Association of dichotomized WC with T2D-related traits.

<p>The bars represent regression coefficients estimated using polygenic regression models.</p

Waist Circumference Independently Associates with the Risk of Insulin Resistance and Type 2 Diabetes in Mexican American Families

<div><p>Objective</p><p>In spite of the growing recognition of the specific association of waist circumference (WC) with type 2 diabetes (T2D) and insulin resistance (IR), current guidelines still use body mass index (BMI) as a tool of choice. Our objective was to determine whether WC is a better T2D predictor than BMI in family-based settings.</p> <p>Research Design and Methods</p><p>Using prospectively collected data on 808 individuals from 42 extended Mexican American families representing 7617.92 person-years follow-up, we examined the performance of WC and BMI as predictors of cumulative and incident risk of T2D. We used robust statistical methods that accounted for the kinships and included polygenic models, discrete trait modeling, Akaike information criterion, odds ratio (OR), relative risk (RR) and Kullback-Leibler R². SOLAR software was used to conduct all the data analyses.</p> <p>Results</p><p>We found that in multivariate polygenic models, WC was an independent predictor of cumulative (OR = 2.76, p = 0.0002) and future risk of T2D (RR = 2.15, p = 3.56×10⁻⁹) and outperformed BMI when compared in a head-to-head fashion. High WC (≥94.65 cm after adjusting for age and sex) was also associated with high fasting glucose, insulin and triglyceride levels and low high-density lipoprotein levels indicating a potential association with IR. Moreover, WC was specifically and significantly associated with insulin resistant T2D (OR = 4.83, p = 1.01×10⁻¹³).</p> <p>Conclusions</p><p>Our results demonstrate the value of using WC as a screening tool of choice for future risk of T2D in Mexican American families. Also, WC is specifically associated with insulin resistant T2D.</p> </div

Univariate and multivariate association of anthropometric indexes with cumulative risk of T2D.

<p>β, regression coefficient; OR, odds ratio; CI, confidence interval; p, significance value</p

Association of dichotomized WC with IR and insulin resistant T2D.

<p>The bars represent regression coefficients estimated using polygenic regression models. Results are shown before (purple bars) and after (red bars) adjusting for the use of antidiabetic medication which includes the oral antidiabetic drugs as well as insulin. Statistical significance of a regression coefficient is shown in color-coded fashion at the top of the graph.</p

Determination of the optimal cut-point for waist circumference as a predictor of cumulative T2D risk.

<p>Figure shows Akaike information criterion (left y-axis) and odds ratio (right y-axis) for a cut-point of waist circumference indicated on the x-axis. Dashed vertical line indicates the optimal cut-point.</p

Genetic Effects on DNA Methylation and Its Potential Relevance for Obesity in Mexican Americans

<div><p>Several studies have identified effects of genetic variation on DNA methylation patterns and associated heritability, with research primarily focused on Caucasian individuals. In this paper, we examine the evidence for genetic effects on DNA methylation in a Mexican American cohort, a population burdened by a high prevalence of obesity. Using an Illumina-based platform and following stringent quality control procedures, we assessed a total of 395 CpG sites in peripheral blood samples obtained from 183 Mexican American individuals for evidence of heritability, proximal genetic regulation and association with age, sex and obesity measures (i.e. waist circumference and body mass index). We identified 16 CpG sites (∼4%) that were significantly heritable after Bonferroni correction for multiple testing and 27 CpG sites (∼6.9%) that showed evidence of genetic effects. Six CpG sites (∼2%) were associated with age, primarily exhibiting positive relationships, including CpG sites in two genes that have been implicated in previous genome-wide methylation studies of age (<i>FZD9</i> and <i>MYOD1</i>). In addition, we identified significant associations between three CpG sites (∼1%) and sex, including DNA methylation in <i>CASP6</i>, a gene that may respond to estradiol treatment, and in <i>HSD17B12</i>, which encodes a sex steroid hormone. Although we did not identify any significant associations between DNA methylation and the obesity measures, several nominally significant results were observed in genes related to adipogenesis, obesity, energy homeostasis and glucose homeostasis (<i>ARHGAP9</i>, <i>CDKN2A</i>, <i>FRZB</i>, <i>HOXA5</i>, <i>JAK3</i>, <i>MEST</i>, <i>NPY</i>, <i>PEG3</i> and <i>SMARCB1</i>). In conclusion, we were able to replicate several findings from previous studies in our Mexican American cohort, supporting an important role for genetic effects on DNA methylation. In addition, we found a significant influence of age and sex on DNA methylation, and report on trend-level, novel associations between DNA methylation and measures of obesity.</p></div

Significant age and sex associations with DNA methylation.

<p>P-values that are significant after correction for multiple testing are given in <b>bold.</b></p>#<p>CpG sites are annotated according to <i>GENE_Position_Strand</i>, as outlined in the methods section.</p>*<p>Note: a positive value for beta indicates increased methylation is associated with increased age and females.</p

Most highly significant associations between DNA methylation and obesity measures.

<p>Note: all significance values are nominal.</p>#<p>CpG sites are annotated according to <i>GENE_Position_Strand</i>, as outlined in the methods section.</p>*<p>A positive value for beta indicates increased methylation is associated with increased obesity measures (i.e. increased waist circumference or increased BMI).</p

Heritability and genetic regulation of DNA methylation.

<p>P-values that are significant after correction for multiple testing are given in <b>bold.</b></p>#<p>CpG sites are annotated according to <i>GENE_Position_Strand</i>, as outlined in the methods section.</p><p><a href="mailto:@Indicates" target="_blank">@Indicates</a> probe sequences containing SNPs with a MAF>5%.</p>*<p>MAF: Minor allele frequency; minor allele is reported second.</p

Improved clinical prediction of incident type 2 diabetes based on sICAM-1 and sVCAM-1 as independent biomarkers^*.

<p>Improved clinical prediction of incident type 2 diabetes based on sICAM-1 and sVCAM-1 as independent biomarkers^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0151177#t004fn001" target="_blank">*</a>}.</p