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1.
Kidney Int ; 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33137338

RESUMO

Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.

2.
Hum Genet ; 139(5): 647-655, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32232557

RESUMO

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.


Assuntos
Grupos Étnicos/genética , Marcadores Genéticos , Variação Genética , Genética Populacional , Modelos Teóricos , Herança Multifatorial/genética , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Fenótipo , Transdução de Sinais
3.
Eur J Hum Genet ; 28(4): 435-444, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31784700

RESUMO

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.

4.
Sci Rep ; 9(1): 15192, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645637

RESUMO

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.


Assuntos
Envelhecimento/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Perda Auditiva/genética , Animais , Vias Auditivas/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Fenótipo , Reprodutibilidade dos Testes
5.
Nat Genet ; 51(10): 1459-1474, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31578528

RESUMO

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.


Assuntos
Doenças Cardiovasculares/sangue , Marcadores Genéticos , Gota/sangue , Doenças Metabólicas/sangue , Polimorfismo de Nucleotídeo Único , Transdução de Sinais , Ácido Úrico/sangue , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Estudos de Coortes , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Gota/epidemiologia , Gota/genética , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Rim/metabolismo , Rim/patologia , Fígado/metabolismo , Fígado/patologia , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/genética , Proteínas de Neoplasias/genética , Especificidade de Órgãos
6.
Nat Commun ; 10(1): 4130, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511532

RESUMO

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.


Assuntos
Albuminúria/genética , Mapeamento Cromossômico , Estudo de Associação Genômica Ampla , Metanálise como Assunto , Animais , Creatinina/urina , Diabetes Mellitus/genética , Diabetes Mellitus/urina , Drosophila melanogaster/genética , Regulação da Expressão Gênica , Loci Gênicos , Predisposição Genética para Doença , Humanos , Fenômica , Fatores de Risco
7.
Nat Genet ; 51(6): 957-972, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31152163

RESUMO

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.


Assuntos
Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Locos de Características Quantitativas , Característica Quantitativa Herdável , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Humanos , Padrões de Herança , Testes de Função Renal , Fenótipo , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/urina , Uromodulina/urina
9.
Front Genet ; 10: 142, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863428

RESUMO

Age-related hearing loss (ARHL) is the most common sensory impairment in the elderly affecting millions of people worldwide. To shed light on the genetics of ARHL, a large cohort of 464 Italian patients has been deeply characterized at clinical and molecular level. In particular, 46 candidate genes, selected on the basis of genome-wide association studies (GWAS), animal models and literature updates, were analyzed by targeted re-sequencing. After filtering and prioritization steps, SLC9A3R1 has been identified as a strong candidate and then validated by "in vitro" and "in vivo" studies. Briefly, a rare (MAF: 2.886e-5) missense variant c.539G > A, p.(R180Q) was detected in two unrelated male patients affected by ARHL characterized by a severe to profound high-frequency hearing loss. The variant, predicted as damaging, was not present in healthy matched controls. Protein modeling confirmed the pathogenic effect of p.(R180Q) variant on protein's structure leading to a change in the total number of hydrogen bonds. In situ hybridization showed slc9a3r1 expression in zebrafish inner ear. A zebrafish knock-in model, generated by CRISPR-Cas9 technology, revealed a reduced auditory response at all frequencies in slc9a3r1 R180Q/R180Q mutants compared to slc9a3r1 +/+ and slc9a3r1 +/R180Q animals. Moreover, a significant reduction (5.8%) in the total volume of the saccular otolith (which is responsible for sound detection) was observed in slc9a3r1 R180Q/R180Q compared to slc9a3r1 +/+ (P = 0.0014), while the utricular otolith, necessary for balance, was not affected in agreement with the human phenotype. Overall, these data strongly support the role of SLC9A3R1 gene in the pathogenesis of ARHL opening new perspectives in terms of diagnosis, prevention and treatment.

