RESUMO
OBJECTIVE: Little consistent evidence is available for the association between the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P) and any of the individual genes in the folate/homocysteine metabolic pathway. We investigated the genes in the folate pathway to further clarify its potential influence on the risk of NSCL/P considering gene-gene (G×G) interaction. SUBJECTS AND METHODS: We selected markers in 18 genes from the pathway and applied Cordell's method to test for G×G interaction using 1,908 NSCL/P case-parent trios ascertained in an international consortium where a genomewide association study (GWAS) of oral clefts was conducted. RESULTS: We found intriguing signals among Asian and European ancestry groups for G×G interaction between markers in betaine-homocysteine methyltransferase gene (BHMT/BHMT2) and dimethylglycine dehydrogenase gene (DMGDH) attaining genomewide significance. In the pooled data, the top significant interaction was found between rs13158309 (BHMT) and rs10514154 (DMGDH, p = 1.45 × 10-12 ). CONCLUSIONS: Our study illustrated the importance of taking into account potential G×G interaction for genetic association analysis in NSCL/P, and this study suggested both BHMT/BHMT2 and DMGDH should be considered as candidate genes for NSCL/P in future studies.
Assuntos
Betaína-Homocisteína S-Metiltransferase/genética , Fenda Labial/genética , Fissura Palatina/genética , Dimetilglicina Desidrogenase/genética , Epistasia Genética , Proteínas Mitocondriais/genética , Povo Asiático/genética , Ácido Fólico/metabolismo , Estudo de Associação Genômica Ampla , Homocisteína/metabolismo , Humanos , Desequilíbrio de Ligação , Redes e Vias Metabólicas , Polimorfismo de Nucleotídeo Único , Fatores de Risco , População Branca/genéticaRESUMO
Short-acting ß2-agonist bronchodilators are the most common medications used in treating chronic obstructive pulmonary disease (COPD). Genetic variants determining bronchodilator responsiveness (BDR) in COPD have not been identified. We performed a genome-wide association study (GWAS) of BDR in 5789 current or former smokers with COPD in one African-American and four white populations. BDR was defined as the quantitative spirometric response to inhaled ß2-agonists. We combined results in a meta-analysis. In the meta-analysis, single-nucleotide polymorphisms (SNPs) in the genes KCNK1 (P=2.02 × 10(-7)) and KCNJ2 (P=1.79 × 10(-7)) were the top associations with BDR. Among African Americans, SNPs in CDH13 were significantly associated with BDR (P=5.1 × 10(-9)). A nominal association with CDH13 was identified in a gene-based analysis in all subjects. We identified suggestive association with BDR among COPD subjects for variants near two potassium channel genes (KCNK1 and KCNJ2). SNPs in CDH13 were significantly associated with BDR in African Americans.The Pharmacogenomics Journal advance online publication, 27 October 2015; doi:10.1038/tpj.2015.65.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Broncodilatadores/uso terapêutico , Pulmão/efeitos dos fármacos , Variantes Farmacogenômicos/genética , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/genética , Negro ou Afro-Americano/genética , Idoso , Caderinas/genética , Europa (Continente) , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nova Zelândia , América do Norte , Testes Farmacogenômicos , Fenótipo , Canais de Potássio Corretores do Fluxo de Internalização/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Risco , Sarcoglicanas/genética , Índice de Gravidade de Doença , Espirometria , Resultado do Tratamento , População Branca/genéticaRESUMO
Van der Woude syndrome (VWS) is an autosomal dominant malformation syndrome characterized by orofacial clefting (OFC) and lower lip pits. The clinical presentation of VWS is variable and can present as an isolated OFC, making it difficult to distinguish VWS cases from individuals with non-syndromic OFCs. About 70% of causal VWS mutations occur in IRF6, a gene that is also associated with non-syndromic OFCs. Screening for IRF6 mutations in apparently non-syndromic cases has been performed in several modestly sized cohorts with mixed results. In this study, we screened 1521 trios with presumed non-syndromic OFCs to determine the frequency of causal IRF6 mutations. We identified seven likely causal IRF6 mutations, although a posteriori review identified two misdiagnosed VWS families based on the presence of lip pits. We found no evidence for association between rare IRF6 polymorphisms and non-syndromic OFCs. We combined our results with other similar studies (totaling 2472 families) and conclude that causal IRF6 mutations are found in 0.24-0.44% of apparently non-syndromic OFC families. We suggest that clinical mutation screening for IRF6 be considered for certain family patterns such as families with mixed types of OFCs and/or autosomal dominant transmission.