Publications by authors named "Paolo Gasparini"

220 Publications

Hearing Function: Identification of New Candidate Genes Further Explaining the Complexity of This Sensory Ability.

Genes (Basel) 2021 Aug 10;12(8). Epub 2021 Aug 10.

Institute for Maternal and Child Health-IRCCS, Burlo Garofolo, 34127 Trieste, Italy.

To date, the knowledge of the genetic determinants behind the modulation of hearing ability is relatively limited. To investigate this trait, we performed Genome-Wide Association Study (GWAS) meta-analysis using genotype and audiometric data (hearing thresholds at 0.25, 0.5, 1, 2, 4, and 8 kHz, and pure-tone averages of thresholds at low, medium, and high frequencies) collected in nine cohorts from Europe, South-Eastern USA, Caucasus, and Central Asia, for an overall number of ~9000 subjects. Three hundred seventy-five genes across all nine analyses were tagged by single nucleotide polymorphisms (SNPs) reaching a suggestive -value ( < 10). Amongst these, 15 were successfully replicated using a gene-based approach in the independent Italian Salus in the Apulia cohort ( = 1774) at the nominal significance threshold ( < 0.05). In addition, the expression level of the replicated genes was assessed in published human and mouse inner ear datasets. Considering expression patterns in humans and mice, eleven genes were considered particularly promising candidates for the hearing function: , , , , , , , and . These findings represent a further contribution to our understanding of the genetic basis of hearing function and its related diseases.
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http://dx.doi.org/10.3390/genes12081228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394865PMC
August 2021

Relationship between clone metrics and clinical outcome in clonal cytopenia.

Blood 2021 Sep;138(11):965-976

Department of Hematology Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Fondazione Policlinico San Matteo, Pavia, Italy.

Clonal cytopenia of undetermined significance (CCUS) is associated with an increased risk of developing a myeloid neoplasm with myelodysplasia (MN). To identify the features of the mutant clone(s) that is associated with clinical phenotype and progression, we studied the following cohorts of individuals: 311 patients with idiopathic cytopenia of undetermined significance (ICUS), 532 community-dwelling individuals without hematologic phenotype (n = 355) or with unexplained anemia (n = 177), and 592 patients with overt MN. Ninety-two of 311 (30%) patients with ICUS carried a somatic genetic lesion that signaled CCUS. Clonal hematopoiesis (CH) was detected in 19.7% and 27.7% of nonanemic and anemic community-dwelling individuals, respectively. Different mutation patterns and variant allele frequencies (VAFs) (clone metrics parameters) were observed in the conditions studied. Recurrent mutation patterns exhibited different VAFs associated with marrow dysplasia (0.17-0.48), indicating variable clinical expressivity of mutant clones. Unsupervised clustering analysis based on mutation profiles identified 2 major clusters, characterized by isolated DNMT3A mutations (CH-like cluster) or combinatorial mutation patterns (MN-like cluster), and showing different overall survival (HR, 1.8). In patients with CCUS, the 2 clusters had different risk of progression to MN (HR, 2.7). Within the MN-like cluster, distinct subsets with different risk of progression to MN were identified based on clone metrics. These findings unveil marked variability in the clinical expressivity of myeloid driver genes and underline the limitations of morphologic dysplasia for clinical staging of mutant hematopoietic clones. Clone metrics appears to be critical for informing clinical decision-making in patients with clonal cytopenia.
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http://dx.doi.org/10.1182/blood.2021011323DOI Listing
September 2021

Taste perception and expression in stomach of bitter taste receptor tas2r38 in obese and lean subjects.

Appetite 2021 11 7;166:105595. Epub 2021 Jul 7.

Department of Medical, Surgical and Health Sciences, University of Trieste, Strada di Fiume, 447, 34149, Trieste, Italy; Surgical Clinic Unit, Cattinara Hospital, ASUGI, Strada di Fiume, 447, 34149, Trieste, Italy.

