RESUMO
As part of a genetic study of type 1 diabetes in Mexican-Americans, 360 first-degree relatives of 108 type 1 diabetic probands were studied. Islet cell antibody (ICA), insulin autoantibody, glutamic acid decarboxylase (GAD(65)), and protein tyrosine phosphatase autoantibodies were measured and human leucocyte antigen (HLA) class II alleles DRB1 and DQB1 genotyping was performed. ICA was positive in 37% of the probands and 5.8% of the relatives. A subgroup of 26 probands (12 ICA+, 14 ICA-) was tested for GAD(65) and was found positive. 4/14 ICA+ first-degree relatives were GAD(65) positive. Four relatives, positive for two antibodies, subsequently developed type 1 diabetes. Life-Table analysis of first-degree relatives with autoantibodies indicated an 80% disease-free survival at 3.5 yr. HLA-DRB1 was found to be associated with the presence of ICA in both probands and relatives, whereas HLA-DPB1 was associated with autoantibody in relatives of type 1 diabetic probands. These results suggest that autoimmunity occurs in type 1 diabetes families of Mexican descent in similar frequencies to that of non-Hispanic, Caucasian families. The presence of autoantibodies appears to be regulated in part by HLA class II genes, even in the absence of overt diabetes.
Assuntos
Autoanticorpos/análise , Diabetes Mellitus Tipo 1/imunologia , Genes MHC da Classe II , Americanos Mexicanos , Adolescente , Adulto , Alelos , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/etnologia , Diabetes Mellitus Tipo 1/genética , Feminino , Glutamato Descarboxilase/análise , Humanos , Insulina/imunologia , Masculino , Pessoa de Meia-IdadeRESUMO
Susceptibility to IDDM has been associated with specific alleles at the HLA class II loci in a variety of human populations. Previous studies among Mexican-Americans, a group ancestrally derived from Native Americans and Hispanic whites, showed that the DR4 haplotypes (DRB1*0405-DQB1*0302 and DRB1*0402-DQB1*0302) and the DR3 haplotype (DRB1*0301-DQB1*0201) were increased among patients and suggested a role for both DR and DQ alleles in susceptibility and resistance. Based on the analysis of 42 Mexican-American IDDM families and ethnically matched control subjects by polymerase chain reaction/sequence-specific oligonucleotide probe typing, we report an association of IDDM with the DPB1 allele, *0301 (relative risk = 6.6; P = 0.0012) in this population. The analysis of linkage disequilibrium patterns in this population indicates that the observed increased frequency in DPB1*0301 among patients cannot be attributed simply to linkage disequilibrium with high-risk DR-DQ haplotypes. These data suggest that in addition to alleles at the DRB1 and DQB1 loci, polymorphism at the DPB1 locus may also influence IDDM risk.
Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Antígenos HLA-DP/genética , Americanos Mexicanos , Linhagem Celular Transformada , Cadeias beta de HLA-DP , Antígeno HLA-DR4/genética , Haplótipos , Humanos , Desequilíbrio de Ligação , Linfócitos/imunologia , Americanos Mexicanos/genética , Linhagem , Reação em Cadeia da Polimerase , Valores de ReferênciaRESUMO
The gene frequencies of nine different genetic polymorphic markers [ABO, MNS and P blood groups; haptoglobin, transferrin, Gc protein, complement (C3), properdin factor B and alpha 1-antitrypsin] were determined in 94 Mexican-Americans residing in the Los Angeles, California area. Comparisons with published data on Mexican-Americans living in other areas of the United States or in Mexico itself revealed no significant differences in the gene frequencies between this and previous studies. However, data from the current study demonstrated significant differences in ABO and haptoglobin allele frequencies compared to published non-Hispanic Caucasian data. These data suggest a large degree of genetic homogeneity in the Mexican-American population residing in the United States. Additional gene marker studies will be important to test this hypothesis and further define the degree of non-Hispanic Caucasian admixture in this population.
Assuntos
Sistema ABO de Grupos Sanguíneos/genética , Frequência do Gene , Haptoglobinas/genética , Americanos Mexicanos/genética , População Branca/genética , Antígenos de Grupos Sanguíneos/genética , Proteínas Sanguíneas/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/etnologia , Marcadores Genéticos , Humanos , Los AngelesRESUMO
Mexican American patients (n = 35) with insulin-dependent diabetes mellitus (IDDM) and control subjects (n = 39) were HLA-DQA and DQB typed by the polymerase chain reaction technique combined with allele-specific oligonucleotide probes. Either DQB1*0302 or DQB1*0201 was present among 91% (32/35) of the patients compared to 67% (26/39) of controls. Either DQA1*0501 or DQA1*0301 was present in all patients (100% or 35/35) compared to 29/39 (74%) (OR 12.06 Pc < 0.05) of controls. All four of these genes, in cis or trans, were present in 15/35 (43%) of the patients compared to 3/39 (8%) of controls (OR 9.0; Pc < 0.01). The presence of one or more non-susceptibility alleles showed a dose-related decrease in relative risk. Presence of aspartic acid (Asp) at position 57 of the DQ beta chain did not confer protection and non-Asp homozygosity did not confer susceptibility to IDDM in this ethnic group. In conclusion, susceptibility to IDDM in Mexican Americans is associated with particular DQA and DQB combinations, illustrates dose-dependent parameters and contradicts the critical residue hypothesis.
