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1.
Hum Mol Genet ; 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35554533

RESUMO

Polygenic risk scores (PRSs) are useful for predicting breast cancer risk, but the prediction accuracy of existing PRSs in women of African ancestry (AA) remains relatively low. We aim to develop optimal PRSs for prediction of overall and estrogen receptor (ER) subtype-specific breast cancer risk in AA women. The AA dataset comprised 9235 cases and 10 184 controls from four genome-wide association study (GWAS) consortia and a GWAS study in Ghana. We randomly divided samples into training and validation sets. We built PRSs using individual level AA data by a forward stepwise logistic regression and then developed joint PRSs that combined 1) the PRSs built in the AA training dataset, and 2) a 313-variant PRS previously developed in women of European ancestry. PRSs were evaluated in the AA validation set. For overall breast cancer, the odd ratio (OR) per standard deviation of the joint PRS in the validation set was 1.34 (95% CI: 1.27-1.42) with area under receiver operating characteristic curve (AUC) of 0.581. Compared to women with average risk (40th-60th PRS percentile), women in the top decile of the PRS had a 1.98-fold increased risk (95% CI: 1.63-2.39). For PRSs of ER-positive and ER-negative breast cancer, the AUCs were 0.608 and 0.576, respectively. Compared to existing methods, the proposed joint PRSs can improve prediction of breast cancer risk in AA women.

3.
Breast Cancer Res ; 24(1): 27, 2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35414113

RESUMO

BACKGROUND: Mammographic density (MD) phenotypes, including percent density (PMD), area of dense tissue (DA), and area of non-dense tissue (NDA), are associated with breast cancer risk. Twin studies suggest that MD phenotypes are highly heritable. However, only a small proportion of their variance is explained by identified genetic variants. METHODS: We conducted a genome-wide association study, as well as a transcriptome-wide association study (TWAS), of age- and BMI-adjusted DA, NDA, and PMD in up to 27,900 European-ancestry women from the MODE/BCAC consortia. RESULTS: We identified 28 genome-wide significant loci for MD phenotypes, including nine novel signals (5q11.2, 5q14.1, 5q31.1, 5q33.3, 5q35.1, 7p11.2, 8q24.13, 12p11.2, 16q12.2). Further, 45% of all known breast cancer SNPs were associated with at least one MD phenotype at p < 0.05. TWAS further identified two novel genes (SHOX2 and CRISPLD2) whose genetically predicted expression was significantly associated with MD phenotypes. CONCLUSIONS: Our findings provided novel insight into the genetic background of MD phenotypes, and further demonstrated their shared genetic basis with breast cancer.


Assuntos
Densidade da Mama , Neoplasias da Mama , Densidade da Mama/genética , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Transcriptoma
4.
Sci Rep ; 12(1): 6199, 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35418701

RESUMO

Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values < 5 × 10-8 as genome-wide significant, and p-values < 1 × 10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants. None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values < 1 × 105. The strongest evidence was found for rs4674019 (p-value = 2.27 × 10-7), which showed genome-wide significant interaction (p-value = 3.8 × 10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT-breast cancer risk association.


Assuntos
Neoplasias da Mama , Mama , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Terapia de Reposição de Estrogênios/efeitos adversos , Feminino , Terapia de Reposição Hormonal/efeitos adversos , Humanos , Masculino , Menopausa , Fatores de Risco
5.
Cancers (Basel) ; 14(5)2022 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-35267517

RESUMO

(1) Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility. (2) Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1-25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls. (3) Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 × 10-8), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2-25 and 113 risk haplotypes of window size 50 at p < 5 × 10-8 on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68. (4) Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population.

6.
Breast Cancer Res ; 24(1): 2, 2022 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-34983606

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.


Assuntos
Neoplasias da Mama , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Risco
7.
Commun Biol ; 5(1): 65, 2022 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-35042965

RESUMO

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.