10.
Eur J Hum Genet ; 26(8): 1167-1179, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29725052

RESUMO

Age-related hearing loss (ARHL) is the most common sensory disorder in the elderly. Although not directly life threatening, it contributes to loss of autonomy and is associated with anxiety, depression and cognitive decline. To search for genetic risk factors underlying ARHL, a large whole-genome sequencing (WGS) approach has been carried out in a cohort of 212 cases and controls, both older than 50 years to select genes characterized by a burden of variants specific to cases or controls. Accordingly, the total variation load per gene was compared and two groups were detected: 375 genes more variable in cases and 371 more variable in controls. In both cases, Gene Ontology analysis showed that the largest enrichment for biological processes (fold > 5, p-value = 0.042) was the "sensory perception of sound", suggesting cumulative genetic effects were involved. Replication confirmed 141 genes, while additional analysis based on natural selection led to a prioritization of 21 genes. The majority of them (20 out of 21) showed positive expression in mouse cochlea cDNA and were associated with two functional pathways. Among them, two genes were previously associated with hearing (CSMD1 and PTRPD) and re-sequenced in a large Italian cohort of ARHL patients (N = 389). Results led to the identification of six coding variants not detected in cases so far, suggesting a possible protective role, which requires investigation. In conclusion, we show that this multistep strategy (WGS, selection, expression, pathway analysis and targeted re-sequencing) can provide major insights into the molecular characterization of complex diseases such as ARHL.


Assuntos
Pleiotropia Genética , Herança Multifatorial , Presbiacusia/genética , Seleção Genética , Idoso , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Sequenciamento Completo do Genoma
11.
Nat Genet ; 50(5): 652-656, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29662168

RESUMO

Hair color is one of the most recognizable visual traits in European populations and is under strong genetic control. Here we report the results of a genome-wide association study meta-analysis of almost 300,000 participants of European descent. We identified 123 autosomal and one X-chromosome loci significantly associated with hair color; all but 13 are novel. Collectively, single-nucleotide polymorphisms associated with hair color within these loci explain 34.6% of red hair, 24.8% of blond hair, and 26.1% of black hair heritability in the study populations. These results confirm the polygenic nature of complex phenotypes and improve our understanding of melanin pigment metabolism in humans.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos , Cor de Cabelo/genética , Herança Multifatorial , Polimorfismo de Nucleotídeo Único/genética , Idoso , Cromossomos Humanos X , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
13.
Am J Hum Genet ; 100(6): 865-884, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28552196

RESUMO

Deep sequence-based imputation can enhance the discovery power of genome-wide association studies by assessing previously unexplored variation across the common- and low-frequency spectra. We applied a hybrid whole-genome sequencing (WGS) and deep imputation approach to examine the broader allelic architecture of 12 anthropometric traits associated with height, body mass, and fat distribution in up to 267,616 individuals. We report 106 genome-wide significant signals that have not been previously identified, including 9 low-frequency variants pointing to functional candidates. Of the 106 signals, 6 are in genomic regions that have not been implicated with related traits before, 28 are independent signals at previously reported regions, and 72 represent previously reported signals for a different anthropometric trait. 71% of signals reside within genes and fine mapping resolves 23 signals to one or two likely causal variants. We confirm genetic overlap between human monogenic and polygenic anthropometric traits and find signal enrichment in cis expression QTLs in relevant tissues. Our results highlight the potential of WGS strategies to enhance biologically relevant discoveries across the frequency spectrum.


Assuntos
Antropometria , Genoma Humano , Estudo de Associação Genômica Ampla , Locos de Características Quantitativas/genética , Análise de Sequência de DNA/métodos , Estatura/genética , Estudos de Coortes , Metilação de DNA/genética , Bases de Dados Genéticas , Feminino , Variação Genética , Humanos , Lipodistrofia/genética , Masculino , Metanálise como Assunto , Obesidade/genética , Mapeamento Físico do Cromossomo , Caracteres Sexuais , Síndrome , Reino Unido
14.
Sci Rep ; 7: 45040, 2017 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-28452372

RESUMO

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10-8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.


