Διερεύνηση της γενετικής αιτιολογίας της υπέρτασης σε ήπιες μορφές πρωτοπαθούς αλδοστερονισμού

ΕΙΣΑΓΩΓΗ: H έκκριση της αλδοστερόνης ρυθμίζεται κυρίως από την αγγειοτενσίνη I και τα επίπεδα καλίου και δευτερευόντως από την φλοιοεπινεφριδροτρόπο ορμόνη ACTH. Ωστόσο, ασθενείς με θεωρούμενη ιδιοπαθή υπέρταση ανταποκρίνονται σε θεραπεία με ανταγωνιστές των αλατοκορτικοειδών (mineralocorticoid receptor antagonists, MRAs). Ο σκοπός της παρούσας εργασίας ήταν να εξεταστεί μια ειδική ομάδα 21 ασθενών με θεωρούμενη ιδιοπαθή υπέρταση αλλά με υπερέκκριση αλδοστερόνης κάτω από συνθήκες στρες για την ύπαρξη πιθανά παθολογικών παραλλαγών σε γονίδια που εμπλέκονται στη βιοσύνθεση/έκκριση αλδοστερόνης. Οι ασθενείς αυτοί ανταποκρίθηκαν σε θεραπεία με MRAs. Οι παραλλαγές αυτές ενδεχομένως να ευαισθητοποιούν τα κύτταρα της σπειροειδούς ζώνης στην ACTH και να οδηγούν σε υπερέκκριση αλδοστερόνης υπό συνθήκες οξέος ή χρόνιου στρες. MΕΘΟΔΟΣ: Εφαρμόστηκε η η μέθοδος αλληλούχησης όλων των κωδικοποιουσών περιοχών του γονιδιώματος (Whole Exome Sequencing) σε 21 ασθενείς αυτή της ομάδας. Αρχικά αναζητήθηκαν παραλλαγές σε γονίδια που έχουν συσχετιστεί με Πρωτοποπαθή Αλδοστερονισμό (ΠΑ) ή σε γονίδια που κωδικοποιούν ιοντικούς διαύλους που ρυθμίζουν την έκκριση αλδοστερόνης. Παραλλαγές με συχνότητα < 0.01 στον Ευρωπαϊκό πληθυσμό της βάσης δεδομένων 1000genomes, και για τις οποίες προβλέπεται in-silico ότι επηρεάζουν τη δομή των πρωτεϊνών και είναι πιθανά παθολογικές, επιλέχθηκαν για περαιτέρω αναλύση. ΑΠΟΤΕΛΕΣΜΑΤΑ: Πιθανά παθολογικές παραλλαγές ταυτοποιήθηκαν σε 9 από τους 21 ασθενείς που εξετάστηκαν. Επτά ασθενείς ήταν φορείς 6 πιθανά παθολογικών παραλλαγών σε 6 γονίδια που έχουν συσχετιστεί με ΠΑ (KCNK9, KCNK5, ATP13A3, SLC26A2, CACNA1H, CACNA1D). Η παραλλαγή p.V221M που ανιχνεύθηκε στο γονίδιο KCNK9 ήταν νέα, και δεν έχει ταυτοποιηθεί σε άλλους πληθυσμούς. Επίσης, 2 ασθενείς βρέθηκαν να φέρουν πιθανά παθολογικές παραλλαγές σε 2 νέα υποψήφια γονίδια για υπερέκκριση αλδοστερόνης, τα γονίδια KCNK16 (p.P255H) και CACNA2D3 (p.V557I). ΣΥΜΠΕΡΑΣΜΑ: Μέσω της τεχνολογίας WES, ταυτοποιήθηκαν πιθανά παθολογικές γενετικές παραλλαγές σε γονίδια που συμμετέχουν στο μονοπάτι βιοσύνθεσης/έκκρισης αλδοστερόνης σε 9 από τους 21 ασθενείς της μελέτης. Οι παραλλαγές αυτές μπορεί να παίζουν ρόλο στην υπερέκκριση αλδοστερόνης υπό συνθήκες στρες. Η παθολογική επίδραση αυτών των παραλλαγών θα πρέπει να εξεταστεί σε μελλοντικές λειτουργικές μελέτες.Introduction: Aldosterone secretion is mainly regulated by aggeiotensin I and potassium concentrations, while ACTH is considered as a secondary regulator. However, patients with apparent essential hypertension respond to treatment with mineralocorticoid receptor antagonists (MRAs). The aim of the present study was to examine a dinstict cohort of patients with apparent idiopathic hypertension but with stress-induced aldosterone hypersecretion for the presence of potentially damaging variants in genes implicated in aldosterone biosynthesis and/or secretion. Patients responded to treatment with MRAs. These variants may potentially sensitize adrenocortical cells to respond to ACTH leading to aldosterone hypresecreation under conditions of acute or chronic stress. METHODS: We performed Whole Exome Sequencing (WES) in 21 patients of this cohort and variants in genes associated with Primary Aldsteronism (PA) or in ion-channels’ genes regulating aldosterone secretion were prioritized. Variants with frequency < 0.01 in the European population of 1000genomes databse, predicted to alter protein structure and deemed as likely pathogenic by in-silico tools were retained. RESULTS: Potentially damaging variants were identified in 9 out of the 21 patients screened. Seven patients were carriers of six potentially damaging variants in six genes associated with PA (KCNK9, KCNK5, ATP13A3, SLC26A2, CACNA1H, CACNA1D). The variant detected in KCNK9 gene (p.V221M) was novel, not previously reported in other cohorts. Moreover, two patients were found to carry 2 variants in 2 novel susceptibility genes for aldosterone hypersecretion, the KCNK16 (p.P255H) and CACNA2D3 (p.V557I) genes. CONCLUSION: Through WES application, potentially damaging germline variants in genes participating in aldosterone biosynthesis/secretion pathways were identified in 9 of the 21 patients of our study. These variants may play a role in aldosterone hypersecretion under conditions of stress, which was observed in these patients. The pathological effects of these variants should be further examined in the future through functional studies

