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1.
Mult Scler ; 27(9): 1332-1340, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33566725

RESUMO

BACKGROUND: Defective alleles within the PRF1 gene, encoding the pore-forming protein perforin, in combination with environmental factors, cause familial type 2 hemophagocytic lymphohistiocytosis (FHL2), a rare, severe autosomal recessive childhood disorder characterized by massive release of cytokines-cytokine storm. OBJECTIVE: The aim of this study was to determine the function of hypomorph PRF1:p.A91V g.72360387 G > A on multiple sclerosis (MS) and type 1 diabetes (T1D). METHODS: We cross-compare the association data for PRF1:p.A91V mutation derived from GWAS on adult MS and pediatric T1D in Sardinians. The novel association with T1D was replicated in metanalysis in 12,584 cases and 17,692 controls from Sardinia, the United Kingdom, and Scotland. To dissect this mutation function, we searched through the coincident association immunophenotypes in additional set of general population Sardinians. RESULTS: We report that PRF1:p.A91V, is associated with increase of lymphocyte levels, especially within the cytotoxic memory T-cells, at general population level with reduced interleukin 7 receptor expression on these cells. The minor allele increased risk of MS, in 2903 cases and 2880 controls from Sardinia p = 2.06 × 10-4, odds ratio OR = 1.29, replicating a previous finding, whereas it protects from T1D p = 1.04 × 10-5, OR = 0.82. CONCLUSION: Our results indicate opposing contributions of the cytotoxic T-cell compartment to MS and T1D pathogenesis.


Assuntos
Autoimunidade , Sistema Imunitário , Autoimunidade/genética , Criança , Humanos , Inflamação , Proteínas com Homeodomínio LIM , Proteínas Musculares , Mutação , Perforina/genética , Fatores de Transcrição
2.
BMC Cancer ; 15: 383, 2015 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-25956309

RESUMO

BACKGROUND: Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. METHODS: We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. RESULTS: Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p < 0(-6) level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10(-5), we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16 x 10(-5)), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts. CONCLUSIONS: This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population.


Assuntos
Neoplasias da Mama/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptores de Progesterona/genética , Proteínas Reguladoras de Apoptose , Estudos de Casos e Controles , Feminino , Genes BRCA1 , Genes BRCA2 , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas de Grupo de Alta Mobilidade , Humanos , Itália , Penetrância , Transativadores
3.
J Clin Invest ; 118(7): 2620-8, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18521185

RESUMO

Identifying the genetic variants that regulate fasting glucose concentrations may further our understanding of the pathogenesis of diabetes. We therefore investigated the association of fasting glucose levels with SNPs in 2 genome-wide scans including a total of 5,088 nondiabetic individuals from Finland and Sardinia. We found a significant association between the SNP rs563694 and fasting glucose concentrations (P = 3.5 x 10(-7)). This association was further investigated in an additional 18,436 nondiabetic individuals of mixed European descent from 7 different studies. The combined P value for association in these follow-up samples was 6.9 x 10(-26), and combining results from all studies resulted in an overall P value for association of 6.4 x 10(-33). Across these studies, fasting glucose concentrations increased 0.01-0.16 mM with each copy of the major allele, accounting for approximately 1% of the total variation in fasting glucose. The rs563694 SNP is located between the genes glucose-6-phosphatase catalytic subunit 2 (G6PC2) and ATP-binding cassette, subfamily B (MDR/TAP), member 11 (ABCB11). Our results in combination with data reported in the literature suggest that G6PC2, a glucose-6-phosphatase almost exclusively expressed in pancreatic islet cells, may underlie variation in fasting glucose, though it is possible that ABCB11, which is expressed primarily in liver, may also contribute to such variation.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Glicemia/análise , Glucose-6-Fosfatase/genética , Polimorfismo de Nucleotídeo Único , Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP , Adulto , Idoso , Análise de Variância , Jejum/sangue , Finlândia , Seguimentos , Frequência do Gene , Genótipo , Humanos , Itália , Desequilíbrio de Ligação , Pessoa de Meia-Idade , População Branca/genética
4.
PLoS Genet ; 2(8): e132, 2006 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-16934002