Differences in taste perception have been related to eating behavior, nutritional status, and diseases. Recently, taste receptors have been identified in several extra-oral tissues, such as the gastrointestinal tract, where they seem to influence processes like digestion, sense of satiety as well as energy balance and intraluminal changes occurring in obesity. Our study aims to analyze differences in taste perception among 42 obese patients (OB) and 41 normal-weight subjects (LEAN). Polymorphisms in the gene codifying for the bitter taste receptor TAS2R38 and its expression on the surface of the gastric mucosa were tested and compared among OB and LEAN. Taste intensity of PROP (6-n-propylthiouracil), quinine, sucrose, citric acid and NaCl were measured on a labeled magnitude scale. DNA from peripheral whole blood was extracted and three polymorphisms in the TAS2R38 gene (rs713598, rs1726866, rs10246939) analyzed. Gastric biopsies were collected during bariatric surgery in OB and during endoscopy in LEAN. RNA was extracted and TAS2R38 gene expression assessed by RT-Real-Time qPCR. Anamnestic and anthropometric data were recorded in all participants during baseline visits. Logistic regression analysis showed that OB perceives sweet (sucrose) and bitter (PROP or 6-n-propylthiouracil) taste more intensely than LEAN (p-value = 0.02 and p-value = 0.005, respectively). While polymorphisms in TAS2R38 gene did not differ among OB and LEAN, we observed a significant increase of TAS2R38 mRNA levels in the stomach of OB compared to LEAN (p = 0.01). Our results provide new evidence of a link between obesity and altered taste perception as well as TAS2R38 expression in the stomach.
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http://dx.doi.org/10.1016/j.appet.2021.105595DOI Listing
November 2021

Variants in USP48 encoding ubiquitin hydrolase are associated with autosomal dominant non-syndromic hereditary hearing loss.

Hum Mol Genet 2021 Sep;30(19):1785-1796

Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.

Non-Syndromic Hereditary Hearing Loss (NSHHL) is a genetically heterogeneous sensory disorder with about 120 genes already associated. Through exome sequencing (ES) and data aggregation, we identified a family with six affected individuals and one unrelated NSHHL patient with predicted-to-be deleterious missense variants in USP48. We also uncovered an eighth patient presenting unilateral cochlear nerve aplasia and a de novo splice variant in the same gene. USP48 encodes a ubiquitin carboxyl-terminal hydrolase under evolutionary constraint. Pathogenicity of the variants is supported by in vitro assays that showed that the mutated proteins are unable to hydrolyze tetra-ubiquitin. Correspondingly, three-dimensional representation of the protein containing the familial missense variant is situated in a loop that might influence the binding to ubiquitin. Consistent with a contribution of USP48 to auditory function, immunohistology showed that the encoded protein is expressed in the developing human inner ear, specifically in the spiral ganglion neurons, outer sulcus, interdental cells of the spiral limbus, stria vascularis, Reissner's membrane and in the transient Kolliker's organ that is essential for auditory development. Engineered zebrafish knocked-down for usp48, the USP48 ortholog, presented with a delayed development of primary motor neurons, less developed statoacoustic neurons innervating the ears, decreased swimming velocity and circling swimming behavior indicative of vestibular dysfunction and hearing impairment. Corroboratingly, acoustic startle response assays revealed a significant decrease of auditory response of zebrafish lacking usp48 at 600 and 800 Hz wavelengths. In conclusion, we describe a novel autosomal dominant NSHHL gene through a multipronged approach combining ES, animal modeling, immunohistology and molecular assays.
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http://dx.doi.org/10.1093/hmg/ddab145DOI Listing
September 2021

The Role of Knockout Olfactory Receptor Genes in Odor Discrimination.

Genes (Basel) 2021 04 23;12(5). Epub 2021 Apr 23.

Institute for Maternal and Child Health-IRCCS, Burlo Garofolo, 34127 Trieste, Italy.

