Analysis of type 2 diabetes and obesity genetic variants in Mexican Pima Indians: Marked allelic differentiation among Amerindians at HLA.

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.

Environmentally Driven Increases in Type 2 Diabetes and Obesity in Pima Indians and Non-Pimas in Mexico Over a 15-Year Period: The Maycoba Project.

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.

High-Risk Populations: The Pimas of Arizona and Mexico.

The purpose of this review is first, to broadly summarize the long-term commitment that began in 1965 to studying type 2 diabetes and obesity through the cooperation of the Pima Indians of Arizona, and second, to discuss the investigations with the Pima Indians of Mexico that started in 1991. The later studies emphasize gene-environment interactions in the pathogenesis of these metabolic disorders. Through the participation of both groups of Pimas, the researchers made key findings with regard to the epidemiology, physiology, clinical assessment and genetics of type 2 diabetes and obesity.

Study design of the Maycoba Project: obesity and diabetes in Mexican Pimas.

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.

Fifteen years of change in the food environment in a rural Mexican community: the Maycoba project.

INTRODUCTION: Indigenous populations worldwide who are shifting to a westernized lifestyle experience high rates of type 2 diabetes and obesity. These conditions are commonly the result of genetic predisposition and environmental factors that promote excess energy intake and decreased energy expenditure. The purpose of this study was to examine changes in the food environment, specifically looking at retail and subsistence-food availability, and food-acquisition behaviors in the rural Mexican town of Maycoba and surrounding communities between 1995 and 2010. The population in this area includes indigenous Pima, genetically-related to the Pima Indians in Arizona who have the highest documented rates of diabetes, and non-Pima Mexican (ie non indigenous and other indigenous). An initial study in 1995 compared the prevalence of diabetes and obesity in the Maycoba population with that of Pima Indians of Arizona and found a dramatically lower type 2 diabetes prevalence in the Maycoba region due to the protective effect of a traditional lifestyle despite a genetic predisposition to diabetes. METHODS: The 2010 follow-up study was undertaken to determine the prevalence of obesity and type 2 diabetes as well as to examine lifestyle changes over the 15 year time span, following changes to housing and the local environment. This study focused on the food environment, examining changes in food acquisition behaviors in the retail and subsistence aspects. The study included a household survey (n=71), two focus group discussions, and participant-observation. To determine changes in retail food availability, seven stores throughout the study region were audited. RESULTS: The main findings were an increasing presence and use of retail stores for food: an expansion in the selection of processed foods, their prominent placement, and refrigeration allowing more perishable foods to be available to the local population. Subsistence activities remained significant, although some aspects of specific subsistence activities are in decline, such as the area allocated to home gardens and a reduction in the variety of crops cultivated in them. CONCLUSION: Although there have been a number of changes in the food environment during the 15 year period, a traditional subsistence-based lifestyle prevails.

Land-use and land-cover assessment for the study of lifestyle change in a rural Mexican community: the Maycoba project.

BACKGROUND: In 1995, a study was conducted to identify the effects of traditional and westernized environments on the prevalence of type 2 diabetes in Pima Indians (Pimas) in Mexico and the United States. The study concluded that the more traditional lifestyle in Mexico had a protective effect against this metabolic disorder. In the ensuing 15 years, the environmental circumstances of the Mexican Pimas changed, and a follow-up study was conducted to determine the role environmental change plays in the development of diabetes in this genetically susceptible population. A major element of environmental transition relates to land-use and land-cover (LULC) changes that could affect physical activity and promote an obesogenic environment. This study examined changes in the region's LULC to determine whether there have been transitions in agricultural land use and urbanization that would be consistent with a more sedentary lifestyle. Changes were assessed from 1994 aerial photographs and 2007 satellite images. RESULTS: The land-cover analysis showed that mixed vegetation and dense trees cover most of the study area. It suggested a rural environment that includes a low percentage of impermeable areas, and it indicated that the area experiencing human intervention covers 7% of the total area. The land-use-change findings showed a decrease or no change in agricultural or ranching areas and a decrease in farmland due to reforestation or revegetation. Three variables from the land-use-change analysis were examined as proxies for lifestyle change: urban development, dwelling-unit density, and variation in the road network. Two of the measures -the amount of urbanization and the number and density of dwelling units-showed increases, most notably in the town of Maycoba. There were only minor changes in the road network: most of the road segments are short and concentrated in Maycoba where most of the buildings, points of interest (e.g., church, stores), and cars are located. CONCLUSIONS: The LULC in Maycoba and surrounding settlements had changed during the study period. LULC change was used as a proxy to examine lifestyle changes that can affect levels of physical activity.