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Encéfalo/anormalidades , Fenda Labial/diagnóstico , Fenda Labial/genética , Fissura Palatina/diagnóstico , Fissura Palatina/genética , Cistos/diagnóstico , Cistos/genética , Fatores Reguladores de Interferon/genética , Lábio/anormalidades , Mutação , Anormalidades Múltiplas/etnologia , Anormalidades Múltiplas/patologia , Adulto , Povo Asiático , Encéfalo/patologia , Criança , Fenda Labial/etnologia , Fenda Labial/patologia , Fissura Palatina/etnologia , Fissura Palatina/patologia , Cistos/etnologia , Cistos/patologia , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Expressão Gênica , Testes Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Lábio/patologia , Masculino , Linhagem , Fenótipo , População BrancaRESUMO
AIM: To investigate the genetic influence of circulating lactate level, a marker of oxidative capacity associated with diabetes. METHODS: We conducted a genome-wide association study of log-transformed plasma lactate levels in 6901 European-American participants in the Atherosclerosis Risk in Communities study. For regions that achieved genome-wide significance in European-American participants, we conducted candidate region analysis in African-American subjects and tested for interaction between metformin use and the index single nucleotide polymorphisms for plasma lactate in European-American subjects. RESULTS: The genome-wide association study in European-American subjects identified two genome-wide significant loci, GCKR (rs1260326, T allele ß=0.08; P=1.8×10(-47) ) and PPP1R3B/LOC157273 (rs9987289, A allele ß=0.06; P=1.6×10(-9) ). The index single nucleotide polymorphisms in these two loci explain 3.3% of the variance in log-transformed plasma lactate levels among the European-American subjects. In the African-American subjects, based on a region-significant threshold, the index single nucleotide polymorphism at GCKR was associated with plasma lactate but that at PPP1R3B/LOC157273 was not. Metformin use appeared to strengthen the association between the index single nucleotide polymorphism at PPP1R3B/LOC157273 and plasma lactate in European-American subjects (P for interaction=0.01). CONCLUSIONS: We identified GCKR and PPP1R3B/LOC157273 as two genome-wide significant loci of plasma lactate. Both loci are associated with other diabetes-related phenotypes. These findings increase our understanding of the genetic control of lactate metabolism.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Ácido Láctico/sangue , Proteína Fosfatase 1/genética , Negro ou Afro-Americano , Alelos , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , População BrancaRESUMO
A collection of 1,108 case-parent trios ascertained through an isolated, nonsyndromic cleft lip with or without cleft palate (CL/P) was used to replicate the findings from a genome-wide association study (GWAS) conducted by Beaty et al. (Nat Genet 42:525-529, 2010), where four different genes/regions were identified as influencing risk to CL/P. Tagging SNPs for 33 different genes were genotyped (1,269 SNPs). All four of the genes originally identified as showing genome-wide significance (IRF6, ABCA4 and MAF, plus the 8q24 region) were confirmed in this independent sample of trios (who were primarily of European and Southeast Asian ancestry). In addition, eight genes classified as 'second tier' hits in the original study (PAX7, THADA, COL8A1/FILIP1L, DCAF4L2, GADD45G, NTN1, RBFOX3 and FOXE1) showed evidence of linkage and association in this replication sample. Meta-analysis between the original GWAS trios and these replication trios showed PAX7, COL8A1/FILIP1L and NTN1 achieved genome-wide significance. Tests for gene-environment interaction between these 33 genes and maternal smoking found evidence for interaction with two additional genes: GRID2 and ELAVL2 among European mothers (who had a higher rate of smoking than Asian mothers). Formal tests for gene-gene interaction (epistasis) failed to show evidence of statistical interaction in any simple fashion. This study confirms that many different genes influence risk to CL/P.