Assuntos
Neoplasias da Mama/genética , Variações do Número de Cópias de DNA , Genoma Humano , Estudo de Associação Genômica Ampla , Células Germinativas , Estudos de Casos e Controles , Feminino , Humanos , Fatores de Risco
8.
Genet Med ; 24(3): 586-600, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34906514

RESUMO

PURPOSE: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups. METHODS: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases). RESULTS: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk. CONCLUSION: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.


Assuntos
Neoplasias da Mama , Teorema de Bayes , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos Prospectivos , Fatores de Risco
9.
Pharmaceuticals (Basel) ; 14(11)2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34832896

RESUMO

Duchenne muscular dystrophy (DMD) is a fatal disorder characterised by progressive muscle wasting. It is caused by mutations in the dystrophin gene, which disrupt the open reading frame leading to the loss of functional dystrophin protein in muscle fibres. Antisense oligonucleotide (AON)-mediated skipping of the mutated exon, which allows production of a truncated but partially functional dystrophin protein, has been at the forefront of DMD therapeutic research for over two decades. Nonetheless, novel nucleic acid modifications and AON designs are continuously being developed to improve the clinical benefit profile of current drugs in the DMD pipeline. We herein designed a series of 15mer and 20mer AONs, consisting of 2'O-Methyl (2'OMe)- and locked nucleic acid (LNA)-modified nucleotides in different percentage compositions, and assessed their efficiency in inducing exon 23 skipping and dystrophin restoration in locally injected muscles of mdx mice. We demonstrate that LNA/2'OMe AONs with a 30% LNA composition were significantly more potent in inducing exon skipping and dystrophin restoration in treated mdx muscles, compared to a previously tested 2'OMe AON and LNA/2'OMe chimeras with lower or higher LNA compositions. These results underscore the therapeutic potential of LNA/2'OMe AONs, paving the way for further experimentation to evaluate their benefit-toxicity profile following systemic delivery.

10.
Front Pediatr ; 9: 713930, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34746051

RESUMO

Background: During the COVID-19 pandemic, telemedicine use has increased within community pediatrics. This trend runs counter to reluctance to adaptation of the new mode of healthcare that existed prior to the pandemic. Little is known about what we can expect after the pandemic: if physicians will opt for telemedicine modalities and if tele-pediatrics will continue to be a significant mode of community pediatric care. Objective: The goal of this study was to survey primary pediatric care providers as to their experiences and clinical decision making with telemedicine modalities prior to and during the COVID-19 pandemic, as well as their projected use after the pandemic ends. Material and methods: Using the EAPRASnet database we surveyed pediatricians throughout Europe, using a web-based questionnaire. The survey was performed during the COVID-19 pandemic (June-July 2020), assessed telemedicine use for several modalities, prior to and during the pandemic as well as predicted use after the pandemic will have resolved. Participants were also surveyed regarding clinical decision making in two hypothetical clinical scenarios managed by telemedicine. Results: A total of 710 physicians participated, 76% were pediatricians. The percentage of respondents who reported daily use for at least 50% of all encounters via telemedicine modalities increased during the pandemic: phone calls (4% prior to the pandemic to 52% during the pandemic), emails (2-9%), text messages (1-6%), social media (3-11%), cell-phone pictures/video (1-9%), and video conferencing (1-7%) (p < 0.005). The predicted post-pandemic use of these modalities partially declined to 19, 4, 3, 6, 9, and 4%, respectively (p < 0.005), yet demonstrating a prospectively sustained use of pictures/videos after the pandemic. Reported high likelihood of remotely treating suspected pneumonia and acute otitis media with antibiotics decreased from 8 to 16% during the pandemic to an assumed 2 and 4% after the pandemic, respectively (p < 0.005). Conclusions: This study demonstrates an increased utilization of telemedicine by pediatric providers during the COVID-19 pandemic, as well as a partially sustained effect that will promote telemedicine use as part of a hybrid care provision after the pandemic will have resolved.

