'ils jouent un rôle dans l'infertilité masculine. L'objectif de cette revue est de mettre en avant les nouvelles avancées scientifiques sur les acides nucléiques circulant et non-circulant en lien avec l'infertilité masculine et de fournir une vue d'ensemble de leurs utilisation comme biomarqueurs en pratique clinique.