Unravelling the Genetic Basis of Primary Aldosteronism

Primary aldosteronism (PA), a condition characterized by autonomous aldosterone hypersecretion, constitutes the most common cause of secondary hypertension. Over the last decade, major breakthroughs have been made in the field of genetics underpinning PA. The advent and wide application of Next Generation Sequencing (NGS) technology led to the identification of several somatic and germline mutations associated with sporadic and familial forms of PA. Somatic mutations in ion-channel genes that participate in aldosterone biosynthesis, including KCNJ5, CACNA1D, ATP1A1, and ATP2B3, have been implicated in the development of aldosterone-producing adenomas (APAs). On the other hand, germline variants in CLCN2, KCNJ5, CACNA1H, and CACNA1D genes have been implicated in the pathogenesis of the familial forms of PA, FH-II, FH-III, and F-IV, as well as PA associated with seizures and neurological abnormalities. However, recent studies have shown that the prevalence of PA is higher than previously thought, indicating the need for an improvement of our diagnostic tools. Further research is required to recognize mild forms of PA and to investigate the underlying molecular mechanisms

Unravelling the Genetic Basis of Primary Aldosteronism

Primary aldosteronism (PA), a condition characterized by autonomous aldosterone hypersecretion, constitutes the most common cause of secondary hypertension. Over the last decade, major breakthroughs have been made in the field of genetics underpinning PA. The advent and wide application of Next Generation Sequencing (NGS) technology led to the identification of several somatic and germline mutations associated with sporadic and familial forms of PA. Somatic mutations in ion-channel genes that participate in aldosterone biosynthesis, including KCNJ5, CACNA1D, ATP1A1, and ATP2B3, have been implicated in the development of aldosterone-producing adenomas (APAs). On the other hand, germline variants in CLCN2, KCNJ5, CACNA1H, and CACNA1D genes have been implicated in the pathogenesis of the familial forms of PA, FH-II, FH-III, and F-IV, as well as PA associated with seizures and neurological abnormalities. However, recent studies have shown that the prevalence of PA is higher than previously thought, indicating the need for an improvement of our diagnostic tools. Further research is required to recognize mild forms of PA and to investigate the underlying molecular mechanisms

Association of Cognitive Polygenic Index and Cognitive Performance with Age in Cognitively Healthy Adults

Genome-wide association studies have discovered common genetic variants associated with cognitive performance. Polygenic scores that summarize these discoveries explain up to 10% of the variance in cognitive test performance in samples of adults. However, the role these genetics play in cognitive aging is not well understood. We analyzed data from 168 cognitively healthy participants aged 23–77 years old, with data on genetics, neuropsychological assessment, and brain-imaging measurements from two large ongoing studies, the Reference Abilities Neural Networks, and the Cognitive Reserve study. We tested whether a polygenic index previously related to cognition (Cog PGI) would moderate the relationship between age and measurements of the cognitive domains extracted from a neuropsychological evaluation: fluid reasoning, memory, vocabulary, and speed of processing. We further explored the relationship of Cog PGI and age on cognition using Johnson–Neyman intervals for two-way interactions. Sex, education, and brain measures of cortical thickness, total gray matter volume, and white matter hyperintensity were considered covariates. The analysis controlled for population structure-ancestry. There was a significant interaction effect of Cog PGI on the association between age and the domains of memory (Standardized coefficient = −0.158, p-value = 0.022), fluid reasoning (Standardized coefficient = −0.146, p-value = 0.020), and vocabulary (Standardized coefficient = −0.191, p-value = 0.001). Higher PGI strengthened the negative relationship between age and the domains of memory and fluid reasoning while PGI weakened the positive relationship between age and vocabulary. Based on the Johnson–Neyman intervals, Cog PGI was significantly associated with domains of memory, reasoning, and vocabulary for younger adults. There is a significant moderation effect of genetic predisposition for cognition for the association between age and cognitive performance. Genetics discovered in genome-wide association studies of cognitive performance show a stronger association in young and midlife older adults