Assuntos
Povo Asiático/genética , Fenda Labial/genética , Fissura Palatina/genética , Ligação Genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , População Branca/genética , Feminino , Humanos , Masculino , Metanálise como AssuntoRESUMO
Two primary chitinases have been identified in humans--acid mammalian chitinase (AMCase) and chitotriosidase (CHIT1). Mammalian chitinases have been observed to affect the host's immune response. The aim of this study was to test for association between genetic variation in the chitinases and phenotypes related to chronic obstructive pulmonary disease (COPD). Polymorphisms in the chitinase genes were selected based on previous associations with respiratory diseases. Polymorphisms that were associated with lung function level or rate of decline in the Lung Health Study (LHS) cohort were analyzed for association with COPD affection status in four other COPD case-control populations. Chitinase activity and protein levels were also related to genotypes. In the caucasian LHS population, the baseline forced expiratory volume in one second (FEV(1)) was significantly different between the AA and GG genotypic groups of the AMCase rs3818822 polymorphism. Subjects with the GG genotype had higher AMCase protein and chitinase activity compared with AA homozygotes. For CHIT1 rs2494303, a significant association was observed between rate of decline in FEV(1) and the different genotypes. In the African American LHS population, CHIT1 rs2494303 and AMCase G339T genotypes were associated with rate of decline in FEV(1). Although a significant effect of chitinase gene alleles was found on lung function level and decline in the LHS, we were unable to replicate the associations with COPD affection status in the other COPD study groups.
Assuntos
Quitinases/genética , Volume Expiratório Forçado , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Idoso , Líquido da Lavagem Broncoalveolar/química , Estudos de Casos e Controles , Quitinases/metabolismo , Feminino , Variação Genética , Genótipo , Humanos , Pulmão/metabolismo , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Doença Pulmonar Obstrutiva Crônica/enzimologia , Fenômenos Fisiológicos Respiratórios , FumarRESUMO
Interleukin (IL)-10 is a regulatory cytokine of the helper T cell type 2 (TH2) pathway, which underlies both the host defense to helminthic infection and atopic diseases, including asthma. Although IL10 promoter polymorphisms are associated with increased atopy risk, IL10 variation has not been thoroughly explored in schistosomiasis-endemic populations. Three atopy-related IL10 promoter polymorphisms (rs1800896, rs1800871 and rs1800872), complemented by six tagging single-nucleotide polymorphisms (SNPs), were genotyped in 812 individuals in 318 nuclear families from a schistosomiasis-endemic area in Brazil. Associations between markers and total serum Immunoglobulin E (tIgE) levels, indicating non-specific activation of the TH2 pathway, and Schistosoma mansoni fecal egg counts, indicating burden of infection reflecting effectiveness of schistosomiasis host immunity, were performed using family-based transmission disequilibrium tests for quantitative traits (QTDTs). Alleles A, T and A at the three promoter SNPs rs1800896, rs1800871 and rs1800872 were associated with high tIgE levels in the same direction as in atopy populations (P=0.0008, 0.026 and 0.045), but not with egg counts. IL10 promoter polymorphisms appear to influence non-specific tIgE levels, but not schistosomiasis-specific immunity. The tagging SNP rs3024495 was associated with high S. mansoni egg counts (P=0.005), suggesting a novel locus in IL10 may influence clinically relevant burden of infection.
