Gm3;5,13,14 and type 2 diabetes mellitus: an association in American Indians with genetic admixture.

In a sample of 4,920 Native Americans of the Pima and Papago tribes, there is a very strong negative association between the Gm haplotype Gm3;5,13,14 and type 2--or non-insulin-dependent--diabetes mellitus (prevalence ratio = 0.27, 95% confidence interval 0.18-0.40). One might conclude from this observation that the absence of this haplotype--or the presence of a closely linked gene--is a causal risk factor for the disease. It is shown that Gm3;5,13,14 is a marker for Caucasian admixture, and it is most likely the presence of Caucasian alleles and the concomitant decrease of Indian alleles that lowers the risk for diabetes, rather than the direct action of the haplotype or of a closely linked locus. This study demonstrates both the potential confounding effect of admixture on the interpretation of disease association studies and the importance of considering genetic admixture (or excluding individuals with genetic admixture) in studies of genetic markers of disease. The relationship between this admixture marker and the prevalence of diabetes also suggests a strong genetic component in the susceptibility to type 2 diabetes in Pima and Papago Indians.     

Mexican American ancestry-informative markers: examination of population structure and marker characteristics in European Americans, Mexican Americans, Amerindians and Asians

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.Electronic Supplementary Material Supplementary material is available in the online version of this article at     

A genomewide single-nucleotide-polymorphism panel for Mexican American admixture mapping

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.     

African ancestry and its correlation to type 2 diabetes in African Americans: a genetic admixture analysis in three U.S. population cohorts

The risk of type 2 diabetes is approximately 2-fold higher in African Americans than in European Americans even after adjusting for known environmental risk factors, including socioeconomic status (SES), suggesting that genetic factors may explain some of this population difference in disease risk. However, relatively few genetic studies have examined this hypothesis in a large sample of African Americans with and without diabetes. Therefore, we performed an admixture analysis using 2,189 ancestry-informative markers in 7,021 African Americans (2,373 with type 2 diabetes and 4,648 without) from the Atherosclerosis Risk in Communities Study, the Jackson Heart Study, and the Multiethnic Cohort to 1) determine the association of type 2 diabetes and its related quantitative traits with African ancestry controlling for measures of SES and 2) identify genetic loci for type 2 diabetes through a genome-wide admixture mapping scan. The median percentage of African ancestry of diabetic participants was slightly greater than that of non-diabetic participants (study-adjusted difference = 1.6%, P<0.001). The odds ratio for diabetes comparing participants in the highest vs. lowest tertile of African ancestry was 1.33 (95% confidence interval 1.13-1.55), after adjustment for age, sex, study, body mass index (BMI), and SES. Admixture scans identified two potential loci for diabetes at 12p13.31 (LOD = 4.0) and 13q14.3 (Z score = 4.5, P = 6.6 × 10(-6)). In conclusion, genetic ancestry has a significant association with type 2 diabetes above and beyond its association with non-genetic risk factors for type 2 diabetes in African Americans, but no single gene with a major effect is sufficient to explain a large portion of the observed population difference in risk of diabetes. There undoubtedly is a complex interplay among specific genetic loci and non-genetic factors, which may both be associated with overall admixture, leading to the observed ethnic differences in diabetes risk.     

Analysis of PBX1 as a candidate gene for type 2 diabetes mellitus in Pima Indians

The human proto-oncogene PBX1 codes for a homeodomain containing protein that modulates expression of several genes, including those contributing to regulation of insulin action and glucose metabolism. PBX1 is located on chromosome 1q22, a region linked with type 2 diabetes in Pima Indians, Caucasians, and an Old Order Amish population. We have investigated the PBX1 genomic sequence to identify polymorphisms that may contribute to diabetes susceptibility in the Pimas. PBX1 is composed of nine exons spanning approx. 117 kb and is located within 300 kb of microsatellite D1S1677, which marks the peak of linkage to diabetes susceptibility in the Pima Indians. We detected 16 single nucleotide polymorphisms in PBX1 including one causing a glycine to serine substitution at residue 21. Comparison of the frequencies of the polymorphisms between affected and unaffected Pima Indians did not detect any significant differences, indicating that mutations in PBX1 do not explain the linkage of 1q with type 2 diabetes in this population. The genomic structure of PBX1 provides a basis for similar systematic examinations of this candidate locus in other populations in relation to both type 2 diabetes and other metabolic disorders.     