11.
BMC Genom Data ; 22(1): 48, 2021 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-34773976

RESUMO

BACKGROUND: This study aims to characterize SARS-CoV-2 mutations which are primarily prevalent in the Cypriot population. Moreover, using computational approaches, we assess whether these mutations are associated with changes in viral virulence. METHODS: We utilize genetic data from 144 sequences of SARS-CoV-2 strains from the Cypriot population obtained between March 2020 and January 2021, as well as all data available from GISAID. We combine this with countries' regional information, such as deaths and cases per million, as well as COVID-19-related public health austerity measure response times. Initial indications of selective advantage of Cyprus-specific mutations are obtained by mutation tracking analysis. This entails calculating specific mutation frequencies within the Cypriot population and comparing these with their prevalence world-wide throughout the course of the pandemic. We further make use of linear regression models to extrapolate additional information that may be missed through standard statistical analysis. RESULTS: We report a single mutation found in the ORF1ab gene (nucleotide position 18,440) that appears to be significantly enriched within the Cypriot population. The amino acid change is denoted as S6059F, which maps to the SARS-CoV-2 NSP14 protein. We further analyse this mutation using regression models to investigate possible associations with increased deaths and cases per million. Moreover, protein structure prediction tools show that the mutation infers a conformational change to the protein that significantly alters its structure when compared to the reference protein. CONCLUSIONS: Investigating Cyprus-specific mutations for SARS-CoV-2 can lead to a better understanding of viral pathogenicity. Researching these mutations can generate potential links between viral-specific mutations and the unique genomics of the Cypriot population. This can not only lead to important findings from which to battle the pandemic on a national level, but also provide insights into viral virulence worldwide.


Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/virologia , Chipre , Exorribonucleases/genética , Humanos , Mutação , Filogenia , SARS-CoV-2/genética , Proteínas não Estruturais Virais/genética
12.
Front Psychiatry ; 12: 707293, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34790134

RESUMO

Background: Data support the link between the coronavirus disease 2019 (COVID-19) pandemic and mental distress in healthcare workers (HCWs). Although previous studies have documented the association between organizational policies and employees' psychological and mental status, there is still scant evidence regarding the effect of perceived organizational support (POS) on mental distress in HCWs during the pandemic. Aims: The present study aimed to assess the association between POS and mental distress in HCWs during the COVID-19 pandemic. The role of POS in stress, depressive and trauma symptoms in HCWs was investigated. Methods: This was an online cross-sectional study in 424 HCWs. Data were collected during the first wave of the pandemic, and included demographics, a 7-item questionnaire assessing POS, the "Patient Health Questionnaire" assessing depressive symptoms, the "Impact of Events Scale Revised," measuring post-traumatic stress disorder (PTSD) symptoms and the "Perceived Stress Scale" assessing perceived stress. Results: The mean POS score was 3.33 [standard deviation:1.85; range 0-7]. Younger (p < 0.001), less experienced (p < 0.001), female (p = 0.002), and non-physician HCWs (p = 0.031) were more likely to report lower self-perceived organizational support than older, male, more experienced physicians. Self-perceived organizational support was significantly and negatively associated with and self-assessed intensity of stress, depressive and traumatic symptoms, after adjusting for putative confounders (p < 0.001). Discussion: Self-perceived organizational support was significantly associated with HCWs' self-assessed mental status during the pandemic. Organizational support and mental distress should be addressed simultaneously in HCWs during the COVID-19 pandemic to increase resilience among them.