Assuntos
Imunoglobulina E/sangue , Interleucina-10/genética , Polimorfismo de Nucleotídeo Único , Schistosoma mansoni/fisiologia , Esquistossomose mansoni/genética , Esquistossomose mansoni/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Brasil , Criança , Feminino , Humanos , Imunoglobulina E/imunologia , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Adulto JovemRESUMO
BACKGROUND: Sensitization to cockroach allergen is one of the strongest predictors of asthma morbidity, especially among African Americans. OBJECTIVE: Our aims were to determine the genomic basis of cockroach sensitization and the specific response to cockroach antigen. METHODS: We investigated the Th1/Th2 cytokine profile of co-cultured plasmacytoid dendritic cells (pDCs) and CD4+ T cells and the 'transcript signature' of the immune response to cockroach antigen using high-throughput expression profiling of co-cultured cells. RESULTS: We observed significantly elevated levels of IL-13, IL-10, and TNF-alpha, but undetectable levels of IL-12p70 and IFN-alpha, when cultures were exposed to crude cockroach antigen. A significant difference was observed for IL-13 between cockroach-allergic and non-allergic individuals (P=0.039). Microarray analyses demonstrated a greater response at 48 h compared with 4 h, with 50 genes being uniquely expressed in cockroach antigen-treated cells, including CD14, S100A8, CCL8, and IFI44L. The increased CD14 expression was further observed in purified pDCs, human monocytic THP-1 cells, and the supernatant of co-cultured pDCs and CD4+ T cells on exposure to cockroach extract. Furthermore, the most differential expression of CD14 between cockroach allergy and non-cockroach allergy was only observed among individuals with the CC 'high-risk' genotype of the CD14-260C/T. Ingenuity Pathways Analysis analyses suggested the IFN signalling as the most significant canonical pathway. CONCLUSION: Our results suggest that these differentially expressed genes, particularly CD14, and genes in the IFN signalling pathway may be important candidates for further investigation of their role in the immune response to cockroach allergen.
Assuntos
Alérgenos/imunologia , Asma/genética , Baratas/imunologia , Citocinas/biossíntese , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Interferon-alfa/imunologia , Receptores de Lipopolissacarídeos/genética , Adolescente , Adulto , Negro ou Afro-Americano , Animais , Asma/etnologia , Asma/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Técnicas de Cocultura , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Genótipo , Humanos , Interferon-alfa/metabolismo , Pessoa de Meia-Idade , Células Th2RESUMO
BACKGROUND: Single nucleotide polymorphisms (SNPs) in thymic stromal lymphopoietin (TSLP) have been associated with IgE (in girls) and asthma (in general). We sought to determine whether TSLP SNPs are associated with asthma in a sex-specific fashion. METHODS: We conducted regular and sex-stratified analyses of association between SNPs in TSLP and asthma in families of children with asthma in Costa Rica. Significant findings were replicated in whites and African-American participants in the Childhood Asthma Management Program, in African-Americans in the Genomic Research on Asthma in the African Diaspora study, in whites and Hispanics in the Children's Health Study, and in whites in the Framingham Heart Study (FHS). MAIN RESULTS: Two SNPs in TSLP (rs1837253 and rs2289276) were significantly associated with a reduced risk of asthma in combined analyses of all cohorts (P values of 2 × 10(-5) and 1 × 10(-5) , respectively). In a sex-stratified analysis, the T allele of rs1837253 was significantly associated with a reduced risk of asthma in males only (P = 3 × 10(-6) ). Alternately, the T allele of rs2289276 was significantly associated with a reduced risk of asthma in females only (P = 2 × 10(-4) ). Findings for rs2289276 were consistent in all cohorts except the FHS. CONCLUSIONS: TSLP variants are associated with asthma in a sex-specific fashion.