Impact of estrogen receptor α gene and oxytocin receptor gene polymorphisms on female sexuality

Over the past decades, research attention has increasingly been paid to the neurobiological component of sexual behavior. The aim of the present study was to investigate the correlation of estrogen receptor α (ERA) gene polymorphism (rs2234693-PvuII) (T→C substitution) and oxytocin receptor gene polymorphism (rs53576) (G→A substitution) with sexuality parameters of young, healthy women. One hundred thirty-three Greek heterosexual women, students in higher education institutions, 20–25 years of age, sexually active, with normal menstrual cycles (28–35 days), were recruited in the study. Exclusion criteria were chronic and/or major psychiatric diseases, use of oral contraceptive pills (OCs), polycystic ovary syndrome (PCOS), thyroid diseases as well as drugs that are implicated in hypothalamus–pituitary–gonadal axis. T allele (wildtype) of rs2234693 (PvuII) polymorphism of ERA gene was correlated with increased levels of arousal and lubrication, whereas A allele (polymorphic) of rs53576 (OXTR) polymorphism was correlated with increased arousal levels. The simultaneous presence of both T allele of rs2234693 (PvuII) and A allele of rs53576 (OXTR) polymorphisms (T + A group) was correlated with increased arousal, orgasm levels as well as female sexual function index full score. To our knowledge, this is the first study to investigate the interaction between ERA and OXTR with regard to sexual function in women. Female sexuality is a complex behavioral trait that encompasses both biological and psychological components. It seems that variability in female sexual response stems from genetic variability that characterizes endocrine, neurotransmitter and central nervous system influences

Sleep Polygenic Risk Score Is Associated with Cognitive Changes over Time

Sleep problems have been associated with cognition, both cross-sectionally and longitudinally. Specific genes have been also associated with both sleep regulation and cognition. In a large group of older non-demented adults, we aimed to (a) validate the association between Sleep Polygenic Risk Score (Sleep PRS) and self-reported sleep duration, and (b) examine the association between Sleep PRS and cognitive changes in a three-year follow-up. Participants were drawn from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). A structured, in-person interview, consisting of a medical history report and physical examination, was conducted for each participant during each of the visits (baseline and first follow-up). In total, 1376 participants were included, having all demographic, genetic, and cognitive data, out of which, 688 had at least one follow-up visit. In addition, an extensive neuropsychological assessment examining five cognitive domains (memory, visuo-spatial ability, attention/speed of processing, executive function, and language) was administered. A PRS for sleep duration was created based on previously published, genome-wide association study meta-analysis results. In order to assess the relationship between the Sleep PRS and the rate of cognitive change, we used generalized estimating equations analyses. Age, sex, education, ApolipoproteinE-ε4 genotype status, and specific principal components were used as covariates. On a further analysis, sleep medication was used as a further covariate. Results validated the association between Sleep PRS and self-reported sleep duration (B = 1.173, E-6, p = 0.001). Further, in the longitudinal analyses, significant associations were indicated between increased Sleep PRS and decreased visuo-spatial ability trajectories, in both the unadjusted (B = −1305.220, p = 0.018) and the adjusted for the covariates model (B = −1273.59, p = 0.031). Similarly, after adding sleep medication as a covariate (B = −1372.46, p = 0.019), none of the associations between Sleep PRS and the remaining cognitive domains were significant. PRS indicating longer sleep duration was associated with differential rates of cognitive decline over time in a group of non-demented older adults. Common genetic variants may influence the association between sleep duration and healthy aging/cognitive health

lncRNA NORAD is consistently detected in breastmilk exosomes and its expression is downregulated in mothers of preterm infants

