The Relationship between Native American Ancestry, Body Mass Index and Diabetes Risk among Mexican-Americans

<div><p>Higher body mass index (BMI) is a well-established risk factor for type 2 diabetes, and rates of obesity and type 2 diabetes are substantially higher among Mexican-Americans relative to non-Hispanic European Americans. Mexican-Americans are genetically diverse, with a highly variable distribution of Native American, European, and African ancestries. Here, we evaluate the role of Native American ancestry on BMI and diabetes risk in a well-defined Mexican-American population. Participants were randomly selected among individuals residing in the Houston area who are enrolled in the Mexican-American Cohort study. Using a custom Illumina GoldenGate Panel, we genotyped DNA from 4,662 cohort participants for 87 Ancestry-Informative Markers. On average, the participants were of 50.2% Native American ancestry, 42.7% European ancestry and 7.1% African ancestry. Using multivariate linear regression, we found BMI and Native American ancestry were inversely correlated; individuals with <20% Native American ancestry were 2.5 times more likely to be severely obese compared to those with >80% Native American ancestry. Furthermore, we demonstrated an interaction between BMI and Native American ancestry in diabetes risk among women; Native American ancestry was a strong risk factor for diabetes only among overweight and obese women (OR = 1.190 for each 10% increase in Native American ancestry). This study offers new insight into the complex relationship between obesity, genetic ancestry, and their respective effects on diabetes risk. Findings from this study may improve the diabetes risk prediction among Mexican-American individuals thereby facilitating targeted prevention strategies.</p></div

Regressing Native American genetic ancestry with diabetes risk by BMI in women.

<p>* Shown in the parentheses are the 95% confidence intervals</p><p>Regressing Native American genetic ancestry with diabetes risk by BMI in women.</p

Genetic ancestries of 4,659 participants in the Mexican-American Cohort.

<p>Each column represents one individual. The lengths of lines with different colors in each column represent the proportion of genetic ancestry for this individual. Green: European; Blue: Native American; Red: African.</p

Demographic characteristics of participants.

<p>* p-values are calculated with Wilcoxon rank sum test for age and BMI, and with Fisher exact test otherwise.</p><p>Demographic characteristics of participants.</p

Association between genetic ancestry and BMI.

<p>*Shown in the parentheses are the 95% confidence interval of the regression coefficient</p><p>Association between genetic ancestry and BMI.</p

Genetic ancestry by gender.

<p>*p-values are calculated with Wilcoxon rank sum test.</p><p>Genetic ancestry by gender.</p

Histogram of BMI values in high-Native American Ancestry group (grey; NA ancestry > 80%) and low-Native American Ancestry group (black; NA ancestry <20%).

<p>Histogram of BMI values in high-Native American Ancestry group (grey; NA ancestry > 80%) and low-Native American Ancestry group (black; NA ancestry <20%).</p

Regression analysis of diabetes status with Native American genetic ancestry.

<p>* Shown in the parentheses are the 95% confidence intervals</p><p>Regression analysis of diabetes status with Native American genetic ancestry.</p

Selection signals identified at the empirical top 2% significance level in Tibetans from Maduo (as reported in Simonson et al. 2010) and Tuo Tuo River Tibetans and/or reported in other studies of human adaptation to high altitude as referenced.

<p>The 200 kb bin refers to the genomic position on the chromosome listed in the second column (positions based on Hg18) from which the selection signal emanates. The empirical p value of this region, which contains the selection candidate gene, is based on the selection analysis performed in the population specified.</p

Shared and Unique Signals of High-Altitude Adaptation in Geographically Distinct Tibetan Populations

<div><p>Recent studies have used a variety of analytical methods to identify genes targeted by selection in high-altitude populations located throughout the Tibetan Plateau. Despite differences in analytic strategies and sample location, hypoxia-related genes, including <i>EPAS1</i> and <i>EGLN1</i>, were identified in multiple studies. By applying the same analytic methods to genome-wide SNP information used in our previous study of a Tibetan population (n = 31) from the township of Maduo, located in the northeastern corner of the Qinghai-Tibetan Plateau (4200 m), we have identified common targets of natural selection in a second geographically and linguistically distinct Tibetan population (n = 46) in the Tuo Tuo River township (4500 m). Our analyses provide evidence for natural selection based on iHS and XP-EHH signals in both populations at the p<0.02 significance level for <i>EPAS1</i>, <i>EGLN1</i>, <i>HMOX2</i>, and <i>CYP17A1</i> and for <i>PKLR</i>, <i>HFE</i>, and <i>HBB</i> and <i>HBG2</i>, which have also been reported in other studies. We highlight differences (i.e., stratification and admixture) in the two distinct Tibetan groups examined here and report selection candidate genes common to both groups. These findings should be considered in the prioritization of selection candidate genes in future genetic studies in Tibet.</p></div