Assuntos
Asma/genética , Citocinas/genética , Predisposição Genética para Doença/genética , Caracteres Sexuais , População Negra/genética , Criança , Estudos de Coortes , Costa Rica , Feminino , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Genótipo , Hispânico ou Latino/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Fatores de Risco , População Branca/genética , Linfopoietina do Estroma do TimoRESUMO
Only a fraction of all smokers develop chronic obstructive pulmonary disease (COPD), suggesting a large role for genetic susceptibility. The leptin receptor (LEPR) is present in human lung tissue and may play a role in COPD pathogenesis. The present study examined the association between genetic variants in the LEPR gene and lung function decline in COPD. In total, 429 European Americans were randomly selected from the National Heart Lung and Blood Institute Lung Health Study. 36 single nucleotide polymorphisms (SNPs) in LEPR were genotyped using the Illumina GoldenGate platform (Broad Institute, Cambridge, MA, USA). Mean annual decline in forced expiratory volume in 1 s % predicted over the 5-yr period was calculated using linear regression. Linear regression models were also used to adjust for potential confounders. In addition, in vivo expression of the receptor gene was assessed with immunohistochemistry on lungs from smoke-exposed inbred mice. We identified significant associations (p<0.05) between lung function decline and 21 SNPs. Haplotype analyses confirmed several of these associations seen with individual markers. Immunohistochemistry results in inbred mice strains support a potential role of LEPR in COPD pathogenesis. We identified genetic variants in the LEPR gene significantly associated with lung function decline in a population of smokers with COPD. Our results support a role for LEPR as a novel candidate gene for COPD.
Assuntos
Pulmão/fisiopatologia , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/metabolismo , Receptores para Leptina/genética , Adulto , Alelos , Animais , Feminino , Regulação da Expressão Gênica , Genótipo , Humanos , Imuno-Histoquímica , Pulmão/metabolismo , Masculino , Camundongos , Pessoa de Meia-IdadeRESUMO
Sib-pair analysis of 170 individuals from 11 Amish families revealed evidence for linkage of five markers in chromosome 5q31.1 with a gene controlling total serum immunoglobulin E (IgE) concentration. No linkage was found between these markers and specific IgE antibody concentrations. Analysis of total IgE within a subset of 128 IgE antibody-negative sib pairs confirmed evidence for linkage to 5q31.1, especially to the interleukin-4 gene (IL4). A combination of segregation and maximum likelihood analyses provided further evidence for this linkage. These analyses suggest that IL4 or a nearby gene in 5q31.1 regulates IgE production in a nonantigen-specific (noncognate) fashion.
Assuntos
Cromossomos Humanos Par 5 , Ligação Genética , Imunoglobulina E/sangue , Interleucina-4/genética , Adolescente , Adulto , Idoso , Alérgenos/imunologia , Sequência de Bases , Criança , Pré-Escolar , Feminino , Genes MHC da Classe II , Marcadores Genéticos , Humanos , Hipersensibilidade Imediata/genética , Funções Verossimilhança , Escore Lod , Masculino , Pessoa de Meia-Idade , Dados de Sequência MolecularRESUMO
Despite its high prevalence, very little is known regarding genetic predisposition to prostate cancer. A genome-wide scan performed in 66 high-risk prostate cancer families has provided evidence of linkage to the long arm of chromosome 1 (1q24-25). Analysis of an additional set of 25 North American and Swedish families with markers in this region resulted in significant evidence of linkage in the combined set of 91 families. The data provide strong evidence of a major prostate cancer susceptibility locus on chromosome 1.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 1 , Genes , Neoplasias da Próstata/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Repetições de Dinucleotídeos , Ligação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Funções Verossimilhança , Masculino , Pessoa de Meia-Idade , América do Norte , Oncogenes , Linhagem , Fatores de Risco , Estatísticas não Paramétricas , SuéciaRESUMO
Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with a complex genetic architecture. Gene-gene interactions have been increasingly regarded as contributing to the etiology of NSCL/P. A recent genome-wide association study revealed that a novel single-nucleotide polymorphism at SPRY1 in 4q28.1 showed a significant association with NSCL/P. In the current study, we explored the role of 3 SPRY genes in the etiology of NSCL/P by detecting gene-gene interactions: SPRY1, SPRY2, and SPRY4-with SPRY3 excluded due to its special location on the X chromosome. We selected markers in 3 SPRY genes to test for gene-gene interactions using 1,908 case-parent trios recruited from an international consortium established for a genome-wide association study of nonsyndromic oral clefts. As the trios came from populations with different ancestries, subgroup analyses were conducted among Europeans and Asians. Cordell's method based on conditional logistic regression models was applied to test for potential gene-gene interactions via the statistical package TRIO in R software. Gene-gene interaction analyses yielded 10 pairs of SNPs in Europeans and 6 pairs in Asians that achieved significance after Bonferroni correction. The significant interactions were confirmed in the 10,000-permutation tests (empirical P = 0.003 for the most significant interaction). The study identified gene-gene interactions among SPRY genes among 1,908 NSCL/P trios, which revealed the importance of potential gene-gene interactions for understanding the genetic architecture of NSCL/P. The evidence of gene-gene interactions in this study also provided clues for future biological studies to further investigate the mechanism of how SPRY genes participate in the development of NSCL/P.