RESUMO

In family studies, phenotypic similarities between relatives yield information on the overall contribution of genes to trait variation. Large samples are important for these family studies, especially when comparing heritability between subgroups such as young and old, or males and females. We recruited a cohort of 6,148 participants, aged 14-102 y, from four clustered towns in Sardinia. The cohort includes 34,469 relative pairs. To extract genetic information, we implemented software for variance components heritability analysis, designed to handle large pedigrees, analyze multiple traits simultaneously, and model heterogeneity. Here, we report heritability analyses for 98 quantitative traits, focusing on facets of personality and cardiovascular function. We also summarize results of bivariate analyses for all pairs of traits and of heterogeneity analyses for each trait. We found a significant genetic component for every trait. On average, genetic effects explained 40% of the variance for 38 blood tests, 51% for five anthropometric measures, 25% for 20 measures of cardiovascular function, and 19% for 35 personality traits. Four traits showed significant evidence for an X-linked component. Bivariate analyses suggested overlapping genetic determinants for many traits, including multiple personality facets and several traits related to the metabolic syndrome; but we found no evidence for shared genetic determinants that might underlie the reported association of some personality traits and cardiovascular risk factors. Models allowing for heterogeneity suggested that, in this cohort, the genetic variance was typically larger in females and in younger individuals, but interesting exceptions were observed. For example, narrow heritability of blood pressure was approximately 26% in individuals more than 42 y old, but only approximately 8% in younger individuals. Despite the heterogeneity in effect sizes, the same loci appear to contribute to variance in young and old, and in males and females. In summary, we find significant evidence for heritability of many medically important traits, including cardiovascular function and personality. Evidence for heterogeneity by age and sex suggests that models allowing for these differences will be important in mapping quantitative traits.


Assuntos
Doenças Cardiovasculares/genética , Fenômenos Fisiológicos Cardiovasculares , Personalidade/genética , Característica Quantitativa Herdável , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Análise de Variância , Cromossomos Humanos X/genética , Estudos de Coortes , Feminino , Genes Mitocondriais , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Herança Multifatorial , Caracteres Sexuais , Irmãos
5.
Am J Med Genet B Neuropsychiatr Genet ; 150B(8): 1070-7, 2009 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-19199283

RESUMO

The polymorphism in the serotonin transporter gene promoter region (5-HTTLPR) is by far the most studied variant hypothesized to influence Neuroticism-related personality traits. The results of previous studies have been mixed and appear moderated by the personality questionnaire used. Studies that used the TCI to assess Harm Avoidance or the EPQ to assess Neuroticism have found no association with the 5-HTTLPR. However, studies that used the NEO-PI-R or related instruments (NEO-PI, NEO-FFI) to measure Neuroticism have found some evidence of association. This study examines the association of variants in the serotonin transporter gene in a sample from a genetically isolated population within Sardinia (Italy) that is several times larger than previous samples that used the NEO-PI-R (N = 3,913). The association was also tested in a sample (N = 548) from the Baltimore Longitudinal Study of Aging (BLSA), in which repeated NEO-PI-R assessments were obtained. In the SardiNIA sample, we found no significant association of the 5-HTTLPR genotypes with Neuroticism or its facets (Anxiety, Angry-Hostility, Depression, Self-Consciousness, Impulsiveness, and Vulnerability). In the BLSA sample, we found lower scores on Neuroticism traits for the heterozygous group, which is inconsistent with previous studies. We also examined eight SNPs in the SardiNIA (N = 3,972) and nine SNPs in the BLSA (N = 1,182) that map within or near the serotonin transporter gene (SLC6A4), and found no association. Along with other large studies that used different phenotypic measures and found no association, this study substantially increases the evidence against a link between 5-HTT variants and Neuroticism-related traits.