An Exploration of Gardens in Maycoba, Mexico: Change in the Environment of a Population Genetically Prone to Diabetes.

Gardens are an important part of the environment as they play multiple roles and are central to the lifestyle and economy of many communities. The investigators use qualitative methods to explore patterns and perceptions about changes in gardening and cultivation in the community of Maycoba, Mexico. Maycoba is home to a large community of Pima Indians, an Indigenous population genetically prone to diabetes. Pima Indians living in the United States have been shown to have an extremely high prevalence of diabetes, but the genetically comparable Pimas in Maycoba, Mexico, were found to have little diabetes in the early 1990s. The authors examine home gardens and other cultivation in the area as an element of a changing environment and lifestyle during the past 15 years. Methods include interviews and focus groups. Preliminary findings are presented in this paper.

Ethnic Pride and Cardiovascular Health Among Mexican American Adults Along the U.S.-Mexico Border.

This study addressed the association between items from the General Acculturation Index (GAI) and cardiovascular health. Specifically, we assessed whether ethnic pride was associated with health outcomes after controlling for items regarding language, place where the childhood was spent and ethnic interaction. The study was a cross sectional analysis of demographic and clinical data from a border population of Mexican American adults (n=316) at risk for cardiovascular disease (CVD). Outcomes included smoking and diabetes status, Framingham risk, and metabolic syndrome. Ethnic pride was associated with lower diabetes prevalence, lower Framingham risk, and fewer risk factors for metabolic syndrome, but was not associated with smoking status. Ethnic pride was not associated with the other acculturation items of the GAI. Among an at-risk border population, ethnic pride functioned independently of other acculturation indicators. Ethnic pride may act as a protective factor for diabetes, metabolic syndrome and CVD risk status.

Differences in insulin resistance in Mexican and U.S. Pima Indians with normal glucose tolerance.

CONTEXT: Insulin resistance is a major risk factor for the development of type 2 diabetes in Pima Indians, a population with the highest prevalence of type 2 diabetes mellitus in the world. Their Mexican counterpart, living a traditional lifestyle in the mountains of Sonora, have at least 5 times less diabetes than the U.S. Pima Indians. OBJECTIVE: We evaluated whether Mexican Pima Indians had lower insulin resistance than U.S. Pima Indians. DESIGN AND PATIENTS: We compared fasting insulin and homeostasis model assessment for insulin resistance (HOMA-IR) in 194 Mexican Pima Indians (100 females, 94 males) and 449 U.S. Pima Indians (246 females, 203 males) with normal glucose tolerance from a cross-sectional study. Adjusted differences of log-transformed outcomes (fasting insulin and HOMA-IR) between groups were evaluated using multiple linear regression models and paired t test in a matched subset. RESULTS: Unadjusted fasting insulin and HOMA-IR were much lower in the Mexican Pima Indians than in their U.S. counterparts. After adjusting by obesity, age, and sex, mean (95% confidence interval) for fasting insulin was 6.22 (5.34-7.24) vs. 13.56 µU/ml (12.27-14.97) and for HOMA-IR 1.40 (1.20-1.64) vs. 3.07 (2.77-3.40), respectively, for Mexican Pima and U.S. Pima Indians. Results were confirmed in subset matched for age, sex, and body fat. CONCLUSION: Our results indicate that Mexican Pima Indians have lower insulin resistance in comparison with their genetically related U.S. counterparts, even after controlling for differences in obesity, age, and sex. This finding underscores the importance of lifestyle factors as protecting factors against insulin resistance in individuals with a high propensity to develop diabetes.

A promotores de salud intervention to reduce cardiovascular disease risk in a high-risk Hispanic border population, 2005-2008.