Familiality of physical and metabolic characteristics that predict the development of non-insulin-dependent diabetes mellitus in Pima Indians.

Susceptibility to non-insulin-dependent diabetes mellitus (NIDDM) is largely genetically determined. In Pima Indians, obesity, insulin resistance, and a low acute insulin response (AIR) to an intravenous glucose infusion are each predictors of the disease. To ascertain whether these phenotypes are genetically determined, we estimated their familiality in nondiabetic Pima Indians with a maximum-likelihood method. Percentage body fat (PFAT) was highly familial (h2 =.76), whereas waist/ thigh circumference ratio (W/T ratio) was not significantly familial after controlling for PFAT (h2 = .16). AIR was also highly familial (h2 = .80 at 10 min), even after controlling for PFAT and insulin action (h2 = .70). Insulin action at physiologic plasma insulin concentrations was familial (h2 = .61) but less so after controlling for PFAT and W/T ratio (h2 = .38). At maximally stimulating insulin concentrations, insulin action was familial (h2 = .45) and was less influenced by controlling for PFAT and W/T ratio (h2 = .49). We conclude that in Pima Indians (1) PFAT and AIR are highly familial traits, (2) central distribution of fat is not a familial trait when controlled for PFAT, (3) 38%-49% of the variance in insulin action, independent of the effect of obesity, is familial, and (4) PFAT, AIR, and insulin action are useful traits to study genetic susceptibility to NIDDM. Because genetic parameter estimates are applicable only to the populations from which they were estimated, it is important to determine whether these estimates of familialities in Pima Indians can be confirmed in other populations before the utility of these traits in searching for NIDDM susceptibility genes in those populations can be fully advocated.     

Genetic admixture, adipocytokines, and adiposity in Black Americans: the Health, Aging, and Body Composition study

Adipocytokines are a subset of cytokines produced by adipose tissue and are associated with risk of type II diabetes and atherosclerosis. Levels of adipocytokines differ between Black and White Americans, even after adjustment for differences in adiposity, diseases associated with adipocytokines including type 2 diabetes and cardiovascular disease, and general socioeconomic status indicators such as income. We used a series of ancestry informative markers to estimate genetic ancestry in a population-based study of older Black Americans, and examined the association between genetic ancestry and adipocytokines and soluble receptors to help determine which of these may be most amenable to admixture mapping. We typed 35 ancestry informative markers in 1,241 self-reported Black Americans with available DNA from the Health, Aging, and Body Composition (Health ABC) study with available DNA and used a maximum likelihood approach to estimate percent European ancestry. We used linear regression models to determine the association between these adipocytokines and percent ancestry, and staged models to examine whether adiposity or other measures affected the associations of genetic ancestry and adipocytokines. Mean European ancestry was 22.3 ± 15.9%. In multivariate adjusted models, the strongest associations observed were between higher European ancestry and interleukin-6 soluble receptor (IL-6 SR), C-reactive protein (CRP), and adiponectin levels, with interleukin-2 soluble receptor (IL-2 SR) and soluble tumor necrosis factor receptor II (TNF-α SR II) also showing more modest but significant associations. The association with adiponectin became stronger after adjustment for adiposity. These novel findings suggest that admixture mapping may identify genetic factors influencing the levels of IL-6 SR, CRP, IL-2 SR, and adiponectin. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Admixture Mapping of Quantitative Trait Loci for BMI in African Americans: Evidence for Loci on Chromosomes 3q, 5q,and 15q