To date, little is known about the role of olfactory receptor (OR) genes on smell performance. Thanks to the availability of whole-genome sequencing data of 802 samples, we identified 41 knockout (KO) OR genes (i.e., carriers of Loss of Function variants) and evaluated their effect on odor discrimination in 218 Italian individuals through recursive partitioning analysis. Furthermore, we checked the expression of these genes in human and mouse tissues using publicly available data and the presence of organ-related diseases in human KO (HKO) individuals for OR expressed in non-olfactory tissues (Fisher test). The recursive partitioning analysis showed that age and the high number (burden) of OR-KO genes impact the worsening of odor discrimination (value < 0.05). Human expression data showed that 33/41 OR genes are expressed in the olfactory system (OS) and 27 in other tissues. Sixty putative mouse homologs of the 41 humans ORs have been identified, 58 of which are expressed in the OS and 37 in other tissues. No association between OR-KO individuals and pathologies has been detected. In conclusion, our work highlights the role of the burden of OR-KO genes in worse odor discrimination.
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http://dx.doi.org/10.3390/genes12050631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145969PMC
April 2021

Dietary Macronutrient Composition in Relation to Circulating HDL and Non-HDL Cholesterol: A Federated Individual-Level Analysis of Cross-Sectional Data from Adolescents and Adults in 8 European Studies.

J Nutr 2021 Aug;151(8):2317-2329

Molecular Epidemiology Research Group, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.

Background: Associations between increased dietary fat and decreased carbohydrate intake with circulating HDL and non-HDL cholesterol have not been conclusively determined.

Objective: We assessed these relations in 8 European observational human studies participating in the European Nutritional Phenotype Assessment and Data Sharing Initiative (ENPADASI) using harmonized data.

Methods: Dietary macronutrient intake was recorded using study-specific dietary assessment tools. Main outcome measures were lipoprotein cholesterol concentrations: HDL cholesterol (mg/dL) and non-HDL cholesterol (mg/dL). A cross-sectional analysis on 5919 participants (54% female) aged 13-80 y was undertaken using the statistical platform DataSHIELD that allows remote/federated nondisclosive analysis of individual-level data. Generalized linear models (GLM) were fitted to assess associations between replacing 5% of energy from carbohydrates with equivalent energy from total fats, SFAs, MUFAs, or PUFAs with circulating HDL cholesterol and non-HDL cholesterol. GLM were adjusted for study source, age, sex, smoking status, alcohol intake and BMI.

Results: The replacement of 5% of energy from carbohydrates with total fats or MUFAs was statistically significantly associated with 0.67 mg/dL (95% CI: 0.40, 0.94) or 0.99 mg/dL (95% CI: 0.37, 1.60) higher HDL cholesterol, respectively, but not with non-HDL cholesterol concentrations. The replacement of 5% of energy from carbohydrates with SFAs or PUFAs was not associated with HDL cholesterol, but SFAs were statistically significantly associated with 1.94 mg/dL (95% CI: 0.08, 3.79) higher non-HDL cholesterol, and PUFAs with -3.91 mg/dL (95% CI: -6.98, -0.84) lower non-HDL cholesterol concentrations. A statistically significant interaction by sex for the association of replacing carbohydrates with MUFAs and non-HDL cholesterol was observed, showing a statistically significant inverse association in males and no statistically significant association in females. We observed no statistically significant interaction by age.

Conclusions: The replacement of dietary carbohydrates with fats had favorable effects on lipoprotein cholesterol concentrations in European adolescents and adults when fats were consumed as MUFAs or PUFAs but not as SFAs.
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http://dx.doi.org/10.1093/jn/nxab077DOI Listing
August 2021

Runs of homozygosity are associated with staging of periodontitis in isolated populations.

Hum Mol Genet 2021 Jun;30(12):1154-1159

Institute for Maternal and Child Health - IRCCS 'Burlo Garofolo', Trieste 34137, Italy.

Periodontitis is a common inflammatory disease characterized by a complex etiology, which is the result of a combination of genetic and environmental factors. Genetic variants linked to the periodontitis disease were already investigated, however, little was known regarding the severity of this disease. Recently, long runs of homozygosity (ROH) were associated with several multifactorial diseases. Therefore, in our work, we tried to assess the role of ROH and periodontitis status. We found an association between the excess of homozygosity owing to ROH and staging of periodontitis. More in detail, the total amount of homozygosity owing to ROH is positively associated with an increased severity of periodontitis (P = 0.0001). Regression tree analysis showed the impact of ROH burden in discriminating individuals with mild periodontitis stages I and II and periodontitis stages III and IV (P < 0.001). Furthermore, ROH mapping highlights several regions associated with a severe status of periodontitis (odds ratio > 1). Among them, we found a total of 33 genes. Interestingly, some of these genes were previously associated with granulocyte or platelet measures, both linked to the onset and the progression of periodontal disease. Our results suggest the not only single variants association test could help to risk assessment but even individual genomic features; furthermore, our ROH mapping highlighted the possible role of multiple genes in periodontal development.
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http://dx.doi.org/10.1093/hmg/ddab085DOI Listing
June 2021

Natural human knockouts and Mendelian disorders: deep phenotyping in Italian isolates.

