BackgroundHypertension is a leading cause of death worldwide. Population-based studies offer an o... more BackgroundHypertension is a leading cause of death worldwide. Population-based studies offer an opportunity to assess the effectiveness of anti-hypertensive drugs (AHD) in real-world scenarios. However, lack of quality AHD documentation, especially when electronic health record linkage is unavailable, leads to reporting and classification bias. Here we assessed to which extent Renin-Angiotensin-Aldosterone System (RAAS) biomarkers can identify AHD treatments in the general population.MethodAngiotensin I, angiotensin II and aldosterone levels were simultaneously determined through mass-spectrometry analysis in 800 participants of the Cooperative Health Research In South Tyrol (CHRIS) study with documented AHD treatment. We conducted unsupervised cluster analysis, assessing agreement, sensitivity and specificity of the resulting clusters against known AHD treatment. Through lasso penalized regression we identified clinical characteristics associated with RAAS biomarkers, accounting fo...
To characterize COVID-19 epidemiology, numerous population-based studies have been undertaken to ... more To characterize COVID-19 epidemiology, numerous population-based studies have been undertaken to model the risk of SARS-CoV-2 infection. Less is known about what may drive the probability to undergo testing. Understanding how much testing is driven by contextual or individual conditions is important to delineate the role of individual behavior and to shape public health interventions and resource allocation. In the Val Venosta/Vinschgau district (South Tyrol, Italy), we conducted a population-representative longitudinal study on 697 individuals susceptible to first infection who completed 4,512 repeated online questionnaires at four week intervals between September 2020 and May 2021. Mixed-effects logistic regression models were fitted to investigate associations of self-reported SARS-CoV-2 testing with individual characteristics (social, demographic, and biological) and contextual determinants. Testing was associated with month of reporting, reflecting the timing of both the pandem...
Recall by genotype (RbG) studies aim to better understand the phenotypes that correspond to genet... more Recall by genotype (RbG) studies aim to better understand the phenotypes that correspond to genetic variants of interest, by recruiting carriers of such variants for further phenotyping. RbG approaches pose major ethical and legal challenges related to the disclosure of possibly unwanted genetic information. The Cooperative Health Research in South Tyrol (CHRIS) study is a longitudinal cohort study based in South Tyrol, Italy. Demand has grown for CHRIS study participants to be enrolled in RbG studies, thus making the design of a suitable ethical framework a pressing need. We here report upon the design of a pilot RbG study conducted with CHRIS study participants. By reviewing the literature and by consulting relevant stakeholders (CHRIS participants, clinical geneticists, ethics board, GPs), we identified key ethical issues in RbG approaches (e.g. complexity of the context, communication of genetic results, measures to further protect participants). The design of the pilot was base...
Background and Objectives: Although several studies demonstrated that platelet count is higher in... more Background and Objectives: Although several studies demonstrated that platelet count is higher in women, decreases with age, and is influenced by genetic background, most clinical laboratories still use the reference interval 150-400610 9 platelets/L for all subjects. The present study was to identify age-and sex-specific reference intervals for platelet count. Methods: We analysed electronic records of subjects enrolled in three population-based studies that investigated inhabitants of seven Italian areas including six geographic isolates. After exclusion of patients with malignancies, liver diseases, or inherited thrombocytopenias, which could affect platelet count, reference intervals were estimated from 40,987 subjects with the non parametric method computing the 2.5u and 97.5u percentiles. Results: Platelet count was similar in men and women until the age of 14, but subsequently women had steadily more platelets than men. The number of platelets decreases quickly in childhood, stabilizes in adulthood, and further decreases in oldness. The final result of this phenomenon is that platelet count in old age was reduced by 35% in men and by 25% in women compared with early infancy. Based on these findings, we estimated reference intervals for platelet count 610 9 /L in children (176-452), adult men (141-362), adult women (156-405), old men (122-350) and, old women (140-379). Moreover, we calculated an ''extended'' reference interval that takes into account the differences in platelet count observed in different geographic areas. Conclusions: The age-, sex-, and origin-related variability of platelet count is very wide, and the patient-adapted reference intervals we propose change the thresholds for diagnosing both thrombocytopenia and thrombocytosis in Italy.