Assuntos
Biologia Computacional/métodos , Loci Gênicos , Rim/fisiologia , Frequência do Gene , Genoma Humano , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Polimorfismo de Nucleotídeo Único
15.
Brain ; 140(3): 555-567, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-28073787

RESUMO

Itch is thought to represent the peculiar response to stimuli conveyed by somatosensory pathways shared with pain through the activation of specific neurons and receptors. It can occur in association with dermatological, systemic and neurological diseases, or be the side effect of certain drugs. However, some patients suffer from chronic idiopathic itch that is frequently ascribed to psychological distress and for which no biomarker is available to date. We investigated three multigenerational families, one of which diagnosed with joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type (JHS/EDS-HT), characterized by idiopathic chronic itch with predominantly proximal distribution. Skin biopsy was performed in all eight affected members and revealed in six of them reduced intraepidermal nerve fibre density consistent with small fibre neuropathy. Whole exome sequencing identified two COL6A5 rare variants co-segregating with chronic itch in eight affected members and absent in non-affected members, and in one unrelated sporadic patient with type 1 painless diabetic neuropathy and chronic itch. Two families and the diabetic patient carried the nonsense c.6814G>T (p.Glu2272*) variant and another family carried the missense c.6486G>C (p.Arg2162Ser) variant. Both variants were predicted as likely pathogenic by in silico analyses. The two variants were rare (minor allele frequency < 0.1%) in 6271 healthy controls and absent in 77 small fibre neuropathy and 167 JHS/EDS-HT patients without itch. Null-allele test on cDNA from patients' fibroblasts of both families carrying the nonsense variant demonstrated functional haploinsufficiency due to activation of nonsense mediated RNA decay. Immunofluorescence microscopy and western blotting revealed marked disorganization and reduced COL6A5 synthesis, respectively. Indirect immunofluorescence showed reduced COL6A5 expression in the skin of patients carrying the nonsense variant. Treatment with gabapentinoids provided satisfactory itch relief in the patients carrying the mutations. Our findings first revealed an association between COL6A5 gene and familiar chronic itch, suggesting a new contributor to the pathogenesis of neuropathic itch and identifying a new candidate therapeutic target.


Assuntos
Colágeno Tipo VI/genética , Saúde da Família , Variação Genética/genética , Doenças do Sistema Nervoso Periférico/genética , Prurido/genética , Adulto , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/complicações , Prurido/complicações , Prurido/patologia , Pele/inervação , Pele/metabolismo , Pele/patologia
16.
J Clin Endocrinol Metab ; 102(2): 576-582, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-27802094

RESUMO

Objective: To assess the frequency of variants, including biallelic pathogenic variants, in minichromosome maintenance 8 (MCM8) and minichromosome maintenance 9 (MCM9), other genes related to MCM8-MCM9, and DNA damage repair (DDR) pathway in participants with primary ovarian insufficiency (POI). Design: MCM8, MCM9, and genes encoding DDR proteins that have been implicated in reproductive aging were sequenced among POI participants. Setting: Academic research institution. Participants: All were diagnosed with POI prior to age 40 years and presented with elevated follicle-stimulating hormone levels. Interventions: None. Main Outcome Measures: We identified nucleotide variants in MCM8, MCM9, and genes thought to be involved in the DNA damage response pathway and/or implicated in reproductive aging. Results: MCM8 was sequenced in 155 POI participants, whereas MCM9 was sequenced in 151 participants. Three of 155 (2%) participants carried possibly damaging heterozygous variants in MCM8, whereas 7 of 151 (5%) individuals carried possibly damaging heterozygous variants in MCM9. One participant carried a novel homozygous variant, c.1651C>T, p.Gln551*, in MCM9, which is predicted to introduce a premature stop codon in exon 9. Biallelic damaging heterozygous variants in both MCM8 and MCM9 were identified in 1 participant. Of a total of 10 participants carrying damaging heterozygous variants in either MCM8 or MCM9, 2 individuals carried heterozygous damaging variants in genes associated with either MCM8 or MCM9 or the DDR pathway. Conclusions: We identified a significant number of potentially damaging and novel variants in MCM8 and MCM9 among participants with POI and examined multiallelic association with variants in DDR and MCM8-MCM9 interactome genes.