Eur J Hum Genet 2021 Aug 16;29(8):1272-1281. Epub 2021 Mar 16.

Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.

Whole genome sequencing (WGS) allows the identification of human knockouts (HKOs), individuals in whom loss of function (LoF) variants disrupt both alleles of a given gene. HKOs are a valuable model for understanding the consequences of genes function loss. Naturally occurring biallelic LoF variants tend to be significantly enriched in "genetic isolates," making these populations specifically suited for HKO studies. In this work, a meticulous WGS data analysis combined with an in-depth phenotypic assessment of 947 individuals from three Italian genetic isolates led to the identification of ten biallelic LoF variants in ten OMIM genes associated with known autosomal recessive diseases. Notably, only a minority of the identified HKOs (C7, F12, and GPR68 genes) displayed the expected phenotype. For most of the genes, instead, (ACADSB, FANCL, GRK1, LGI4, MPO, PGAM2, and RP1L1), the carriers showed none or few of the signs and symptoms typically associated with the related diseases. Of particular interest is a case presenting with a FANCL biallelic LoF variant and a positive diepoxybutane test but lacking a full Fanconi anemia phenotypic spectrum. Identifying KO subjects displaying expected phenotypes suggests that the lack of correct genetic diagnoses may lead to inappropriate and delayed treatment. In contrast, the presence of HKOs with phenotypes deviating from the expected patterns underlines how LoF variants may be responsible for broader phenotypic spectra. Overall, these results highlight the importance of in-depth phenotypical characterization to understand the role of LoF variants and the advantage of studying these variants in genetic isolates.
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http://dx.doi.org/10.1038/s41431-021-00850-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384846PMC
August 2021

Genome-wide association study in almost 195,000 individuals identifies 50 previously unidentified genetic loci for eye color.

Sci Adv 2021 Mar 10;7(11). Epub 2021 Mar 10.

Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.

Human eye color is highly heritable, but its genetic architecture is not yet fully understood. We report the results of the largest genome-wide association study for eye color to date, involving up to 192,986 European participants from 10 populations. We identify 124 independent associations arising from 61 discrete genomic regions, including 50 previously unidentified. We find evidence for genes involved in melanin pigmentation, but we also find associations with genes involved in iris morphology and structure. Further analyses in 1636 Asian participants from two populations suggest that iris pigmentation variation in Asians is genetically similar to Europeans, albeit with smaller effect sizes. Our findings collectively explain 53.2% (95% confidence interval, 45.4 to 61.0%) of eye color variation using common single-nucleotide polymorphisms. Overall, our study outcomes demonstrate that the genetic complexity of human eye color considerably exceeds previous knowledge and expectations, highlighting eye color as a genetically highly complex human trait.
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http://dx.doi.org/10.1126/sciadv.abd1239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946369PMC
March 2021

Systematic analysis of factors that improve homologous direct repair (HDR) efficiency in CRISPR/Cas9 technique.

PLoS One 2021 5;16(3):e0247603. Epub 2021 Mar 5.

Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Trieste, Italy.

The CRISPR/Cas9 bacterial system has proven to be an powerful tool for genetic manipulation in several organisms, but the efficiency of sequence replacement by homologous direct repair (HDR) is substantially lower than random indel creation. Many studies focused on improving HDR efficiency using double sgRNA, cell synchronization cycle, and the delivery of single-stranded oligo DNA nucleotides (ssODN) with a rational design. In this study, we evaluate these three methods' synergistic effects to improve HDR efficiency. For our tests, we have chosen the TNFα gene (NM_000594) for its crucial role in various biological processes and diseases. For the first time, our results showed how the use of two sgRNA with asymmetric donor design and triple transfection events dramatically increase the HDR efficiency from an undetectable HDR event to 39% of HDR efficiency and provide a new strategy to facilitate CRISPR/Cas9-mediated human genome editing. Besides, we demonstrated that the TNFα locus could be edited with CRISPR/Cas9 methodology, an opportunity to safely correct, in the future, the specific mutations of each patient.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247603PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935300PMC
September 2021

SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.