Breast milk is the ideal food for infants and undoubtedly has immediate and long-term benefits. Breast milk contains extracellular vesicles (EVs) i.e., exosomes secreted by maternal breast cells. Exosomes carry genetic material, such as long non-coding RNAs (lncRNAs), which possibly participate in cell-to-cell communications, as they are known to regulate critical gene pathways. The aim of the present study was to screen human breastmilk exosomes for their lncRNA cargo and to examine exosomal lncRNA levels associated with milk obtained from mothers that gave birth at term or prematurely (<37 weeks of gestation). Samples were collected at 3 weeks postpartum from 20 healthy, breastfeeding mothers; 10 mothers had given birth at full-term and 10 mothers preterm. Exosomal RNA was extracted from all samples and the expression of 88 distinct lncRNAs was determined using reverse transcription-quantitative PCR. A total of 13 lncRNAs were detected in >= 85% of the samples, while 31 were detected in >= 50% of the samples. Differential expression analysis of the lncRNAs between the two groups revealed >= 2-fold differences, with generally higher lncRNA concentrations found in the milk of the mothers that gave birth at term compared with those that gave birth preterm. Among these, the non-coding RNA activated at DNA damage (NORAD) was prominently detected in both groups, and its expression was significantly downregulated in the breast milk exosomes of mothers who delivered preterm. On the whole, the present study demonstrates that breast milk lncRNAs may be important factors of normal early human development. Collectively, the presence of lncRNAs in human breast milk may explain the consistent inability of researchers to fully ‘humanize’ animal milk

Sleep Polygenic Risk Score Is Associated with Cognitive Changes over Time

Sleep problems have been associated with cognition, both cross-sectionally and longitudinally. Specific genes have been also associated with both sleep regulation and cognition. In a large group of older non-demented adults, we aimed to (a) validate the association between Sleep Polygenic Risk Score (Sleep PRS) and self-reported sleep duration, and (b) examine the association between Sleep PRS and cognitive changes in a three-year follow-up. Participants were drawn from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD). A structured, in-person interview, consisting of a medical history report and physical examination, was conducted for each participant during each of the visits (baseline and first follow-up). In total, 1376 participants were included, having all demographic, genetic, and cognitive data, out of which, 688 had at least one follow-up visit. In addition, an extensive neuropsychological assessment examining five cognitive domains (memory, visuo-spatial ability, attention/speed of processing, executive function, and language) was administered. A PRS for sleep duration was created based on previously published, genome-wide association study meta-analysis results. In order to assess the relationship between the Sleep PRS and the rate of cognitive change, we used generalized estimating equations analyses. Age, sex, education, ApolipoproteinE-epsilon 4 genotype status, and specific principal components were used as covariates. On a further analysis, sleep medication was used as a further covariate. Results validated the association between Sleep PRS and self-reported sleep duration (B = 1.173, E-6, p = 0.001). Further, in the longitudinal analyses, significant associations were indicated between increased Sleep PRS and decreased visuo-spatial ability trajectories, in both the unadjusted (B = -1305.220, p = 0.018) and the adjusted for the covariates model (B = -1273.59, p = 0.031). Similarly, after adding sleep medication as a covariate (B = -1372.46, p = 0.019), none of the associations between Sleep PRS and the remaining cognitive domains were significant. PRS indicating longer sleep duration was associated with differential rates of cognitive decline over time in a group of non-demented older adults. Common genetic variants may influence the association between sleep duration and healthy aging/cognitive health

Association of the Polygenic Risk Score With the Probability of Prodromal Parkinson's Disease in Older Adults

Several studies have investigated the association of the Parkinson's disease (PD) polygenic risk score (PRS) with several aspects of well-established PD. We sought to evaluate the association of PRS with the prodromal stage of PD. We calculated PRS in a longitudinal sample (n = 1120) of community dwelling individuals >= 65 years from the HELIAD (The Hellenic Longitudinal Investigation of Aging and Diet) study in order to evaluate the association of this score with the probability of prodromal PD or any of the established risk and prodromal markers in MDS research criteria, using regression multi-adjusted models. Increases in PRS estimated from GWAS summary statistics' ninety top SNPS with p = 30% probability, OR = 1.033, 95%CI: 1.009-1.057 p = 0.006). From the prodromal PD risk markers, significant association was found between PRS and global cognitive deficit exclusively (p = 0.003). To our knowledge, our study is the first population based study investigating the association between PRS scores and prodromal markers of Parkinson's disease. Our results suggest a strong relationship between the accumulation of many common genetic variants, as measured by PRS, and cognitive deficits

Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy

© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remain unclear. We performed a systematic secondary-variant burden analysis of two independent cohorts of patients with Bardet–Biedl syndrome (BBS) with known recessive biallelic pathogenic mutations in one of 17 BBS genes for each individual. We observed a significant enrichment of trans-acting rare nonsynonymous secondary variants in patients with BBS compared with either population controls or a cohort of individuals with a non-BBS diagnosis and recessive variants in the same gene set. Strikingly, we found a significant over-representation of secondary alleles in chaperonin-encoding genes—a finding corroborated by the observation of epistatic interactions involving this complex in vivo. These data indicate a complex genetic architecture for BBS that informs the biological properties of disease modules and presents a model for secondary-variant burden analysis in recessive disorders