Assuntos
Povo Asiático , Fenda Labial/genética , Fissura Palatina/genética , Epistasia Genética , Predisposição Genética para Doença/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , População Branca , Adulto , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Humanos , Proteínas de Membrana , Fosfoproteínas , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Recent work suggests that multiple genes and several environmental risk factors influence risk for non-syndromic oral clefts, one of the most common birth defects in humans. Advances in high-throughput genotyping technology now make it possible to test multiple markers in many candidate genes simultaneously. METHODS: We present findings from family based association tests of single nucleotide polymorphism (SNP) markers in 64 candidate genes genotyped using the BeadArray approach in 58 case-parent trios from Maryland (USA) to illustrate how multiple markers in multiple genes can be analysed. To assess whether these genes were expressed in human craniofacial structures relevant to palate and lip development, we also analysed data from the Craniofacial and Oral Gene Expression Network (COGENE) consortium, and searched public databases for expression profiles of these genes. RESULTS: Thirteen candidate genes showed significant evidence of linkage in the presence of disequilibrium, and ten of these were found to be expressed in relevant embryonic tissues: SP100, MLPH, HDAC4, LEF1, C6orf105, CD44, ALX4, ZNF202, CRHR1, and MAPT. Three other genes showing statistical evidence (ADH1C, SCN3B, and IMP5) were not expressed in the embryonic tissues examined here. CONCLUSIONS: This approach demonstrates how statistical evidence on large numbers of SNP markers typed in case-parent trios can be combined with expression data to identify candidate genes for complex disorders. Many of the genes reported here have not been previously studied as candidates for oral clefts and warrant further investigation.
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Anormalidades da Boca/genética , Polimorfismo de Nucleotídeo Único , Mapeamento Cromossômico/métodos , Anormalidades Craniofaciais/genética , DNA/genética , DNA/isolamento & purificação , Humanos , Desequilíbrio de Ligação , Maryland , Análise de Sequência com Séries de Oligonucleotídeos , Valores de ReferênciaRESUMO
Analysis of haplotypes based on multiple single-nucleotide polymorphisms (SNP) is becoming common for both candidate gene and fine-mapping studies. Before embarking on studies of haplotypes from genetically distinct populations, however, it is important to consider variation both in linkage disequilibrium (LD) and in haplotype frequencies within and across populations, as both vary. Such diversity will influence the choice of "tagging" SNPs for candidate gene or whole-genome association studies because some markers will not be polymorphic in all samples and some haplotypes will be poorly represented or completely absent. Here we analyze 11 genes, originally chosen as candidate genes for oral clefts, where multiple markers were genotyped on individuals from four populations. Estimated haplotype frequencies, measures of pairwise LD, and genetic diversity were computed for 135 European-Americans, 57 Chinese-Singaporeans, 45 Malay-Singaporeans, and 46 Indian-Singaporeans. Patterns of pairwise LD were compared across these four populations and haplotype frequencies were used to assess genetic variation. Although these populations are fairly similar in allele frequencies and overall patterns of LD, both haplotype frequencies and genetic diversity varied significantly across populations. Such haplotype diversity has implications for designing studies of association involving samples from genetically distinct populations.