Am J Hum Genet 2021 03 16;108(3):502-516. Epub 2021 Feb 16.

Division of Medical Genetics, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008487PMC
March 2021

Differences in taste and smell perception between type 2 diabetes mellitus patients and healthy controls.

Nutr Metab Cardiovasc Dis 2021 01 5;31(1):193-200. Epub 2020 Sep 5.

Institute for Maternal and Child Health - IRCCS ''Burlo Garofolo", Via dell'Istria 65/1, 34137, Trieste, Italy.

Background And Aims: The senses of taste and smell are essential determinants of food choice, which in turn may contribute to the development of chronic diseases, including diabetes. Although past studies have evaluated the relationship between type 2 diabetes mellitus (DM2) and senses disorders, this relationship remains controversial. In this study, we evaluated taste and smell perception in DM2 patients and healthy controls (HC). Moreover, we analyzed the association of chemosensory impairments with anthropometric and clinical outcomes (e.g. Body Mass Index (BMI), Fasting blood glucose (FBG), drugs, cardiovascular diseases (CVD), and hypertension) in DM2 patients.

Methods And Results: The study included 94 DM2 patients and 244 HC. Taste recognition for 6-n-propylthiouracil (PROP), quinine, citric acid, sucrose, and sodium chloride (NaCl) compounds was assessed using a filter paper method, while smell recognition of 12 odorants was performed using a Sniffin' sticks test. We found that a higher percentage of DM2 patients showed identification impairment in salt taste (22% vs. 5%, p-value<0.0009) and smell recognition (55% vs. 27%, p-value = 0.03) compared to HC. We also observed that 65% of hypertensive DM2 subjects presented smell identification impairment compared to 18% of non-hypertensive patients (p-value = 0.019). Finally, patients with impairments in both taste and smell showed elevated FBG compared to patients without impairment (149.6 vs.124.3 mg/dL, p-value = 0.04).

Conclusion: The prevalence of taste and smell identification impairments was higher in DM2 patients compared to HC, and a possible relationship with glycemic levels emerged.
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http://dx.doi.org/10.1016/j.numecd.2020.08.025DOI Listing
January 2021

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

J Clin Endocrinol Metab 2021 01;106(2):e660-e674

Department of Child Neurology, University Children's Hospital Tübingen, Tübingen, Germany.

Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.

Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.

Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated.

Setting: This was a multicenter retrospective study using information collected from 3 predominant centers.

Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.

Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts.

Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients.

Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
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http://dx.doi.org/10.1210/clinem/dgaa700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823228PMC
January 2021

Primary Ciliary Dyskinesia: The Impact of Taste Receptor (TAS2R38) Gene Polymorphisms on Disease Outcome and Severity.

Int Arch Allergy Immunol 2020 13;181(9):727-731. Epub 2020 Jul 13.

Department of Medicine, Surgery and Health Sciences, University of Trieste, Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy.

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disease leading to recurrent respiratory infections of upper and lower airways. Chronic rhinosinusitis (CRS) and bronchiectasis are very common in PCD patients. Recently, it has been shown the presence of taste receptors in respiratory tract and the possible involvement of bitter taste receptor TAS2R38 gene in susceptibility to respiratory infections and rhinosinusitis.

Objective: Aim of this study was to evaluate the frequency of TAS2R38 polymorphisms in PCD patients and their possible correlations with clinical outcomes of the disease.

Methods: Genetic and phenotypic data of 35 PCD patients were collected. Clinical evaluation included neonatal respiratory distress (NRD) at birth, presence of situs inversus, CRS, and bronchiectasis. We also measured the number of respiratory infections per year and the relevant pathogens, Lund-Mackay score, FEV1, and modified Bhalla score. With regard to genetics data, 3 polymorphisms (rs1726866, rs713598, and rs10246939) within TAS2R38 gene were analyzed and the patients were classified as PAV/PAV, PAV/AVI, and AVI/AVI.