INTRODUCTION: The high prevalence of cardiovascular disease (CVD) in the Hispanic population of the United States, together with low rates of health insurance coverage, suggest a potential cardiovascular health crisis. The objective of Project HEART (Health Education Awareness Research Team) was to promote behavior changes to decrease CVD risk factors in a high-risk Hispanic border population. METHODS: Project HEART took place from 2005 through 2008 as a randomized community trial with a community-based participatory research framework using promotores de salud (community health workers). A total of 328 participants with at least 1 CVD risk factor were selected by randomizing 10 US Census tracts in El Paso, Texas, to either the experimental or the control group. The experimental group (n = 192) was assigned to a series of 8 health classes using the Su Corazón, Su Vida curriculum. After 2 months of educational sessions, the group was followed for 2 months. The control group (n = 136) was given basic educational materials at baseline, and no other intervention was used. Main outcomes of interest included changes in health behaviors and clinical measures. RESULTS: Participants in the experimental group showed more awareness of CVD risk factors, more confidence in the control of these factors, and improved dietary habits (ie, lower salt and cholesterol intake, better weight-control practices) compared with the control group. Total cholesterol was 3% lower in the experimental than in the control participants, and nonhigh-density lipoprotein cholesterol and low-density lipoprotein cholesterol were both 5% lower. CONCLUSION: The HEART trial suggests that community health education using promotores de salud is a viable strategy for CVD risk reduction in a Hispanic border community.

Effects of traditional and western environments on prevalence of type 2 diabetes in Pima Indians in Mexico and the U.S.

OBJECTIVE: Type 2 diabetes and obesity have genetic and environmental determinants. We studied the effects of different environments on these diseases in Pima Indians in Mexico and the U.S. RESEARCH DESIGN AND METHODS: Adult Pima-Indian and non-Pima populations in the Sierra Madre mountains of Mexico were examined using oral glucose tolerance tests and assessments for obesity, physical activity, and other risk factors. Results were compared with those from Pima Indians in Arizona. Both Pima populations were typed for DNA polymorphisms to establish their genetic similarity. RESULTS: The age- and sex-adjusted prevalence of type 2 diabetes in the Mexican Pima Indians (6.9%) was less than one-fifth that in the U.S. Pima Indians (38%) and similar to that of non-Pima Mexicans (2.6%). The prevalence of obesity was similar in the Mexican Pima Indians (7% in men and 20% in women) and non-Pima Mexicans (9% in men and 27% in women) but was much lower than in the U.S. Pima Indians. Levels of physical activity were much higher in both Mexican groups than in the U.S. Pima Indians. The two Pima groups share considerable genetic similarity relative to other Native Americans. CONCLUSIONS: The much lower prevalence of type 2 diabetes and obesity in the Pima Indians in Mexico than in the U.S. indicates that even in populations genetically prone to these conditions, their development is determined mostly by environmental circumstances, thereby suggesting that type 2 diabetes is largely preventable. This study provides compelling evidence that changes in lifestyle associated with Westernization play a major role in the global epidemic of type 2 diabetes.

Developing a SNP panel for forensic identification of individuals.

Single nucleotide polymorphisms (SNPs) are likely in the near future to have a fundamental role in forensics in both human identification and description. However, considerable research is necessary to establish adequate scientific foundations for these applications. In the case of identification, because allele frequencies can vary greatly among populations, the population genetics of match probabilities is a critical issue. Some SNPs, however, show little allele frequency variation among populations while remaining highly informative. We describe here both an efficient strategy for identifying and characterizing such SNPs, and test that strategy on a broad representation of world populations. Markers with high heterozygosity and little frequency variation among African American, European American, and East Asian populations are selected for additional screening on seven populations that provide a sampling of genetic variation from the world's major geographical regions. Those with little allele frequency variation on the seven populations are then screened on a total of 40 populations ( approximately 2100 individuals) and the most promising retained. The preliminary panel of 19 SNPs, from an initial selection of 195 SNPs, gives an average match probability of <10(-7) in most of 40 populations studied and no greater than 10(-6) in the most isolated, inbred populations. Expansion of this panel to approximately 50 comparable SNPs should give match probabilities of about 10(-15) with a small global range.

Considerable haplotype diversity within the 23kb encompassing the ADH7 gene.