Assuntos
Diabetes Mellitus Tipo 1/genética , Genes MHC da Classe II , Antígenos HLA-DQ/genética , Americanos Mexicanos/genética , Adulto , Alelos , Southern Blotting , Criança , Diabetes Mellitus Tipo 1/etnologia , Suscetibilidade a Doenças/imunologia , Frequência do Gene , Predisposição Genética para Doença , Cadeias alfa de HLA-DQ , Cadeias beta de HLA-DQ , Haplótipos/genética , Humanos , Sondas de Oligonucleotídeos , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de RestriçãoRESUMO
To test the hypothesis that insulin-dependent diabetes mellitus in the Mexican-American population is due to Spanish genetic admixture, we obtained ancestral information on 106 Mexican-American families with an insulin-dependent diabetic index case and 80 Mexican-American control families from 1987 to 1991. The Mexican states of origin were available on 395 grandparents of the insulin-dependent diabetic index cases and 291 grandparents of the controls. Analysis of the individual states of origin revealed that there were significantly more Mexican-American grandparents of diabetic index cases from the states of Jalisco and Michoacan when compared to the control families (31% and 16% diabetic versus 22% and 11% controls respectively, P less than 0.01). The states of Zacatecas and Durango had a lower frequency of diabetic grandparents as compared to controls (6% diabetic versus 12% controls, P less than 0.001). Analysis of the origin by Northern and Southern states of México revealed a significant decrease in the number of grandparents of the insulin-dependent diabetic cases from the Northern regions of México, 19.5%, versus 32% in controls, (P less than 0.001). These data indicate that the grandparents of the insulin-dependent diabetic index cases originate from states and regions of México which were those of the early entry of the Europeans. These data thus support the hypothesis that insulin-dependent diabetes mellitus in the Mexican-American population may be due in significant part to an original genetic contribution from the Spanish-European population.
Assuntos
Diabetes Mellitus Tipo 1/etnologia , Americanos Mexicanos , Adolescente , Adulto , Idoso , California/epidemiologia , Criança , Pré-Escolar , Coleta de Dados , Diabetes Mellitus Tipo 1/genética , Feminino , Humanos , Masculino , Americanos Mexicanos/genética , Pessoa de Meia-Idade , Estatística como AssuntoRESUMO
The study of HLA histocompatibility antigens and insulin-dependent diabetes mellitus (IDDM) in non-White populations may provide a unique opportunity to more accurately define the diabetes susceptibility gene(s) located within the HLA region. To determine whether HLA haplotypes differ between ethnic groups, we compared 105 HLA haplotypes from 55 Mexican-American IDDM patients with 272 haplotypes from 136 IDDM patients of non-Hispanic White descent. The accurate determination of genotypes and haplotypes requires the study of family units. Therefore, all diabetic patients in this study were from studies of families having one or more siblings with IDDM. In the Mexican-American group, HLA-DR3 and -DR4 were the most common HLA-DR alleles and were present in comparable frequencies in the non-Hispanic White group (HLA-DR3, 27% of Mexican-American and 29% of non-Hispanic White haplotypes; DR4, 46% of Mexican-American and 43% of non-Hispanic White haplotypes). However, the HLA-B/DR-containing haplotypes and haplotype frequencies differed between the two groups. Several common haplotypes (B8/DR3, B15/DR4) in the non-Hispanic White group occurred less frequently in the Mexican-American group. In contrast, uncommon haplotypes in the non-Hispanic White group comprised nearly 50% of the DR4-containing haplotypes (B35/DR4, B40/DR4, B44/DR4) in the Mexican-American group. Although both DR3- and DR4-haplotype frequencies differed significantly between the two groups, the relative frequency of DR3- but not DR4-containing haplotypes was similar in both ethnic groups. This adds to the evidence suggesting that different susceptibilities are provided by the haplotypes carrying the DR3 and DR4 alleles.
Assuntos
Diabetes Mellitus Tipo 1/imunologia , Antígenos HLA-DR/genética , Haplótipos , Hispânico ou Latino/genética , Alelos , Diabetes Mellitus Tipo 1/genética , Humanos , Valores de Referência , Estados Unidos , População BrancaRESUMO
Because Alaskan Eskimos have the greatest known endemic risk of Haemophilus influenzae type b (Hib) disease and represent a comparatively homogeneous population, we selected this population to evaluate the presence or absence of an association of 35 genetic markers (alleles or allotypes) at 12 chromosomal loci with susceptibility to both invasive Hib disease risk and level of Hib anticapsular antibody. We studied nearly all Alaskan Eskimo children who had had invasive Hib disease between 1971 and 1982 in southwestern Alaska (n = 103) and an equivalent number of controls matched for age, race, and village of residence, and verified not to have had proved or suspected Hib disease. We found no significant associations with Hib disease for the single alleles of HLA-A, -B, -C, -DR, Gm, Km, Am, Kidd, MNSs, ABO, esterase D, or glutamate pyruvate transaminase loci. However, we observed a significant interaction of two loci, Gm(a;..;g,s,t) allotype and HLA-DR8 (P = 0.002), with increased Hib disease susceptibility, and an interaction of the same Gm allotype and HLA-DR5 with decreased disease susceptibility (P = 0.01). We also compared the level of anticapsular antibody to Hib with each genetic marker and two-locus interactions, but no genetic association with antibody level was found. We conclude that some genetic factors contribute to the susceptibility to invasive Hib disease in this population.
Assuntos
Infecções por Haemophilus/genética , Alaska , Anticorpos/análise , Pré-Escolar , Suscetibilidade a Doenças , Feminino , Antígenos HLA/genética , Haemophilus influenzae , Humanos , Lactente , Inuíte , Masculino , RiscoRESUMO
Standard growth curves for achondroplasia, the most common form of short-limbed dwarfism, have been constructed based on measurements of height, growth velocity, upper and lower segment, and head circumference in 400 achondroplastic dwarfs. These standard curves provide the basis to assess normal growth in these individuals, to aid in the determination of superimposed disorders, and to assess any growth accelerating therapy.