RESUMO
Two of the three class I alcohol dehydrogenase (ADH) genes (ADH2 and ADH3) encode known functional variants that act on alcohol with different efficiencies. Variants at both these genes have been implicated in alcoholism in some populations because allele frequencies differ between alcoholics and controls. Specifically, controls have higher frequencies of the variants with higher Vmax (ADH2*2 and ADH3*1). In samples both of alcoholics and of controls from three Taiwanese populations (Chinese, Ami, and Atayal) we found significant pairwise disequilibrium for all comparisons of the two functional polymorphisms and a third, presumably neutral, intronic polymorphism in ADH2. The class I ADH genes all lie within 80 kb on chromosome 4; thus, variants are not inherited independently, and haplotypes must be analyzed when evaluating the risk of alcoholism. In the Taiwanese Chinese we found that, only among those chromosomes containing the ADH3*1 variant (high Vmax), the proportions of chromosomes with ADH2*1 (low Vmax) and those with ADH2*2 (high Vmax) are significantly different between alcoholics and controls (P<10-5). The proportions of chromosomes with ADH3*1 and those with ADH3*2 are not significantly different between alcoholics and controls, on a constant ADH2 background (with ADH2*1, P=.83; with ADH2*2, P=.53). Thus, the observed differences in the frequency of the functional polymorphism at ADH3, between alcoholics and controls, can be accounted for by the disequilibrium with ADH2 in this population.
Assuntos
Álcool Desidrogenase/genética , Alcoolismo/genética , Predisposição Genética para Doença , Desequilíbrio de Ligação/genética , Alcoolismo/prevenção & controle , Alelos , Sequência de Bases , China/etnologia , Cromossomos Humanos Par 4/genética , Clonagem Molecular , Frequência do Gene/genética , Variação Genética/genética , Haplótipos/genética , Humanos , Indígenas Centro-Americanos/genética , México , Dados de Sequência Molecular , Família Multigênica/genética , Havaiano Nativo ou Outro Ilhéu do Pacífico/genética , Polimorfismo de Nucleotídeo Único/genética , Grupos Raciais , TaiwanRESUMO
A girl 5 years 11 months of age, belonging to an extensive kindred with multiple endocrine neoplasia, type IIA (MEN IIA), was found to have multifocal medullary thyroid carcinoma with metastasis in one paraglandular lymph node after positive findings on a calcium-pentagastrin stimulation test. Her sister, 3 years 8 months of age, also had an elevated calcitonin level, and thyroidectomy revealed C-cell hyperplasia and a focus of medullary thyroid carcinoma. These two cases underscore the need for prophylactic thyroidectomies in MEN IIA patients as young as 5 years of age and strict yearly provocative screening beginning at age 1 year.
Assuntos
Carcinoma Medular/diagnóstico , Carcinoma Medular/secundário , Neoplasia Endócrina Múltipla Tipo 2a/diagnóstico , Neoplasias da Glândula Tireoide/genética , Carcinoma Medular/genética , Carcinoma Medular/cirurgia , Criança , Pré-Escolar , Feminino , Humanos , Linfonodos/patologia , Metástase Linfática , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/terapia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , TireoidectomiaRESUMO
The dopamine D4 receptor gene (DRD4) has an expressed polymorphism in the third exon that may have functional relevance. The polymorphism exists at two levels. At the higher level there is an imperfect tandem repeat of 48 base pairs (bp) coding for 16 amino acids; alleles have been identified with 2 (32 amino acids) to 10 (160 amino acids) repeats. The imperfect nature of the repeats is responsible for a more subtle level of variation since alleles with the same number of repeats can differ in the exact sequences or in the order of the variants of the 48-bp unit. We have undertaken a global survey of this expressed polymorphism as one approach to understanding the evolutionary significance and origins of the polymorphism as well as understanding what selective forces, if any, may be operating at this locus. As the first step, we have determined the repeat number genotype of the DRD4 repeat polymorphism in 1,327 individuals from 36 different populations. The allele frequencies differ considerably among the different populations. The 4-repeat allele was the most prevalent (global mean allele frequency = 64.3%) and appeared in every population with a frequency ranging from 0.16 to 0.96. The 7-repeat allele was the second most common (global mean = 20.6%), appearing quite frequently in the Americas (mean frequency = 48.3%) but only occasionally in East and South Asia (mean frequency = 1.9%). The 2-repeat allele was the third most common (global mean frequency = 8.2%) and was quite frequent in East and South Asia (mean frequency = 18.1%) while uncommon in the Americas (mean frequency = 2.9%) and Africa (mean frequency = 1.7%). The universality of the polymorphism with only three common repeat-number alleles (4, 7, and 2) indicates that the polymorphism is ancient and arose before the global dispersion of modern humans. The diversity of actual allele frequencies for this expressed polymorphism among different populations emphasizes the importance of population considerations in the design and interpretation of any association studies carried out with this polymorphism.
Assuntos
Frequência do Gene/genética , Polimorfismo Genético , Receptores de Dopamina D2/genética , Sequências Repetitivas de Ácido Nucleico , África , Alelos , Ásia , Europa (Continente) , Evolução Molecular , Éxons/genética , Humanos , Oriente Médio , América do Norte , Oceano Pacífico , Receptores de Dopamina D4 , América do SulRESUMO
Three Amerindian populations, two from Rondônia, Brazil (Karitiana and Rondônia Suruí), and one from Campeche, Mexico (Mayan), were typed for up to 30 nuclear restriction fragment length polymorphisms (RFLPs). Heterozygosities, both observed and expected, were compared with those of Europeans. Average heterozygosity is reduced among these Amerindians (relative to that of Europeans) by 7.0% (Mayan) to 27.1% (Karitiana). This amount of heterozygosity in the nuclear DNA is nevertheless high enough that it is unlikely that there was a severe or prolonged bottleneck.