BACKGROUND: Of the seven known human alcohol dehydrogenase (ADH) genes, the non-liver expressed ADH7 gene codes for the enzyme with the highest maximal activity for ethanol. Previous study from our laboratory has suggested that ADH7 has an epistatic role for protection against alcoholism based on a single ADH7 SNP. METHODS: We have now studied seven SNPs, additional populations for the SNP previously examined, and six more new SNPs, across 23 kb of ADH7 in 38 population samples originating from different geographical regions of the world. RESULTS: The overall linkage disequilibrium is moderate to strong across this region even though considerable 7-SNP haplotype diversity is observed. This uncommonly high haplotype diversity is explained by high LD within each "half," the three upstream SNPs and the four downstream SNPs, but near randomization between the "halves." This division significantly simplified the haplotype pattern: only four major haplotypes account for almost all chromosomes in all populations in each "half." CONCLUSIONS: The low linkage disequilibrium between these two "halves" suggests multiple recombination(s) have occurred in this region, specifically, within intron 7. The absence of strong LD between the functional variation in ADH1B that is strongly associated with alcoholism and any of the variation in ADH7 supports the genetic independence of ADH7 in association studies. Thus, the previously observed epistatic effect of ADH7 cannot be explained by its linkage disequilibrium with a causative factor in ADH1B.

Impact of lifestyle on prevalence of kidney disease in Pima Indians in Mexico and the United States.

Pima Indians in the United States and Mexico share a common genetic background but have very different lifestyles. Comparisons were made of the frequency of obesity, diabetes, hypertension, and kidney disease in these geographically separated but susceptible populations. Mexican Pimas had higher levels of physical activity, less obesity, and a lower prevalence of diabetes than their US Pima counterparts. Mean blood pressure rose with worsening glucose tolerance, and the prevalence of elevated urinary albumin excretion was higher in patients with diabetes than in those without, regardless of whether they lived in the United States or Mexico. These findings illustrate the importance of lifestyle in the development of diabetes and in the subsequent occurrence of diabetic kidney disease.

Population variation in linkage disequilibrium across the COMT gene considering promoter region and coding region variation.

Catechol-O-methyl transferase (COMT) catalyzes the first step in one of the major pathways in the degradation of catecholamines. The COMT gene on chromosome 22 has been considered a candidate gene for many neuropsychiatric disorders, in part because an exon 4 single nucleotide polymorphism (SNP) in COMT causes an amino acid substitution associated with significantly altered enzyme activity. This functional variant, detected as an NlaIII restriction site polymorphism (RSP), is polymorphic in populations from around the world. A four-site haplotype spanning 28 kb effectively encompasses COMT. This haplotype is comprised of two novel polymorphisms [a tetranucleotide short tandem repeat polymorphism (STRP) in intron 1 and a HindIII RSP at the 5' end of COMT], the NlaIII site, and another previously published site - a BglI RSP at the 3' end of the gene. Overall linkage disequilibrium (LD) for this haplotype is strong and significant in 32 population samples from around the world. Conditional probabilities indicate that, in spite of moderate to strong disequilibrium in most non-African populations, the NlaIII site, although often used for prediction, would not always be a reliable predictor of allelic variation at the other sites. Because other functional variation might exist, especially regulatory variation, these findings indicate that haplotypes would be more effective indicators of possible involvement of COMT in disease etiology.

A global perspective on genetic variation at the ADH genes reveals unusual patterns of linkage disequilibrium and diversity.

Variants of different Class I alcohol dehydrogenase (ADH) genes have been shown to be associated with an effect that is protective against alcoholism. Previous work from our laboratory has shown that the two sites showing the association are in linkage disequilibrium and has identified the ADH1B Arg47His site as causative, with the ADH1C Ile349Val site showing association only because of the disequilibrium. Here, we describe an initial study of the nature of linkage disequilibrium and genetic variation, in population samples from different regions of the world, in a larger segment of the ADH cluster (including the three Class I ADH genes and ADH7). Linkage disequilibrium across approximately 40 kb of the Class I ADH cluster is moderate to strong in all population samples that we studied. We observed nominally significant pairwise linkage disequilibrium, in some populations, between the ADH7 site and some Class I ADH sites, at moderate values and at a molecular distance as great as 100 kb. Our data indicate (1) that most ADH-alcoholism association studies have failed to consider many sites in the ADH cluster that may harbor etiologically significant alleles and (2) that the relevance of the various ADH sites will be population dependent. Some individual sites in the Class I ADH cluster show Fst values that are among the highest seen among several dozen unlinked sites that were studied in the same subset of populations. The high Fst values can be attributed to the discrepant frequencies of specific alleles in eastern Asia relative to those in other regions of the world. These alleles are part of a single haplotype that exists at high (>65%) frequency only in the eastern-Asian samples. It seems unlikely that this haplotype, which is rare or unobserved in other populations, reached such high frequency because of random genetic drift alone.