Assuntos
Envelhecimento/genética , Dano ao DNA/genética , Reparo do DNA/genética , Proteínas de Manutenção de Minicromossomo/genética , Insuficiência Ovariana Primária/genética , Adulto , Feminino , Humanos , Análise de Sequência de DNA
17.
Nat Genet ; 48(10): 1279-83, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27548312

RESUMO

We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.


Assuntos
Genótipo , Haplótipos , Polimorfismo de Nucleotídeo Único , Alelos , Técnicas Genéticas , Estudo de Associação Genômica Ampla , Humanos , Internet , Valores de Referência
18.
J Transl Med ; 14: 22, 2016 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-26801900

RESUMO

BACKGROUND: Breast cancer is the most common cancer in women characterized by a high variable clinical outcome among individuals treated with equivalent regimens and novel targeted therapies. In this study, we performed a population based approach intersecting high-throughput genotype data from Friuli Venezia Giulia (FVG) isolated populations with publically available pharmacogenomics information to estimate the frequency of genotypes correlated with responsiveness to breast cancer treatment thus improving the clinical management of this disease in an efficient and cost effective way. METHODS: A list of 80 variants reported to be related to the efficacy or toxicity of breast cancer drugs was obtained from PharmGKB database. Fourty-one were present in FVG, 1000G European (EUR) and ExAC (Non Finnish European) databases. Their frequency was extracted using PLINK software and the differences tested by Fisher's exact test. RESULTS: Statistical analyses revealed that 13 out of the 41 (32 %) variants were significantly different in frequency in our sample as compared to the EUR/ExAC cohorts. For nine variants the available level of evidence (LOE) included polymorphisms related to cyclophosphamide, tamoxifen, doxorubicin, fluorpyrimidine and paclitaxel. In particular, for trastuzumab two variants were detected: (1) rs1801274-G within FCGR2A and associated with decreased efficacy (LOE 2B); (2) rs1136201-G located within ERBB2 and associated with increased toxicity (LOE 3). Both these two variants were underrepresented in the FVG population compared to EUR/ExAC population thus suggesting a high therapeutic index of this drug in our population. Moreover, as regards fluoropyrimidines, the frequency of two polymorphisms within the DPYD gene associated with drug toxicity (e.g., rs2297595-C allele and rs3918290-T allele, LOE 2A and 1, respectively) was extremely low in FVG population thus suggesting that a larger number of FVG patients could benefit from full dosage of fluoropyrimidine therapy. CONCLUSIONS: All these findings increase the overall knowledge on the prevalence of specific variants related with breast cancer treatment responsiveness in FVG population and highlight the importance of assessing gene polymorphisms related with cancer medications in isolated communities.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Predisposição Genética para Doença , Polimorfismo Genético , Medicina de Precisão , Feminino , Frequência do Gene/genética , Genótipo , Geografia , Humanos , Itália , Farmacogenética , Fatores de Risco
20.
Nat Commun ; 5: 4871, 2014 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-25225788

RESUMO

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10(-8))) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e.=0.173), P-value=7.32 × 10(-9)). This is consistent with an effect between 0.5 and 1.5 mmol l(-1) dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.


Assuntos
Alelos , Apolipoproteína C-III/genética , Lipoproteínas VLDL/sangue , Triglicerídeos/sangue , Processamento Alternativo , Criança , Grupo com Ancestrais do Continente Europeu , Feminino , Frequência do Gene , Humanos , Lipoproteínas HDL/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Gêmeos/genética
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