Anaemia is a chief determinant of globalill health, contributing to cognitive impairment, growth ... more Anaemia is a chief determinant of globalill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P <10 −8 , which together explain 4-9% of
Background: Not all obese subjects have an adverse metabolic profile predisposing them to develop... more Background: Not all obese subjects have an adverse metabolic profile predisposing them to developing type 2 diabetes or cardiovascular disease. The BioSHaRE-EU Healthy Obese Project aims to gain insights into the consequences of (healthy) obesity using data on risk factors and phenotypes across several large-scale cohort studies. Aim of this study was to describe the prevalence of obesity, metabolic syndrome (MetS) and metabolically healthy obesity (MHO) in ten participating studies. Methods: Ten different cohorts in seven countries were combined, using data transformed into a harmonized format. All participants were of European origin, with age 18-80 years. They had participated in a clinical examination for anthropometric and blood pressure measurements. Blood samples had been drawn for analysis of lipids and glucose. Presence of MetS was assessed in those with obesity (BMI ≥ 30 kg/m 2) based on the 2001 NCEP ATP III criteria, as well as an adapted set of less strict criteria. MHO was defined as obesity, having none of the MetS components, and no previous diagnosis of cardiovascular disease. Results: Data for 163,517 individuals were available; 17% were obese (11,465 men and 16,612 women). The prevalence of obesity varied from 11.6% in the Italian CHRIS cohort to 26.3% in the German KORA cohort. The age-standardized percentage of obese subjects with MetS ranged in women from 24% in CHRIS to 65% in the Finnish Health2000 cohort, and in men from 43% in CHRIS to 78% in the Finnish DILGOM cohort, with elevated blood pressure the most frequently occurring factor contributing to the prevalence of the metabolic syndrome. The age-standardized prevalence of MHO varied in women from 7% in Health2000 to 28% in NCDS, and in men from 2% in DILGOM to 19% in CHRIS. MHO was more prevalent in women than in men, and decreased with age in both sexes.
Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonl... more Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonly used to screen for coagulation-factor deficiencies. One genome-wide association study (GWAS) has been reported previously for aPTT, but no GWAS has been reported for PT. We conducted a GWAS and meta-analysis to identify genetic loci for aPTT and PT. The GWAS for aPTT was conducted in 9,240 individuals of European ancestry from the Atherosclerosis Risk in Communities (ARIC) study, and the GWAS for PT was conducted in 2,583 participants from the Genetic Study of Three Population Microisolates in South Tyrol (MICROS) and the Lothian Birth Cohorts (LBC) of 1921 and 1936. Replication was assessed in 1,041 to 3,467 individuals. For aPTT, previously reported associations with KNG1, HRG, F11, F12, and ABO were confirmed. A second independent association in ABO was identified and replicated (rs8176704, p = 4.26 × 10). Pooling the ARIC and replication data yielded two additional loci in F5 (rs6028, p = 3.22 × 10) and AGBL1 (rs2469184, p = 3.61 × 10). For PT, significant associations were identified and confirmed in F7 (rs561241, p = 3.71 × 10) and PROCR/EDEM2 (rs2295888, p = 5.25 × 10). Assessment of existing gene expression and coronary artery disease (CAD) databases identified associations of five of the GWAS loci with altered gene expression and two with CAD. In summary, eight genetic loci that account for 29% of the variance in aPTT and two loci that account for 14% of the variance in PT were detected and supported by functional data. Main Text Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonly used to screen for coagulation-factor deficiencies.1-3 aPTT measures the clotting time between the activation of factor XII (FXII) and the formation of a fibrin clot; thus, aPTT reflects the integrity of the intrinsic and common coagulation pathways.2,3 PT measures the clotting time from the activation of FVII and reflects the integrity of the extrinsic and common coagulation pathways.2,3 Shorter aPTT is a risk marker for incident and recurrent venous thromboembolism (VTE) in the general population,4,5 and activated coagulation is implicated in arterial thrombosis.6 An abnormal PT may reflect liver damage, deficiencies in clotting factors and vitamin K, or the use of blood thinners.3
Variation in body iron is associated with or causes diseases, including anaemia and iron overload... more Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant…
Platelets are the second most abundant cell type in blood and are essential for maintaining haemo... more Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determ...
Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth... more Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P , 10 28 , which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
BackgroundHypertension is a leading cause of death worldwide. Population-based studies offer an o... more BackgroundHypertension is a leading cause of death worldwide. Population-based studies offer an opportunity to assess the effectiveness of anti-hypertensive drugs (AHD) in real-world scenarios. However, lack of quality AHD documentation, especially when electronic health record linkage is unavailable, leads to reporting and classification bias. Here we assessed to which extent Renin-Angiotensin-Aldosterone System (RAAS) biomarkers can identify AHD treatments in the general population.MethodAngiotensin I, angiotensin II and aldosterone levels were simultaneously determined through mass-spectrometry analysis in 800 participants of the Cooperative Health Research In South Tyrol (CHRIS) study with documented AHD treatment. We conducted unsupervised cluster analysis, assessing agreement, sensitivity and specificity of the resulting clusters against known AHD treatment. Through lasso penalized regression we identified clinical characteristics associated with RAAS biomarkers, accounting fo...
To characterize COVID-19 epidemiology, numerous population-based studies have been undertaken to ... more To characterize COVID-19 epidemiology, numerous population-based studies have been undertaken to model the risk of SARS-CoV-2 infection. Less is known about what may drive the probability to undergo testing. Understanding how much testing is driven by contextual or individual conditions is important to delineate the role of individual behavior and to shape public health interventions and resource allocation. In the Val Venosta/Vinschgau district (South Tyrol, Italy), we conducted a population-representative longitudinal study on 697 individuals susceptible to first infection who completed 4,512 repeated online questionnaires at four week intervals between September 2020 and May 2021. Mixed-effects logistic regression models were fitted to investigate associations of self-reported SARS-CoV-2 testing with individual characteristics (social, demographic, and biological) and contextual determinants. Testing was associated with month of reporting, reflecting the timing of both the pandem...
Recall by genotype (RbG) studies aim to better understand the phenotypes that correspond to genet... more Recall by genotype (RbG) studies aim to better understand the phenotypes that correspond to genetic variants of interest, by recruiting carriers of such variants for further phenotyping. RbG approaches pose major ethical and legal challenges related to the disclosure of possibly unwanted genetic information. The Cooperative Health Research in South Tyrol (CHRIS) study is a longitudinal cohort study based in South Tyrol, Italy. Demand has grown for CHRIS study participants to be enrolled in RbG studies, thus making the design of a suitable ethical framework a pressing need. We here report upon the design of a pilot RbG study conducted with CHRIS study participants. By reviewing the literature and by consulting relevant stakeholders (CHRIS participants, clinical geneticists, ethics board, GPs), we identified key ethical issues in RbG approaches (e.g. complexity of the context, communication of genetic results, measures to further protect participants). The design of the pilot was base...
Background and Objectives: Although several studies demonstrated that platelet count is higher in... more Background and Objectives: Although several studies demonstrated that platelet count is higher in women, decreases with age, and is influenced by genetic background, most clinical laboratories still use the reference interval 150-400610 9 platelets/L for all subjects. The present study was to identify age-and sex-specific reference intervals for platelet count. Methods: We analysed electronic records of subjects enrolled in three population-based studies that investigated inhabitants of seven Italian areas including six geographic isolates. After exclusion of patients with malignancies, liver diseases, or inherited thrombocytopenias, which could affect platelet count, reference intervals were estimated from 40,987 subjects with the non parametric method computing the 2.5u and 97.5u percentiles. Results: Platelet count was similar in men and women until the age of 14, but subsequently women had steadily more platelets than men. The number of platelets decreases quickly in childhood, stabilizes in adulthood, and further decreases in oldness. The final result of this phenomenon is that platelet count in old age was reduced by 35% in men and by 25% in women compared with early infancy. Based on these findings, we estimated reference intervals for platelet count 610 9 /L in children (176-452), adult men (141-362), adult women (156-405), old men (122-350) and, old women (140-379). Moreover, we calculated an ''extended'' reference interval that takes into account the differences in platelet count observed in different geographic areas. Conclusions: The age-, sex-, and origin-related variability of platelet count is very wide, and the patient-adapted reference intervals we propose change the thresholds for diagnosing both thrombocytopenia and thrombocytosis in Italy.