Obesity is a heritable trait and a major risk factor for highly prevalent common diseases such as hypertension and type 2 diabetes. Previously we showed that BMI was positively correlated with African ancestry among the African Americans (AAs) in the US National Heart, Lung, and Blood Institute's Family Blood Pressure Program (FBPP). In a set of 1,344 unrelated AAs, using Individual Ancestry (IA) estimates at 284 marker locations across the genome, we now present a quantitative admixture mapping analysis of BMI. We used a set of unrelated individuals from Nigeria to represent the African ancestral population and the European American (EA) in the FBPP as the European ancestral population. The analysis was based on a common set of 284 microsatellite markers genotyped in all three groups. We considered the quantitative trait, BMI, as the response variable in a regression analysis with the marker location specific excess European ancestry as the explanatory variable. After suitably adjusting for different covariates such as sex, age, and network, we found strong evidence for a positive association with European ancestry at chromosome locations 3q29 and 5q14 and a negative association on chromosome 15q26. To our knowledge, this is the largest quantitative admixture mapping effort in terms of sample size and marker locus involvement for the trait. These results suggest that these regions may harbor genes influencing BMI in the AA population.     

Admixture in Mexico City: implications for admixture mapping of Type 2 diabetes genetic risk factors

Admixture mapping is a recently developed method for identifying genetic risk factors involved in complex traits or diseases showing prevalence differences between major continental groups. Type 2 diabetes (T2D) is at least twice as prevalent in Native American populations as in populations of European ancestry, so admixture mapping is well suited to study the genetic basis of this complex disease. We have characterized the admixture proportions in a sample of 286 unrelated T2D patients and 275 controls from Mexico City and we discuss the implications of the results for admixture mapping studies. Admixture proportions were estimated using 69 autosomal ancestry-informative markers (AIMs). Maternal and paternal contributions were estimated from geographically informative mtDNA and Y-specific polymorphisms. The average proportions of Native American, European and, West African admixture were estimated as 65, 30, and 5%, respectively. The contributions of Native American ancestors to maternal and paternal lineages were estimated as 90 and 40%, respectively. In a logistic model with higher educational status as dependent variable, the odds ratio for higher educational status associated with an increase from 0 to 1 in European admixture proportions was 9.4 (95%, credible interval 3.8–22.6). This association of socioeconomic status with individual admixture proportion shows that genetic stratification in this population is paralleled, and possibly maintained, by socioeconomic stratification. The effective number of generations back to unadmixed ancestors was 6.7 (95% CI 5.7–8.0), from which we can estimate that genome-wide admixture mapping will require typing about 1,400 evenly distributed AIMs to localize genes underlying disease risk between populations of European and Native American ancestry. Sample sizes of about 2,000 cases will be required to detect any locus that contributes an ancestry risk ratio of at least 1.5.     

Identification of genetic variation that determines human trehalase activity and its association with type 2 diabetes

A prior linkage scan in Pima Indians identified a putative locus for type two diabetes (T2D) and body mass index (BMI) on chromosome 11q23-25. Association mapping across this region identified single nucleotide polymorphisms (SNPs) in the trehalase gene (TREH) that were associated with T2D. To assess the putative connection between trehalase activity and T2D, we performed a linkage study for trehalase activity in 570 Pima Indians who had measures of trehalase activity. Strong evidence of linkage of plasma trehalase activity (LOD = 7.0) was observed in the TREH locus. Four tag SNPs in TREH were genotyped in these subjects and plasma trehalase activity was highly associated with three SNPs: rs2276064, rs117619140 and rs558907 (p = 2.2 × 10^?11–1.4 × 10^?23), and the fourth SNP, rs10790256, was associated conditionally on these three (p = 2.9 × 10^?7). Together, the four tag SNPs explained 51 % of the variance in plasma trehalase activity and 79 % of the variance attributed to the linked locus. These four tag SNPs were further genotyped in 828 subjects used for association mapping of T2D, and rs558907 was associated with T2D (odds ratio (OR) 1.94, p = 0.002). To assess replication of the T2D association, all four tag SNPs were additionally genotyped in two non-overlapping samples of Native Americans. Rs558907 was reproducibly associated with T2D in 2,942 full-heritage Pima Indians (OR 1.27 p = 0.03) and 3,897 “mixed” heritage Native Americans (OR 1.21, p = 0.03), and the strongest evidence for association came from combining all samples (OR 1.27 p = 1.6 × 10^?4, n = 7,667). However, among 320 longitudinally studied subjects, measures of trehalase activity from a non-diabetic exam did not predict those who would eventually develop diabetes versus those who would remain non-diabetic (hazard ratio 0.94 per SD of trehalase activity, p = 0.29). We conclude that variants in TREH control trehalase activity, and although one of these variants is also reproducibly associated with T2D, it is likely that the effect of the SNP on risk of T2D occurs by a mechanism different than affecting trehalase activity. Alternatively, TREH variants may be tagging a nearby T2D locus.     