Assuntos
Povo Asiático/genética , Predisposição Genética para Doença/etnologia , Haplótipos/genética , Polimorfismo de Nucleotídeo Único , População Branca/genética , Análise de Variância , Fenda Labial/etnologia , Fenda Labial/genética , Fissura Palatina/etnologia , Fissura Palatina/genética , Feminino , Frequência do Gene , Variação Genética/genética , Humanos , Índia/etnologia , Desequilíbrio de Ligação , Malásia/etnologia , Masculino , Maryland , Singapura , Taiwan/etnologiaRESUMO
BACKGROUND: It is estimated that there will be more than 244,000 new prostate cancer cases diagnosed and that more than 40,000 men will die of this disease during 1995. Evidence exists for a hereditary predisposition to prostate cancer, but the proportion of cases attributable to the inheritance of a specific gene or genes is not large. Some hereditary cancer syndromes involve more than one tumor site, and some studies have reported a familial association between prostate cancer and other cancers. The presence of other cancers in prostate cancer families may indicate a specific type of hereditary predisposition. PURPOSE: We studied families that were selected because of the presence of prostate cancer to determine whether hereditary prostate cancer is associated with cancers at other sites and possibly with other heritable cancer syndromes. METHODS: Data from two distinct study populations were studied retrospectively. The first population consisted of 690 case patients undergoing radical prostatectomy who were not selected for family history of prostate cancer and 640 control subjects who were the spouses or female companions of the case patients. The second population consisted of 75 multiplex families (i.e., families with multiple cases of prostate cancer) referred because they fulfilled the criteria for hereditary prostate cancer. A comparison between case and control populations for the occurrence of 14 aggregated groups of cancer was performed. Data were analyzed using Poisson regression, and relative risks (RRs) and their 95% confidence intervals (CIs) were calculated. RESULTS: Brothers and fathers of prostate cancer probands have a statistically significant higher risk of prostate cancer than the male first-degree relatives of control subjects (RR = 1.76; 95% CI = 1.28-2.43). Therefore, the risk for prostate cancer is 76% higher among first-degree relatives of prostate cancer patients compared with first-degree relatives of control subjects. This higher risk was not modified by an occurrence of breast cancer in the pedigree. Also, a statistically significant higher risk was found for tumors of the central nervous system in hereditary families (RR = 3.02; 95% CI = 1.08-8.41). Statistically significant higher risks of cancer at other major sites, such as breast, ovary, or endometrium were not observed in these families. CONCLUSIONS: Even among families that were specifically selected because of the presence of prostate cancer, risks for cancer at other sites appeared not to be increased. Therefore, hereditary prostate cancer appears to be a relatively site-specific disease, and it does not seem to be a part of other hereditary cancer syndromes.
Assuntos
Neoplasias/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias da Próstata/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição de Poisson , Estudos Retrospectivos , RiscoRESUMO
The St. Thomas Hospital (STH) rabbit has been previously shown to have a Mendelian form of hypertriglyceridemia, accompanied by accelerated atherosclerosis, and these animals may serve as a useful model for human dyslipoproteinemia syndromes. Here we describe the establishment of a new colony of these STH animals, and present genetic analysis of triglyceride (TG) and apolipoprotein B (apoB) levels. Segregation analysis of TG in 39 STH animals and 24 controls gave evidence of Mendelian segregation for an allele leading to both elevated TG levels and increased variability in these levels. Predicted means from the most parsimonious model for the Johns Hopkins STH colony were quite similar to that seen in the original London colony, and this model accounted for 80% of the variation in TG seen in the sample. This hypertriglyceridemia locus indirectly influenced the mean apoB levels in these rabbits, and segregation analysis of mean apoB levels suggested a second locus controlling apoB levels. Analysis of residual apoB levels (adjusted for predicted effects of the hypertriglyceridemia locus) revealed clearer evidence for a second locus controlling mean apoB levels in this colony. Arguments for two distinct genetic mechanisms operating in these STH animals are presented.
