RESUMO
BACKGROUND: The development of vascular disease involves the interaction of genetic and environmental factors. Because vascular disease is a major contributor to mortality in Western societies, we hypothesized that deleterious polymorphisms associated with hemostasis decrease in frequency among a healthy population as a function of age. METHODS: The frequencies of factor V G1691A Leiden (FVL), factor II (FII) G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T, glycoprotein Ia (GPIa) C807T, glycoprotein IIIa (Pl(A1)/Pl(A2)) T1565C, and angiotensin-converting enzyme (ACE) intron 16 insertion/deletion (I/D) alleles were determined among 2689 healthy Caucasian whole-blood donors. For analysis, participants were divided into three age groups: 17-39 years (n = 979; 505 males and 474 females), 40-59 years (n = 900; 526 males and 374 females), and 60-85 years (n = 810; 530 males and 280 females). RESULTS: The Pl(A2) allele frequency decreased from 17.5% to 15.7% and 14.1% in the 17-39 years, 40-59 years, and 60-85 years age groups, respectively (n = 5094 alleles; P = 0.025). Among ACE DD males, the Pl(A2) allele frequency decreased from 20.8% to 16.1% and 9.1% in the same groups, respectively (n = 810 alleles; P = 0.001). No statistically significant decrease in genotype or allele frequency was observed among carriers of FVL, FII 20210A, MTHFR 677T, GPIa 807T, or ACE D. CONCLUSIONS: These data suggest that Pl(A2) carriers, especially those who are ACE DD, are statistically less prevalent among older healthy blood donors compared with their younger counterparts. These observations suggest an important, deleterious, time-dependent impact of the Pl(A2) allele, as well as the ACE DD/Pl(A2) allelic combination, on overall health and longevity.
Assuntos
Polimorfismo Genético , Doenças Vasculares/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Doadores de Sangue , Estudos de Coortes , Fator V/genética , Feminino , Humanos , Integrina alfa2 , Integrina beta3 , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2) , Pessoa de Meia-Idade , Mutação , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Peptidil Dipeptidase A/genética , Glicoproteínas da Membrana de Plaquetas/genética , Prevalência , Protrombina/genética , População Branca/genéticaRESUMO
Due to the expanding number of known HLA class II DQB1 alleles, high-resolution oligotyping is becoming ineffective, therefore a sequence-based typing (SBT) strategy was developed to provide rapid and definitive typing of HLA-DQB1. HLA-DQB1*02, *03, *04, *05, and *06 alleles were individually amplified by polymerase chain reaction (PCR) using exon 2 group-specific primers. Forward and reverse PCR primers were tailed with M13 universal and M13 reverse sequences, respectively. Subsequent bi-directional cycle-sequencing was carried out using Cy5.5-labeled M13 universal primer and Cy5.0-labeled M13 reverse primer. Automated sequencing was performed in 30 min using a Visible Genetics, Inc. (VGI) MicroGene Clipper Sequencer. Full concordance was observed between this SBT method and oligotyping among 151 individuals.
Assuntos
Antígenos HLA-DQ/genética , Teste de Histocompatibilidade/métodos , Primers do DNA , Éxons/genética , Genótipo , Cadeias beta de HLA-DQ , Humanos , Reação em Cadeia da Polimerase , Análise de Sequência de DNARESUMO
Two linked silent dimorphisms, 807 C --> T (Phe224) and 873 G --> A (Thr246) within the glycoprotein Ia (GPIa) gene have been correlated with low and high platelet receptor density, respectively, and associated with vascular disease. A multiplexed allele-specific PCR assay was used to determine the GPIa 807T/873A allele frequency among 331 Caucasian venous thrombosis patients and 3571 unrelated individuals belonging to six different racial groups. The 807T/873A allele frequencies were 54%, 51%, 39%, 39%, 38%, 34% and 30% among Native Americans, Hispanics, Caucasians, Caucasian venous thrombosis patients, Asian Indians, African-Americans, and Koreans, respectively. Significant differences in the GPIa allele frequency among racial groups were revealed which emphasized the need for appropriate controls in studies evaluating the association of GPIa genotype to vascular disease.
Assuntos
Antígenos CD/genética , Grupos Raciais/genética , Trombose Venosa/genética , Alelos , Frequência do Gene , Genótipo , Humanos , Integrina alfa2 , Reação em Cadeia da Polimerase/métodosRESUMO
The cooperative effects of the GPIa 807TT, MTHFR 677TT and prothrombin 20210GA genotypes with the FV Leiden 1691GA (FVL) genotype were evaluated by comparing these genotype frequencies in 77 asymptomatic and 156 symptomatic heterozygous FVL carriers. The GPIa 807TT and MTHFR 677TT genotypes did not segregate within the symptomatic FVL carrier group and did not contribute to venous thrombotic risk in this patient cohort. There was no difference in the prothrombin 20210GA genotype frequency between asymptomatic FVL carriers and a random Caucasian control group; however, the prothrombin 20210GA genotype was nearly 5 times as prevalent (19/156 v 2/77; P < 0.02) in the symptomatic FVL carriers (odds ratio 5.21; 95% confidence interval 1.20-47.62), demonstrating that this important prothrombotic risk factor acts synergistically with FVL.
Assuntos
Fator V/genética , Heterozigoto , Integrinas/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Protrombina/genética , Trombose/genética , Genótipo , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2) , Receptores de Colágeno , Fatores de RiscoAssuntos
Etnicidade/genética , Isoformas de Proteínas/genética , Grupos Raciais/genética , Receptores de IgG/genética , Negro ou Afro-Americano , Alelos , Substituição de Aminoácidos , População Negra/genética , Frequência do Gene , Hispânico ou Latino/genética , Humanos , Índia/etnologia , Indígenas Norte-Americanos/genética , Coreia (Geográfico)/etnologia , População Branca/genética , WisconsinRESUMO
HLA-DRB1 molecules contain extensive polymorphism localized to specific functional regions of the antigen binding site (ABS). Position 86 of HLA-DRB1 molecules modulates a hydrophobic pocket in the ABS which acts as a peptide anchoring site [1]. We report the nucleotide sequence of HLA-DRB1*1316 which is identical to HLA-DRB1*1301 and *1302 except at codon 86. The novel allele encodes aspartate rather than valine or glycine at position 86. Val86 and Gly86 have been exclusively observed in thousands of oligotyped specimens; thus Asp86 is a rare polymorphism which is significant with respect to hypotheses concerning evolution and structure-function relationships of HLA-DRB1 molecules.