RESUMO
Prevalence of diabetes and obesity in Mexican Pima Indians is low, while prevalence in US Pima Indians is high. Although lifestyle likely accounts for much of the difference, the role of genetic factors is not well explored. To examine this, we genotyped 359 single nucleotide polymorphisms, including established type 2 diabetes and obesity variants from genome-wide association studies (GWAS) and 96 random markers, in 342 Mexican Pimas. A multimarker risk score of obesity variants was associated with body mass index (BMI; ß = 0.81 kg/m2 per SD, P = 0.0066). The mean value of the score was lower in Mexican Pimas than in US Pimas (P = 4.3 × 10-11 ), and differences in allele frequencies at established loci could account for approximately 7% of the population difference in BMI; however, the difference in risk scores was consistent with evolutionary neutrality given genetic distance. To identify loci potentially under recent natural selection, allele frequencies at 283 variants were compared between US and Mexican Pimas, accounting for genetic distance. The largest differences were seen at HLA markers (e.g., rs9271720, difference = 0.75, P = 8.7 × 10-9 ); genetic distances at HLA were greater than at random markers (P = 1.6 × 10-46 ). Analyses of GWAS data in 937 US Pimas also showed sharing of alleles identical by descent at HLA that exceeds its genomic expectation (P = 7.0 × 10-10 ). These results suggest that, in addition to the widely recognized balancing selection at HLA, recent directional selection may also occur, resulting in marked allelic differentiation between closely related populations.
Assuntos
Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/genética , Antígenos HLA/genética , Indígenas Norte-Americanos/genética , Obesidade/etnologia , Obesidade/genética , Alelos , Índice de Massa Corporal , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , México , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with â¼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between IGF2 exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage-dependent reduction in the expression of IGF2 isoform 2. In individuals who do not carry the protective allele, expression of IGF2 isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in IGF2 isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing IGF2 isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.
Assuntos
Diabetes Mellitus Tipo 2/genética , Fator de Crescimento Insulin-Like II/metabolismo , Sítios de Splice de RNA/genética , Tecido Adiposo , Linhagem Celular , Regulação da Expressão Gênica/fisiologia , Variação Genética , Genótipo , Humanos , Fator de Crescimento Insulin-Like II/genética , Fígado , Americanos Mexicanos/genética , México , Isoformas de Proteínas , Células-Tronco , População BrancaRESUMO
We previously identified a locus linked to total cholesterol (TC) concentration in Pima Indians on chromosome 19p. To characterize this locus, we genotyped >2000 SNPs in 1838 Pimas and assessed association with log(TC). We observed evidence for association with log(TC) with rs2278426 (3.5% decrease/copy of the T allele; P=5.045×10(-6)) in the ANGPTL8 (angiopoietin-like 8) gene. We replicated this association in 2413 participants of the San Antonio Mexican American Family Study (SAMAFS: 2.0% decrease per copy of the T allele; P=0.005842). In a meta-analysis of the combined data, we found the strongest estimated effect with rs2278426 (P=2.563×10(-7)). The variant T allele at rs2278426 predicts an Arg59Trp substitution and has previously been associated with LDL-C and HDL-C. In Pimas and SAMAFS participants, the T allele of rs2278426 was associated with reduced HDL-C levels (P=0.000741 and 0.00002, respectively), and the combined estimated effect for the two cohorts was -3.8% (P=8.526×10(-8)). ANGPTL8 transcript and protein levels increased in response to both glucose and insulin. The variant allele was associated with increased levels of cleaved ANGPTL3. We conclude that individuals with the variant allele may have lower TC and HDL-C levels due to increased activation of ANGPTL3 by ANGPTL8.
Assuntos
Proteínas Semelhantes a Angiopoietina/genética , Proteínas Semelhantes a Angiopoietina/metabolismo , HDL-Colesterol/genética , Indígenas Norte-Americanos/genética , Americanos Mexicanos/genética , Hormônios Peptídicos/genética , Adulto , Alelos , Substituição de Aminoácidos , Proteína 3 Semelhante a Angiopoietina , Proteína 8 Semelhante a Angiopoietina , Arginina/genética , Glicemia/metabolismo , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , LDL-Colesterol/sangue , LDL-Colesterol/genética , LDL-Colesterol/metabolismo , Cromossomos Humanos Par 19/genética , Estudos de Coortes , Doença das Coronárias/sangue , Doença das Coronárias/genética , Diabetes Mellitus/genética , Feminino , Estudo de Associação Genômica Ampla , Células Hep G2 , Humanos , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Hormônios Peptídicos/metabolismo , Polimorfismo de Nucleotídeo Único , Triptofano/genéticaRESUMO
OBJECTIVE: The global epidemics of type 2 diabetes and obesity have been attributed to the interaction between lifestyle changes and genetic predisposition to these diseases. We compared the prevalences of type 2 diabetes and obesity in Mexican Pima Indians, presumed to have a high genetic predisposition to these diseases, to those in their non-Pima neighbors, both of whom over a 15-year period experienced a transition from a traditional to a more modern lifestyle. RESEARCH DESIGN AND METHODS: Prevalence of diabetes, impaired fasting glucose, impaired glucose tolerance, and obesity in Mexican Pimas (n = 359) and non-Pima Mexicans (n = 251) were determined in 2010 using methods identical to those used in 1995. RESULTS: During this 15-year period, age-adjusted diabetes prevalence was unchanged in Pima men (5.8% in 1995 vs. 6.1% in 2010) yet increased in non-Pima men from 0.0 to 8.6% (P < 0.05). Diabetes prevalence tended to increase in both Pima women (9.4 vs. 13.4%) and non-Pima women (4.8 vs. 9.5%). Age-adjusted prevalence of obesity increased significantly in all groups (6.6 vs. 15.7% in Pima men; 8.5 vs. 20.5% in non-Pima men; 18.9. vs 36.3% in Pima women; 29.5 vs. 42.9% in non-Pima women). CONCLUSIONS: Type 2 diabetes prevalence increased between 1995 and 2010 in non-Pima men, and to a lesser degree in women of both groups, but it did not increase in Pima men. Prevalence of obesity increased among Pimas and non-Pimas of both sexes. These changes occurred concomitantly with an environmental transition from a traditional to a more modernized lifestyle.
Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Indígenas Norte-Americanos/estatística & dados numéricos , Acontecimentos que Mudam a Vida , Obesidade/epidemiologia , Adulto , Estudos Transversais , Meio Ambiente , Feminino , Humanos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Prevalência , Adulto JovemRESUMO
OBJECTIVE: To focus on the rationale and methods of the Maycoba Project. METHODS: Study population included Mexican Pima Indians (MPI) and Blancos aged ≥20-years, living in the village of Maycoba and surrounding area. Surveys in 1995 and 2010 included a medical history, biochemical and anthropomet- ric measurements. Additionally, socio- economic, physical activity, and dietary interviews were conducted. The 2010 study incorporated investigations on type 2 diabetes (T2D) and obesity-associated genetic alleles and human-envi- ronment changes. RESULTS: The study results are limited to demographic data and description of the eligible and ex- amined sample. CONCLUSIONS: This study may yield important information on T2D and obesity etiology in a traditional population exposed to environmental changes.
Assuntos
Diabetes Mellitus Tipo 2/etnologia , Indígenas Norte-Americanos , Obesidade/etnologia , Projetos de Pesquisa , Adulto , Antropometria , Metabolismo Basal , Censos , Diabetes Mellitus Tipo 2/etiologia , Dieta , Metabolismo Energético , Exercício Físico , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Anamnese , México/epidemiologia , Pessoa de Meia-Idade , Obesidade/genética , Pesquisa Qualitativa , Adulto JovemRESUMO
For admixture mapping studies in Mexican Americans (MAM), we define a genomewide single-nucleotide-polymorphism (SNP) panel that can distinguish between chromosomal segments of Amerindian (AMI) or European (EUR) ancestry. These studies used genotypes for >400,000 SNPs, defined in EUR and both Pima and Mayan AMI, to define a set of ancestry-informative markers (AIMs). The use of two AMI populations was necessary to remove a subset of SNPs that distinguished genotypes of only one AMI subgroup from EUR genotypes. The AIMs set contained 8,144 SNPs separated by a minimum of 50 kb with only three intermarker intervals >1 Mb and had EUR/AMI FST values >0.30 (mean FST = 0.48) and Mayan/Pima FST values <0.05 (mean FST < 0.01). Analysis of a subset of these SNP AIMs suggested that this panel may also distinguish ancestry between EUR and other disparate AMI groups, including Quechuan from South America. We show, using realistic simulation parameters that are based on our analyses of MAM genotyping results, that this panel of SNP AIMs provides good power for detecting disease-associated chromosomal segments for genes with modest ethnicity risk ratios. A reduced set of 5,287 SNP AIMs captured almost the same admixture mapping information, but smaller SNP sets showed substantial drop-off in admixture mapping information and power. The results will enable studies of type 2 diabetes, rheumatoid arthritis, and other diseases among which epidemiological studies suggest differences in the distribution of ancestry-associated susceptibility.
Assuntos
Mapeamento Cromossômico , Genoma Humano , Americanos Mexicanos/genética , Polimorfismo de Nucleotídeo Único , Algoritmos , Cromossomos Humanos , Marcadores Genéticos , Predisposição Genética para Doença , Testes Genéticos , Genética Populacional , Genótipo , Humanos , Indígenas Norte-Americanos/genética , Indígenas Sul-Americanos/genética , Cadeias de Markov , Método de Monte Carlo , População BrancaRESUMO
Markers with large differences in allele frequencies between ethnicities provide ancestry information that can be applied to genetic studies. We identified over 100 biallelic ancestry informative markers (AIMs) with large allele frequency differences between European Americans (EA) and Pima Amerindians from laboratory and database screens. For 35 of these markers, Mayan, Yavapai and Quechuan Amerindians were genotyped and compared with EA and Pima allele frequencies. Markers with large allele frequency differences between EA and one Amerindian tribe showed only small differences between the Amerindian tribes. Examination of structure in individuals demonstrated a clear separation of subjects of European from those of Amerindian ancestry, and similarity between individuals from disparate Amerindian populations. The AIMs demonstrated the variation in ancestral composition of individual Mexican Americans, providing evidence of applicability in admixture mapping and in controlling for structure in association tests. In addition, a high percentage of single-nucleotide polymorphisms (SNPs) selected on the basis of large frequency differences between EA and Asian populations had large allele frequency differences between EA and Amerindians, suggesting an efficient method for greatly expanding AIMs for use in admixture mapping/structure analysis in Mexican Americans. Together, these data provide additional support for the practical application of admixture mapping in the Mexican American population.