Results: A significant difference in the distribution of TAS2R38 haplotype between patients with and without NRD emerged (p value = 0.01). A lower percentage of PAV/PAV individuals showed frequent respiratory exacerbations (≥2/year) (p value = 0.04) compared to those with AVI/AVI and AVI/PAV haplotypes. Moreover, no patients homozygous for PAV/PAV haplotype presented chronic colonization by Pseudomonas aeruginosa, thus supporting the possible role of TAS2R38 gene in susceptibility to respiratory infections.

Conclusions: Here, we report, for the first time, a possible association of TAS2R38 polymorphisms with PCD phenotype.
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http://dx.doi.org/10.1159/000508938DOI Listing
February 2021

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction.

Nat Commun 2020 05 21;11(1):2542. Epub 2020 May 21.

Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-020-15706-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242331PMC
May 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2021 Jun 5;26(6):2111-2125. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
June 2021

A population-based approach for gene prioritization in understanding complex traits.

Hum Genet 2020 May 30;139(5):647-655. Epub 2020 Mar 30.

Institute for Maternal and Child Health IRCCS Burlo Garofolo, Via dell'Istria 65/1, 34137, Trieste, Italy.

Gene prioritization is the process of determining which variants and genes identified in genetic analyses are likely to cause a disease or a variation in a phenotype. For many genes, neither in vitro nor in vivo testing is available, thus assessing their pathogenic role could be challenging, leading to false-positive or false-negative results. In this paper, we propose an innovative score of gene prioritization based on the population of interest. We introduce the concept of singleton-cohort variants (SC variant), a variant that has allele count equal to one in the cohort under study. The difference between the normalized count of SC variants in the coding region and the normalized count of SC variants in the non-coding region should give a hint regarding the level of constraints for that gene in a specific population. This scoring system is negative when there are constraints that allow the presence of SC variants only in the non-coding region; on the contrary, it is positive when there are no constraints. A complimentary score is the sum of SC variants normalized count in both coding and non-coding regions, which could be used as a proxy of positive or strong purifying selection in a specific population. Our methodology showed a high level of constraining for genes such as USP34 in all subpopulations tested (1000 G dataset). In contrast, some genes showed a high negative score only in specific populations, e.g., MYT1L in Europeans, UBR5 in East Asians, and FBXO11 in Africans.
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http://dx.doi.org/10.1007/s00439-020-02152-4DOI Listing
May 2020

A bird's-eye view of Italian genomic variation through whole-genome sequencing.

Eur J Hum Genet 2020 04 29;28(4):435-444. Epub 2019 Nov 29.

Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste, Italy.

The genomic variation of the Italian peninsula populations is currently under characterised: the only Italian whole-genome reference is represented by the Tuscans from the 1000 Genome Project. To address this issue, we sequenced a total of 947 Italian samples from three different geographical areas. First, we defined a new Italian Genome Reference Panel (IGRP1.0) for imputation, which improved imputation accuracy, especially for rare variants, and we tested it by GWAS analysis on red blood traits. Furthermore, we extended the catalogue of genetic variation investigating the level of population structure, the pattern of natural selection, the distribution of deleterious variants and occurrence of human knockouts (HKOs). Overall the results demonstrate a high level of genomic differentiation between cohorts, different signatures of natural selection and a distinctive distribution of deleterious variants and HKOs, confirming the necessity of distinct genome references for the Italian population.
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http://dx.doi.org/10.1038/s41431-019-0551-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080768PMC
April 2020

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
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http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment.

Sci Rep 2019 10 23;9(1):15192. Epub 2019 Oct 23.

Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.

Previous research has shown that genes play a substantial role in determining a person's susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden.
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http://dx.doi.org/10.1038/s41598-019-51630-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811684PMC
October 2019

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Nat Genet 2019 10 2;51(10):1459-1474. Epub 2019 Oct 2.