Three novel mtDNA restriction site polymorphisms allow exploration of population affinities of African Americans

To develop informative tools for the study of population affinities in African Americans, we sequenced the hypervariable segments I and II (HVS I and HVS II) of mitochondrial DNA (mtDNA) from 96 Sierra Leoneans; European Americans; rural, Gullah-speaking African Americans; urban African Americans living in Charleston, South Carolina; and Jamaicans. We identified single nucleotide polymorphisms (SNPs) exhibiting ethnic affinities, and developed restriction endonuclease tools to screen these SNPs. Here we show that three HVS restriction site polymorphisms (RSPs), EcoRV, FokI, and MfeI, exhibit appreciable differences in frequency (average delta = 0.4165) between putative African American parental populations (i.e., extant Africans living in Sierra Leone and European Americans). Estimates of European American mtDNA admixture, calculated from haplotypes composed of these three novel RSPs, show a cline of increasing admixture from Gullah-speaking African American (m = 0.0300) to urban Charleston African American (m = 0.0689) to West Coast African American (m = 0.1769) populations. This haplotype admixture in the Gullahs is the lowest recorded to date among African Americans, consistent with previous studies using autosomal markers. These RSPs may become valuable new tools in the study of ancestral affinities and admixture dynamics of African Americans.     

Birth weight and non-insulin dependent diabetes: thrifty genotype,thrifty phenotype,or surviving small baby genotype?

OBJECTIVE--To determine the prevalence of diabetes in relation to birth weight in Pima Indians. DESIGN--Follow up study of infants born during 1940-72 who had undergone a glucose tolerance test at ages 20-39 years. SETTING--Gila River Indian community, Arizona. SUBJECTS--1179 American Indians. MAIN OUTCOME MEASURE--Prevalence of non-insulin dependent diabetes mellitus (plasma glucose concentration > or = 11.1 mmol/l two hours after ingestion of carbohydrate). RESULTS--The prevalence was greatest in those with the lowest and highest birth weights. The age adjusted prevalences for birth weights < 2500 g, 2500-4499 g, and > or = 4500 g were 30%, 17%, and 32%, respectively. When age, sex, body mass index, maternal diabetes during pregnancy, and birth year were controlled for, subjects with birth weights < 2500 g had a higher rate than those with weights 2500-4499 g (odds ratio 3.81; 95% confidence interval 1.70 to 8.52). The risk for subsequent diabetes among higher birthweight infants (> or = 4500 g) was associated with maternal diabetes during pregnancy. Most diabetes, however, occurred in subjects with intermediate birth weights (2500-4500 g). CONCLUSIONS--The relation of the prevalence of diabetes to birth weight in the Pima Indians is U shaped and is related to parental diabetes. Low birth weight is associated with non-insulin dependent diabetes. Given the high mortality of low birthweight infants selective survival in infancy of those genetically predisposed to insulin resistance and diabetes provides an explanation for the observed relation between low birth weight and diabetes and the high prevalence of diabetes in many populations.     

Population admixture associated with disease prevalence in the Boston Puerto Rican health study

Older Puerto Ricans living in the continental U.S. suffer from higher rates of diabetes, obesity, cardiovascular disease and depression compared to non-Hispanic White populations. Complex diseases, such as these, are likely due to multiple, potentially interacting, genetic, environmental and social risk factors. Presumably, many of these environmental and genetic risk factors are contextual. We reasoned that racial background may modify some of these risk factors and be associated with health disparities among Puerto Ricans. The contemporary Puerto Rican population is genetically heterogeneous and originated from three ancestral populations: European settlers, native Taíno Indians, and West Africans. This rich-mixed ancestry of Puerto Ricans provides the intrinsic variability needed to untangle complex gene–environment interactions in disease susceptibility and severity. Herein, we determined whether a specific ancestral background was associated with either of four major disease outcomes (diabetes, obesity, cardiovascular disease, and depression). We estimated the genetic ancestry of 1,129 subjects from the Boston Puerto Rican Health Study based on genotypes of 100 ancestry informative markers (AIMs). We examined the effects of ancestry on tests of association between single AIMs and disease traits. The ancestral composition of this population was 57.2% European, 27.4% African, and 15.4% Native American. African ancestry was negatively associated with type 2 diabetes and cardiovascular disease, and positively correlated with hypertension. It is likely that the high prevalence rate of diabetes in Africans, Hispanics, and Native Americans is not due to genetic variation alone, but to the combined effects of genetic variation interacting with environmental and social factors. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