Assuntos
Apolipoproteínas B/sangue , Hiperlipoproteinemia Tipo IV/genética , Animais , Colesterol/sangue , Genes , Genótipo , Linhagem , Fenótipo , Coelhos , Triglicerídeos/sangueRESUMO
Atopic dermatitis is a chronic inflammatory skin disease that affects 10-20% of the population. Linkage of atopy, asthma, allergic rhinitis, and total serum IgE levels to several different chromosomal regions have been described extensively, but little is known about the genetic control of atopic dermatitis. We tested for the association and linkage between atopic dermatitis and five chromosomal regions: 5q31-33, 6p21.3, 12q15-24.1, 13q12-31, and 14q11.2/14q32.1-32.3. Marker analysis was performed in two Caucasian populations: (i) 192 unrelated German children with atopic dermatitis and 59 non-atopic children from a German birth cohort study (MAS'90), parental DNA was tested in 77 of 192 children with atopic dermatitis; (ii) 40 Swedish families with at least one family member with atopic dermatitis selected from the International Study of Asthma and Allergy in Children. Evidence for linkage and allelic association for atopic dermatitis was observed for markers on chromosome 13q12-14 and 5q31-33.
Assuntos
Cromossomos Humanos Par 13 , Cromossomos Humanos Par 5 , Dermatite Atópica/genética , Marcadores Genéticos/genética , Criança , Pré-Escolar , Alemanha , Humanos , SuéciaRESUMO
The methylenetetrahydrofolate reductase (MTHFR) gene has been associated with increased risk for cardiovascular disease in some, but not all studies. Our data sources included a MEDLINE search of the literature published before December 1998, a bibliography review, and expert consultation. Of 23 studies initially identified, 18 (9855 persons) met the inclusion criteria. Information on sample size, study design, Hardy-Weinberg equilibrium, method of genotype determination, plasma folate and homocysteine were abstracted by two reviewers using a standardized protocol. The overall odds ratio of the MTHFR gene on cardiovascular disease was estimated using the Mantel-Haenzel method. From 12 studies with angiographically-confirmed coronary artery disease (CAD), the overall odds ratio (OR) for CAD among those with heterozygous (V/A) was 1.3 (95% CI, 1.1-1.5), while it was 1.4 (1.2-1.6) for the homozygous mutant (V/V) compared to those with homozygous normal (A/A). However, the overall odds ratio for CAD among those with the V/V genotype versus A/A genotype was not statistically significant (OR: 1.1; 95% CI: 0.9-1.3) after excluding three Japanese studies. The corresponding OR for the three Japanese studies was 2.0 (1.6-2.7). For six studies with myocardial infarction (MI), the overall OR of MI was 1.0 (0.8-1.1) for those with the V/A genotype and 0.9 (0.7-1.1) for those with the V/V genotype, respectively; none of these ORs for MI was statistically significant. The MTHFR gene is associated with increased risk for CAD in Japan, but not in other populations.
Assuntos
Povo Asiático/genética , Doenças Cardiovasculares/genética , Predisposição Genética para Doença , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Doença das Coronárias/genética , Genótipo , Humanos , Japão , Metilenotetra-Hidrofolato Redutase (NADPH2) , Infarto do Miocárdio/genética , Razão de ChancesRESUMO
Although crude correlations are useful in family studies, some adjustment for effects of risk factors that vary both within and among families if often needed. A linear model for estimating sibship correlations while simultaneously considering height, age, race, sex, ascertainment, and smoking status was used on pulmonary function data on 1-second forced expiratory volume (FEV1) and the natural logarithm of the ratio of FEV1 to forced vital capacity (lnFEV%) from 402 adults in 152 white sibships and 172 adults in 59 black sibships. Crude correlations of .271 +/- .048 (FEV1) and .342 +/- .047 (lnFEV%) decreased significantly to .206 +/- .048 and .231 +/- .048, respectively, after adjustment. For black and white sibs, adjusted intraclass correlations, although not statistically different, were .153 +/- .089 and .225 +/- .055 (FEV1), respectively, and were .103 +/- .088 and .275 +/- .054 (lnFEV%), respectively, suggesting that pulmonary function may aggregate more strongly among whites. This analysis illustrates how risk factor adjustment can be readily incorporated into familial correlation studies.