Department of Neurobiology, Care Sciences and Society, Division of Family Medicine and Primary Care, Karolinska Institutet, Stockholm, Sweden.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.
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http://dx.doi.org/10.1038/s41588-019-0504-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858555PMC
October 2019

Mutations in PLS1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss.

Hum Mutat 2019 12 1;40(12):2286-2295. Epub 2019 Oct 1.

Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.

Nonsyndromic hearing loss (NSHL), a common sensory disorder, is characterized by high clinical and genetic heterogeneity (i.e., approximately 115 genes and 170 loci so far identified). Nevertheless, almost half of patients submitted for genetic testing fail to receive a conclusive molecular diagnosis. We used next-generation sequencing to identify causal variants in PLS1 (c.805G>A, p.[E269K]; c.713G>T, p.[L238R], and c.383T>C, p.[F128S]) in three unrelated families of European ancestry with autosomal dominant NSHL. PLS1 encodes Plastin 1 (also called fimbrin), one of the most abundant actin-bundling proteins of the stereocilia. In silico protein modeling suggests that all variants destabilize the structure of the actin-binding domain 1, likely reducing the protein's ability to bind F actin. The role of PLS1 gene in hearing function is further supported by the recent demonstration that Pls1 mice show a hearing loss phenotype similar to that of our patients. In summary, we report PLS1 as a novel gene for autosomal dominant NSHL, suggesting that this gene is required for normal hearing in humans and mice.
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http://dx.doi.org/10.1002/humu.23891DOI Listing
December 2019

Next generation sequencing study in a cohort of Italian patients with syndromic hearing loss.

Hear Res 2019 09 13;381:107769. Epub 2019 Jul 13.

Institute for Maternal and Child Health - IRCCS "Burlo Garofolo", Trieste, Italy; University of Trieste, Department of Medicine, Surgery and Health Sciences, Trieste, Italy.

Hearing loss (HL), one of the most common congenital disorder, affects about one child in 1000. Among the genetic forms of HL, ∼30% of the cases are associated with other signs or symptoms, leading to Syndromic Hearing Loss (SHL) with about 700 different forms described so far. In this report, we refer the clinical and molecular data of 38 Italian SHL unrelated patients, and their relatives, affected by the most common syndromes associated with HL (i.e., Usher, Pendred, Charge, Waardenburg, Alport, Stickler, Branchiootorenal and Microdeletions syndromes). Patients have been analysed using next-generation sequencing (NGS) and High Density (HD)-SNP array technologies. Data analysis led to the identification of nine novel and 27 known causative mutations in 12 genes and two microdeletions in chromosomes 1 and 10, respectively. In particular, as regards to Usher syndrome, that affects 32% of our patients, we were able to reach a molecular diagnosis in 83% of the cases and to identify in Northern Eastern Italy a very common USH2A gene mutation (39%) (c.11864G > A, p.(Trp3955*) which can be defined "Central-Eastern European allele." As regards to Alport syndrome, we were able to potentially reclassify a pathogenic allele in the COL4A3 gene, previously associated only with benign familial hematuria. In all the other cases, the genomic analysis allowed us to confirm the role of known causative genes and to identify several novel and known alleles. Overall, our results highlight the effectiveness of combining an accurate clinical characterization with the use of genomic technologies (NGS and SNP arrays) for the molecular diagnosis of SHL, with a clear positive impact in the management and treatment of all the patients.
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http://dx.doi.org/10.1016/j.heares.2019.07.006DOI Listing
September 2019

A Brief Review of Genetic Approaches to the Study of Food Preferences: Current Knowledge and Future Directions.

Nutrients 2019 Jul 26;11(8). Epub 2019 Jul 26.

Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Via dell'Istria 65/1, 34137, Trieste, Italy.

Genetic variation plays a crucial role in individual differences in food preferences which ultimately influence food selection and health. Our current understanding of this pathway has been informed through twin studies (to assess the heritability of food preferences), candidate gene studies, and genome-wide association studies (GWAS). However, most of this literature is mainly focused on genes previously identified as having taste or smell functions. New data suggests that genes not associated with taste or smell perception may be involved in food preferences and contribute to health outcomes. This review highlights these emerging findings and suggests a polygenic risk assessment approach to explore new relationships between food preferences and health risks.
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http://dx.doi.org/10.3390/nu11081735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722914PMC
July 2019

A catalog of genetic loci associated with kidney function from analyses of a million individuals.