The interleukin-6 (-174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in Native Americans and Caucasians

Chronic low-grade activation of the immune system may play a role in the pathogenesis of type-2 diabetes mellitus (T2DM). Interleukin-6 (IL6), a powerful inducer of hepatic acute phase response, has been implicated in the etiology of insulin resistance and T2DM. Recently, an IL6 promoter polymorphism (G/C) at position -174 was found to be associated with measures of insulin sensitivity. Because we have previously found an association between high IL6 levels and insulin resistance in both Pima Indians - a population with high rates of insulin resistance and T2DM - and Caucasians, we aimed to assess whether the IL6 promoter polymorphism is associated with T2DM in these populations. We genotyped the IL6 (-174) G/C polymorphism using pyrosequencing in 463 Native Americans and by PCR-RFLP in 329 Spanish Caucasians. Among the Spanish Caucasian subjects, there was a significant difference in genotypic distribution between diabetic and non-diabetic subjects (P=0.028); the GG genotype was more common in diabetic (0.40) than in non-diabetic (0.29) subjects. The G allele was much more frequent in the Native American sample, and among a sample of 143 cases and 145 controls, the GG genotype was significantly more common in diabetic subjects (P=0.019). When this sample population was stratified according to ethnic heritage, all 211 subjects who were of full Pima Indian heritage had the GG genotype, whereas in the 77 American Indian subjects with non-Pima admixture, T2DM was associated with IL6 genotype (P=0.001). These findings are consistent with a role for genetic determinants of inflammation in the development of T2DM in both Native Americans and Caucasians.     

Genome-wide analysis in brazilian xavante indians reveals low degree of admixture

Characterization of population genetic variation and structure can be used as tools for research in human genetics and population isolates are of great interest. The aim of the present study was to characterize the genetic structure of Xavante Indians and compare it with other populations. The Xavante, an indigenous population living in Brazilian Central Plateau, is one of the largest native groups in Brazil. A subset of 53 unrelated subjects was selected from the initial sample of 300 Xavante Indians. Using 86,197 markers, Xavante were compared with all populations of HapMap Phase III and HGDP-CEPH projects and with a Southeast Brazilian population sample to establish its population structure. Principal Components Analysis showed that the Xavante Indians are concentrated in the Amerindian axis near other populations of known Amerindian ancestry such as Karitiana, Pima, Surui and Maya and a low degree of genetic admixture was observed. This is consistent with the historical records of bottlenecks experience and cultural isolation. By calculating pair-wise F(st) statistics we characterized the genetic differentiation between Xavante Indians and representative populations of the HapMap and from HGDP-CEPH project. We found that the genetic differentiation between Xavante Indians and populations of Ameridian, Asian, European, and African ancestry increased progressively. Our results indicate that the Xavante is a population that remained genetically isolated over the past decades and can offer advantages for genome-wide mapping studies of inherited disorders.     