Anaemia is a chief determinant of globalill health, contributing to cognitive impairment, growth ... more Anaemia is a chief determinant of globalill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P <10 −8 , which together explain 4-9% of
Background: Not all obese subjects have an adverse metabolic profile predisposing them to develop... more Background: Not all obese subjects have an adverse metabolic profile predisposing them to developing type 2 diabetes or cardiovascular disease. The BioSHaRE-EU Healthy Obese Project aims to gain insights into the consequences of (healthy) obesity using data on risk factors and phenotypes across several large-scale cohort studies. Aim of this study was to describe the prevalence of obesity, metabolic syndrome (MetS) and metabolically healthy obesity (MHO) in ten participating studies. Methods: Ten different cohorts in seven countries were combined, using data transformed into a harmonized format. All participants were of European origin, with age 18-80 years. They had participated in a clinical examination for anthropometric and blood pressure measurements. Blood samples had been drawn for analysis of lipids and glucose. Presence of MetS was assessed in those with obesity (BMI ≥ 30 kg/m 2) based on the 2001 NCEP ATP III criteria, as well as an adapted set of less strict criteria. MHO was defined as obesity, having none of the MetS components, and no previous diagnosis of cardiovascular disease. Results: Data for 163,517 individuals were available; 17% were obese (11,465 men and 16,612 women). The prevalence of obesity varied from 11.6% in the Italian CHRIS cohort to 26.3% in the German KORA cohort. The age-standardized percentage of obese subjects with MetS ranged in women from 24% in CHRIS to 65% in the Finnish Health2000 cohort, and in men from 43% in CHRIS to 78% in the Finnish DILGOM cohort, with elevated blood pressure the most frequently occurring factor contributing to the prevalence of the metabolic syndrome. The age-standardized prevalence of MHO varied in women from 7% in Health2000 to 28% in NCDS, and in men from 2% in DILGOM to 19% in CHRIS. MHO was more prevalent in women than in men, and decreased with age in both sexes.
Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonl... more Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonly used to screen for coagulation-factor deficiencies. One genome-wide association study (GWAS) has been reported previously for aPTT, but no GWAS has been reported for PT. We conducted a GWAS and meta-analysis to identify genetic loci for aPTT and PT. The GWAS for aPTT was conducted in 9,240 individuals of European ancestry from the Atherosclerosis Risk in Communities (ARIC) study, and the GWAS for PT was conducted in 2,583 participants from the Genetic Study of Three Population Microisolates in South Tyrol (MICROS) and the Lothian Birth Cohorts (LBC) of 1921 and 1936. Replication was assessed in 1,041 to 3,467 individuals. For aPTT, previously reported associations with KNG1, HRG, F11, F12, and ABO were confirmed. A second independent association in ABO was identified and replicated (rs8176704, p = 4.26 × 10). Pooling the ARIC and replication data yielded two additional loci in F5 (rs6028, p = 3.22 × 10) and AGBL1 (rs2469184, p = 3.61 × 10). For PT, significant associations were identified and confirmed in F7 (rs561241, p = 3.71 × 10) and PROCR/EDEM2 (rs2295888, p = 5.25 × 10). Assessment of existing gene expression and coronary artery disease (CAD) databases identified associations of five of the GWAS loci with altered gene expression and two with CAD. In summary, eight genetic loci that account for 29% of the variance in aPTT and two loci that account for 14% of the variance in PT were detected and supported by functional data. Main Text Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonly used to screen for coagulation-factor deficiencies.1-3 aPTT measures the clotting time between the activation of factor XII (FXII) and the formation of a fibrin clot; thus, aPTT reflects the integrity of the intrinsic and common coagulation pathways.2,3 PT measures the clotting time from the activation of FVII and reflects the integrity of the extrinsic and common coagulation pathways.2,3 Shorter aPTT is a risk marker for incident and recurrent venous thromboembolism (VTE) in the general population,4,5 and activated coagulation is implicated in arterial thrombosis.6 An abnormal PT may reflect liver damage, deficiencies in clotting factors and vitamin K, or the use of blood thinners.3
Variation in body iron is associated with or causes diseases, including anaemia and iron overload... more Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant…
Platelets are the second most abundant cell type in blood and are essential for maintaining haemo... more Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determ...
Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth... more Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P , 10 28 , which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
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Papers by Martin Goegele