Assuntos
Estudos de Associação Genética , Transtornos Neuróticos/genética , Polimorfismo Genético , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/genética , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/genética , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Transtornos Neuróticos/epidemiologia , Polimorfismo de Nucleotídeo Único , Adulto Jovem
6.
Neuropsychopharmacology ; 35(5): 1083-9, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20042999

RESUMO

Brain-derived neurotrophic factor (BDNF) regulates synaptic plasticity and neurotransmission, and has been linked to neuroticism, a major risk factor for psychiatric disorders. A recent genome-wide association (GWA) scan, however, found the BDNF Val66Met polymorphism (rs6265) associated with extraversion but not with neuroticism. In this study, we examine the links between BDNF and personality traits, assessed using the Revised NEO Personality Inventory (NEO-PI-R), in a sample from SardiNIA (n=1560) and the Baltimore Longitudinal Study of Aging (BLSA; n=1131). Consistent with GWA results, we found that BDNF Met carriers were more introverted. By contrast, in both samples and in a meta-analysis inclusive of published data (n=15251), we found no evidence for a main effect of BDNF Val66Met on neuroticism. Finally, on the basis of recent reports of an epistatic effect between BDNF and the serotonin transporter, we explored a Val66Met x 5-HTTLPR interaction in a larger SardiNIA sample (n=2333). We found that 5-HTTLPR LL carriers scored lower on neuroticism in the presence of the BDNF Val variant, but scored higher on neuroticism in the presence of the BDNF Met variant. Our findings support the association between the BDNF Met variant and introversion and suggest that BDNF interacts with the serotonin transporter gene to influence neuroticism.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Personalidade/genética , Polimorfismo Genético , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Personalidade , Análise de Sequência de DNA , Adulto Jovem
7.
Am J Hum Genet ; 80(6): 1103-14, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17503328

RESUMO

Asthma is a multifactorial disease influenced by genetic and environmental factors. In the past decade, several loci and >100 genes have been found to be associated with the disease in at least one population. Among these loci, region 12q13-24 has been implicated in asthma etiology in multiple populations, suggesting that it harbors one or more asthma susceptibility genes. We performed linkage and association analyses by transmission/disequilibrium test and case-control analysis in the candidate region 12q13-24, using the Sardinian founder population, in which limited heterogeneity of pathogenetic alleles for monogenic and complex disorders as well as of environmental conditions should facilitate the study of multifactorial traits. We analyzed our cohort, using a cutoff age of 13 years at asthma onset, and detected significant linkage to a portion of 12q13-24. We identified IRAK-M as the gene contributing to the linkage and showed that it is associated with early-onset persistent asthma. We defined protective and predisposing SNP haplotypes and replicated associations in an outbred Italian population. Sequence analysis in patients found mutations, including inactivating lesions, in the IRAK-M coding region. Immunohistochemistry of lung biopsies showed that IRAK-M is highly expressed in epithelial cells. We report that IRAK-M is involved in the pathogenesis of early-onset persistent asthma. IRAK-M, a negative regulator of the Toll-like receptor/IL-1R pathways, is a master regulator of NF- kappa B and inflammation. Our data suggest a mechanistic link between hyperactivation of the innate immune system and chronic airway inflammation and indicate IRAK-M as a potential target for therapeutic intervention against asthma.


Assuntos
Asma/epidemiologia , Asma/etiologia , Asma/genética , Quinases Associadas a Receptores de Interleucina-1/genética , Adolescente , Idade de Início , Alelos , Processamento Alternativo , Substituição de Aminoácidos , Asma/diagnóstico , Asma/patologia , Estudos de Casos e Controles , Mapeamento Cromossômico , Cromossomos Humanos Par 12 , Estudos de Coortes , Feminino , Efeito Fundador , Frequência do Gene , Ligação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Haplótipos , Humanos , Imuno-Histoquímica , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Itália/epidemiologia , Desequilíbrio de Ligação , Escore Lod , Pulmão/metabolismo , Pulmão/cirurgia , Masculino , Repetições de Microssatélites , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Irmãos
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