Nat Genet 2019 06 31;51(6):957-972. Epub 2019 May 31.

Diabetes and Cardiovascular Disease-Genetic Epidemiology, Department of Clincial Sciences in Malmö, Lund University, Malmö, Sweden.

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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http://dx.doi.org/10.1038/s41588-019-0407-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698888PMC
June 2019

A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure.

Hum Mol Genet 2019 08;28(15):2615-2633

Icelandic Heart Association, Kopavogur, Iceland.

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene-smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene-smoking interaction analysis and 38 were newly identified (P < 5 × 10-8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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http://dx.doi.org/10.1093/hmg/ddz070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6644157PMC
August 2019

TAS2R38 bitter taste genotype is associated with complementary feeding behavior in infants.

Genes Nutr 2019 3;14:13. Epub 2019 May 3.

1Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", Via dell'Istria 65/1, 34137 Trieste, Italy.

Background: Genetically mediated sensitivity to bitter taste has been associated with food preferences and eating behavior in adults and children. The aim of this study was to assess the association between TAS2R38 bitter taste genotype and the first complementary food acceptance in infants.Parents of healthy, breastfed, term-born infants were instructed, at discharge from the nursery, to feed their baby with a first complementary meal of 150 mL at 4 to 6 months of age. They recorded the day when the child ate the whole meal in a questionnaire. Additional data included food composition, breastfeeding duration, feeding practices, and growth at 6 months. Infants' TAS2R38 genotypes were determined at birth, and infants were classified as "bitter-insensitive" (genotype AVI/AVI) and "bitter-sensitive" (genotypes AVI/PAV or PAV/PAV).

Results: One hundred seventy-six infants and their mothers were enrolled; completed data were available for 131/176 (74.4%) infants (gestational age 39.3 ± 1.1 weeks, birth weight 3390 ± 430 g). Bitter-insensitive were 45/131 (34.3%), and bitter-sensitive were 86/131 (65.6%). Thirty-one percent of bitter-insensitive infants consumed the whole complementary meal at first attempt, versus 13% of bitter-sensitive ones ( = 0.006). This difference was significant independently of confounding variables such as sex, breastfeeding, or foods used in the meal. Growth at 6 months did not differ between the two groups.

Conclusions: Differences in bitter taste gene were associated with acceptance of the first complementary food in infants, suggesting a possible involvement in eating behavior at weaning.
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http://dx.doi.org/10.1186/s12263-019-0640-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499955PMC
May 2019

Heterogeneity in Circulating Tumor Cells: The Relevance of the Stem-Cell Subset.

Cancers (Basel) 2019 Apr 5;11(4). Epub 2019 Apr 5.

Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy.

The release of circulating tumor cells (CTCs) into vasculature is an early event in the metastatic process. The analysis of CTCs in patients has recently received widespread attention because of its clinical implications, particularly for precision medicine. Accumulated evidence documents a large heterogeneity in CTCs across patients. Currently, the most accepted view is that tumor cells with an intermediate phenotype between epithelial and mesenchymal have the highest plasticity. Indeed, the existence of a meta-stable or partial epithelial⁻mesenchymal transition (EMT) cell state, with both epithelial and mesenchymal features, can be easily reconciled with the concept of a highly plastic stem-like state. A close connection between EMT and cancer stem cells (CSC) traits, with enhanced metastatic competence and drug resistance, has also been described. Accordingly, a subset of CTCs consisting of CSC, present a stemness profile, are able to survive chemotherapy, and generate metastases after xenotransplantation in immunodeficient mice. In the present review, we discuss the current evidence connecting CTCs, EMT, and stemness. An improved understanding of the CTC/EMT/CSC connections may uncover novel therapeutic targets, irrespective of the tumor type, since most cancers seem to harbor a pool of CSCs, and disclose important mechanisms underlying tumorigenicity.
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http://dx.doi.org/10.3390/cancers11040483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521045PMC
April 2019
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