13.
Front Endocrinol (Lausanne) ; 12: 745048, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630334

RESUMO

Background: Central precocious puberty (CPP) due to premature activation of GnRH secretion results in early epiphyseal fusion and to a significant compromise in the achieved final adult height. Currently, few genetic determinants of children with CPP have been described. In this translational study, rare sequence variants in MKRN3, DLK1, KISS1, and KISS1R genes were investigated in patients with CPP. Methods: Fifty-four index girls and two index boys with CPP were first tested by Sanger sequencing for the MKRN3 gene. All children found negative (n = 44) for the MKRN3 gene were further investigated by whole exome sequencing (WES). In the latter analysis, the status of variants in genes known to be related with pubertal timing was compared with an in-house Cypriot control cohort (n = 43). The identified rare variants were initially examined by in silico computational algorithms and confirmed by Sanger sequencing. Additionally, a genetic network for the MKRN3 gene, mimicking a holistic regulatory depiction of the crosstalk between MKRN3 and other genes was designed. Results: Three previously described pathogenic MKRN3 variants located in the coding region of the gene were identified in 12 index girls with CPP. The most prevalent pathogenic MKRN3 variant p.Gly312Asp was exclusively found among the Cypriot CPP cohort, indicating a founder effect phenomenon. Seven other CPP girls harbored rare likely pathogenic upstream variants in the MKRN3. Among the 44 CPP patients submitted to WES, nine rare DLK1 variants were identified in 11 girls, two rare KISS1 variants in six girls, and two rare MAGEL2 variants in five girls. Interestingly, the frequent variant rs10407968 (p.Gly8Ter) of the KISS1R gene appeared to be less frequent in the cohort of patients with CPP. Conclusion: The results of the present study confirm the importance of the MKRN3-imprinted gene in genetics of CPP and its key role in pubertal timing. Overall, the results of the present study have emphasized the importance of an approach that aligns genetics and clinical aspects, which is necessary for the management and treatment of CPP.


Assuntos
Puberdade Precoce/genética , Encefalopatias/epidemiologia , Encefalopatias/genética , Proteínas de Ligação ao Cálcio/genética , Criança , Pré-Escolar , Estudos de Coortes , Chipre/epidemiologia , Análise Mutacional de DNA , Feminino , Frequência do Gene , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Kisspeptinas/genética , Masculino , Proteínas de Membrana/genética , Mutação , Puberdade Precoce/epidemiologia , Receptores de Kisspeptina-1/genética , Ubiquitina-Proteína Ligases/genética , Sequenciamento Completo do Exoma
14.
Cancers (Basel) ; 13(18)2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34572793

RESUMO

The PRS combines multiplicatively the effects of common low-risk single nucleotide polymorphisms (SNPs) and has the potential to be used for the estimation of an individual's risk for a trait or disease. PRS has been successfully implemented for the prediction of breast cancer risk. The combination of PRS with classical breast cancer risk factors provides a more comprehensive risk estimation and could, thus, improve risk stratification and personalized preventative strategies. In this study, we assessed the predictive performance of the combined effect of PRS15 with classical breast-cancer risk factors in Cypriot women using 1109 cases and 1177 controls from the MASTOS study. The PRS15 was significantly associated with an increased breast cancer risk in Cypriot women OR (95% CI) 1.66 (1.25-2.19). The integrated risk model obtained an AUC (95% CI) 0.70 (0.67-0.72) and had the ability to stratify women according to their disease status at the extreme deciles. These results provide evidence that the combination of PRS with classical risk factors may be used in the future for the stratification of Cypriot women based on their disease risk, and support its potential clinical utility for targeted preventative actions and population screening.

15.
Hum Mutat ; 2021 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-34510646

RESUMO

Accurate and consistent interpretation of sequence variants is integral to the delivery of safe and reliable diagnostic genetic services. To standardize the interpretation process, in 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published a joint guideline based on a set of shared standards for the classification of variants in Mendelian diseases. The generality of these standards and their subjective interpretation between laboratories has prompted efforts to reduce discordance of variant classifications, with a focus on the expert specification of the ACMG/AMP guidelines for individual genes or diseases. Herein, we describe our experience as a ClinGen Variant Curation Expert Panel to adapt the ACMG/AMP criteria for the classification of variants in three globin genes (HBB, HBA2, and HBA1) related to recessively inherited hemoglobinopathies, including five evidence categories, as use cases demonstrating the process of specification and the underlying rationale.