Racial admixture and its impact on BMI and blood pressure in African and Mexican Americans

Admixed populations such as African Americans and Hispanic Americans present both challenges and opportunities in genetic epidemiologic research. Because of variation in admixture levels among individuals, case-control association studies may be subject to stratification bias. On the other hand, admixed populations also present special opportunities both for examining the role of genetic and environmental factors for observed racial/ethnic differences, and for possibly mapping alleles that contribute to such differences. Here we examined the distribution and relationship of individual admixture (IA) estimates with BMI and three measures of blood pressure in two admixed populations in the NHLBI Family Blood Pressure Program (FBPP): African Americans and Mexican Americans. For the African Americans, we observed modest but significant differences in average African IA among four recruitment sites. We observed a slight excess of African IA among hypertensives compared to normotensives, and a positive (non-significant) regression of African IA on blood pressure in untreated participants. Within Mexican Americans, we found no difference in average IA between hypertensives and normotensives, but a positive (marginally significant) regression of African IA on diastolic blood pressure. We also observed a significant positive regression of Caucasian IA (and negative regression of Native American IA) on BMI. Our results are suggestive of genetic differences between Africans and non-Africans that influence blood pressure, but such effects are likely to be modest compared to environmental ones. Excess obesity among Native Americans compared to whites is not consistent with a simple genetic explanation.     

Psammomys obesus and the albino rat--two different models of nutritional insulin resistance, representing two different types of human populations.

Animal models for insulin resistance and type 2 diabetes are required for the study of the mechanism of these phenomena and for a better understanding of diabetes complications in human populations. Type 2 diabetes is a syndrome that affects 5-10% of the adult population. Hyperinsulinaemia, hypertriglyceridaemia, decreased high-density lipoprotein (HDL) cholesterol levels, obesity and hypertension, all form a cluster of risk factors that increase the risk of coronary artery disease, and are known as insulin resistance syndrome or syndrome X. The gerbil, Psammomys obesus is characterized by primary insulin resistance and is a well-defined model for dietary induced type 2 diabetes. Weanling Psammomys and Albino rats were held individually for several weeks on high energy (HE) and low energy (LE) diets in order to determine the development of metabolic changes leading to diabetes. Feeding Psammomys on HE diet resulted in hyperglycaemia (303 +/- 40 mg/dl), hyperinsulinaemia (194 +/- 31 microU/ml) and a moderate elevation in body weight, obesity and plasma triglycerides. Albino rats on HE diet demonstrated an elevation in plasma insulin (30 +/- 4 microU/ml), hypertriglyceridaemia (170 +/- 11 mg/dl), an elevation in body weight and obesity, but maintained normoglycaemia (98 +/- 6 mg/dl). Psammomys represent a model that is similar to human populations, with primary insulin resistance expressed in young age, which leads to a high percentage of adult type 2 diabetes. Examples for such populations are the Pima Indians, Australian Aborigines and many other Third World populations. The results indicate that the metabolism of Psammomys is well adapted towards life in a low energy environment, where Psammomys takes advantage of its capacity for a constant accumulation of adipose tissue that will serve for maintenance and breeding in periods of scarcity. This metabolism known as 'thrifty metabolism', is compromised at a high nutrient intake.     

Association of PPARG2 Pro12Ala variant with larger body mass index in Mestizo and Amerindian populations of Mexico

Previous studies have sought to associate the Pro12Ala variant of the peroxisome proliferator-activated receptor gamma2 (PPARG2) gene with type 2 diabetes, insulin resistance, and obesity, with controversial results. We have determined the Pro12Ala variant frequency in 370 nondiabetic Mexican Mestizo subjects and in five Mexican Amerindian groups and have investigated its possible association with lipid metabolism, insulin serum levels, and obesity in three of these populations. Two independent case-control studies were conducted in 239 nondiabetic individuals: 135 case subjects (BMI > or = 25 kg/m2) and 104 control subjects (BMI < 25 kg/m2). The PPARG2 Ala12 allele frequency was higher in most Amerindian populations (0.17 in Yaquis, 0.16 in Mazahuas, 0.16 in Mayans, and 0.20 in Triquis) than in Asians, African Americans, and Caucasians. The Pro12Ala and Ala12Ala (X12Ala) genotypes were significantly associated with greater BMI in Mexican Mestizos and in two Amerindian groups. X12Ala individuals had a higher risk of overweight or obesity than noncarriers in Mestizos (OR = 3.67; 95% CI, 1.42-9.48; p = 0.007) and in Yaquis plus Mazahuas (OR = 3.21; 95% CI, 1.27-8.11; p = 0.013). Our results provide further support of the association between the PPARG2 Ala12 allele and risk of overweight or obesity in Mestizos and two Amerindian populations from Mexico.