16.
PLoS One ; 16(8): e0255140, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34424929

RESUMO

Y-chromosome analysis provides valuable information regarding the migration patterns of male ancestors, ranging from the Paleolithic age to the modern humans. STR and SNP genotyping analysis provides data regarding the genetic and geographical ancestry of the populations studied. This study focused on the analysis of the Y-chromosome in Maronite Cypriots and Armenian Cypriots, who came to the island as a result of different historical events. The aim was to provide information on the paternal genetic ancestry of Maronites and Armenians of Cyprus and investigate any affinity with the Greek Cypriots and Turkish Cypriots of the island. Since there is limited information in the current literature, we proceeded and used 23 Y-chromosome STRs and 28 Y-chromosome SNPs to genotype 57 Maronite Cypriots and 56 Armenian Cypriots, which were then compared to data from 344 Greek Cypriots and 380 Turkish Cypriots. All samples were assigned to eight major Y-haplogroups but the most frequent haplogroup among all Cypriots is haplogroup J in the major subclade J2a-L559. The calculated pairwise genetic distances between the populations show that Armenian Cypriots are genetically closer to Greek and Turkish Cypriots compared to Maronite Cypriots. Median Joining Network analysis in 17 Y-STR haplotypes of all Cypriots assigned to J2a-L559, revealed that Cypriots share a common paternal ancestor, prior to the migration of the Armenians and Maronites to Cyprus, estimated in the Late Bronze Age and Early Iron Age.


Assuntos
Cromossomos Humanos Y/genética , Migração Humana , Chipre , Genética Populacional , Geografia , Haplótipos/genética , Humanos , Repetições de Microssatélites/genética , Polimorfismo de Nucleotídeo Único/genética , Fatores de Tempo
17.
Genes (Basel) ; 12(8)2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34440451

RESUMO

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder, and literature suggests that genetics and lifestyle/environmental factors may play a key role in the triggering of the disease. This study aimed to evaluate the predictive performance of a 12-Single Nucleotide Polymorphisms (SNPs) polygenic risk score (PRS) in combination with already established PD-environmental/lifestyle factors. METHODS: Genotypic and lifestyle/environmental data on 235 PD-patients and 464 controls were obtained from a previous study carried out in the Cypriot population. A PRS was calculated for each individual. Univariate logistic-regression analysis was used to assess the association of PRS and each risk factor with PD-status. Stepwise-regression analysis was used to select the best predictive model for PD combining genetic and lifestyle/environmental factors. RESULTS: The 12-SNPs PRS was significantly increased in PD-cases compared to controls. Furthermore, univariate analyses showed that age, head injury, family history, depression, and Body Mass Index (BMI) were significantly associated with PD-status. Stepwise-regression suggested that a model which includes PRS and seven other independent lifestyle/environmental factors is the most predictive of PD in our population. CONCLUSIONS: These results suggest an association between both genetic and environmental factors and PD, and highlight the potential for the use of PRS in combination with the classical risk factors for risk prediction of PD.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Doença de Parkinson/genética , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Feminino , Interação Gene-Ambiente , Perfil Genético , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/epidemiologia , Doença de Parkinson/patologia , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
19.
HGG Adv ; 2(3): 100041, 2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34355204

RESUMO

Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.

20.
Br J Cancer ; 125(8): 1135-1145, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34341517

RESUMO

BACKGROUND: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. METHODS: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. RESULTS: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. CONCLUSION: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.


Assuntos
Neoplasias da Mama/epidemiologia , Fumar Cigarros/epidemiologia , Polimorfismo de Nucleotídeo Único , Neoplasias da Mama/etiologia , Neoplasias da Mama/genética , Estudos de Casos e Controles , Fumar Cigarros/efeitos adversos , Fumar Cigarros/genética , Feminino , Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Análise da Randomização Mendeliana
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