Relationship of percent body fat (PBF) with body adiposity index (BAI) and body mass index (BMI) in men and women.

<p>A. BAI versus PBF. B. BMI versus PBF. The graphs are generated on untransformed data for the BAI and BMI variables, while the main analyses in our study are based on log transformations of these variables. Therefore, the correlation coefficients (r) here are slightly different than those reported elsewhere in the text.</p

Clinical characteristics of the study cohort.

<p>Data are medians (interquartile range).</p><p>BAI, body adiposity index; BMI, body mass index; Carotid IMT, carotid intima-media thickness; CRP, C-reactive protein; DBP, diastolic blood pressure; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; MCRI, metabolic clearance rate of insulin; M/I, insulin sensitivity index from the euglycemic-hyperinsulinemic clamp; PAI-1, plasminogen activator inhibitor-1; PBF, percent total body fat; SBP, systolic blood pressure; TG, triglycerides.</p

Correlations of anthropometric measurements with cardiometabolic risk factors.

<p>Data are correlation coefficients with <i>P</i> values in parentheses.</p

Comparison of correlation coefficients between cardiometabolic risk factors and BMI versus BAI.

<p>Correlation coefficients that are significantly greater are highlighted in bold.</p>a<p><i>P</i> values from Hotelling’s T-test.</p

Systems Genetics Reveals the Functional Context of PCOS Loci and Identifies Genetic and Molecular Mechanisms of Disease Heterogeneity

<div><p>Genome wide association studies (GWAS) have revealed 11 independent risk loci for polycystic ovary syndrome (PCOS), a common disorder in young women characterized by androgen excess and oligomenorrhea. To put these risk loci and the single nucleotide polymorphisms (SNPs) therein into functional context, we measured DNA methylation and gene expression in subcutaneous adipose tissue biopsies to identify PCOS-specific alterations. Two genes from the <i>LHCGR</i> region, <i>STON1-GTF2A1L</i> and <i>LHCGR</i>, were overexpressed in PCOS. In analysis stratified by obesity, <i>LHCGR</i> was overexpressed only in non-obese PCOS women. Although not differentially expressed in the entire PCOS group, <i>INSR</i> was underexpressed in obese PCOS subjects only. Alterations in gene expression in the <i>LHCGR</i>, <i>RAB5B</i> and <i>INSR</i> regions suggest that SNPs in these loci may be functional and could affect gene expression directly or indirectly via epigenetic alterations. We identified reduced methylation in the <i>LHCGR</i> locus and increased methylation in the <i>INSR</i> locus, changes that are concordant with the altered gene expression profiles. Complex patterns of meQTL and eQTL were identified in these loci, suggesting that local genetic variation plays an important role in gene regulation. We propose that non-obese PCOS women possess significant alterations in LH receptor expression, which drives excess androgen secretion from the ovary. Alternatively, obese women with PCOS possess alterations in insulin receptor expression, with underexpression in metabolic tissues and overexpression in the ovary, resulting in peripheral insulin resistance and excess ovarian androgen production. These studies provide a genetic and molecular basis for the reported clinical heterogeneity of PCOS.</p></div

PCOS risk loci contain alterations in gene regulation and expression in PCOS adipose tissue.

<p><b>i.</b> Chromosomal co-ordinates, gene structure and gene expression profile (grey = not expressed in adipose, black = expressed in adipose). The index PCOS GWAS risk SNP is marked by a filled black triangle and is labeled with rs number. <b>ii.</b> Methylation sites are shown as open (unmethylated), grey filled (semi-methylated) or black (fully methylated) circles, and meQTL relationships between these sites and local SNPs are shown with a green arrow. eQTL results are shown by an orange star marking the gene and orange arrows marking SNP position of independent signals. <b>iii.</b> UCSC Genome Browser ENCODE tracks show <b>1</b> SNP position from dbSNP143, <b>2</b> poised enhancer activity, <b>3</b> active enhancer activity, <b>4</b> active promoter activity and <b>5</b> transcriptional activity, in 7 Encode reference cell types. <b>iv.</b> meQTL results are shown with box and whisker plots demonstrating mean methylation (Beta level) in each genotype group.</p

Methylation (Beta) levels at CpG sites with significantly different methylation between PCOS and controls.

<p>On the X axis are the significant CpG sites in the windows around the PCOS GWAS SNPs. On the Y axis is the methylation status, measured as the mean beta level. Error bars represent standard deviation.</p

Expression levels of differentially expressed mRNA transcripts.

<p><b>(A)</b> Expression levels of differentially expressed mRNA transcripts between PCOS and controls in the <i>LHCGR</i> and <i>RAB5B/SUOX</i> loci. On the X axis are gene names. On the Y axis are the mean expression levels. Error bars represent standard deviation. <b>(B)</b> Expression levels of mRNA transcripts differentially expressed between PCOS and controls, stratified by obesity. On the X axis is the obesity status of the subjects, non-obese and obese subjects analyzed separately. On the Y axis are the mean expression levels. * Denotes results that remained significant after correction for multiple testing. Error bars represent standard deviation.</p

Clinical Characteristics of PCOS and control subjects.

<p>*P<0.001 compared to control group. Data are median (interquartile range). In the replication cohort, androgen measurements were available only in the cases and controls recruited by R. S. Legro.</p><p>Abbreviations: BMI: body mass index; mFG: modified Ferriman-Gallwey hirsutism score; NA: Data not Available; HOMA-IR, homeostasis model assessment of insulin resistance; HOMA-%B, homeostasis model assessment of beta-cell function (insulin secretion).</p

Gene structure and linkage disequilibrium plot for <i>DKK1</i> and <i>DNAJB1</i>.

<p>The gene structure is shown at top, with exons shown as filled boxes, untranslated regions as unfilled boxes and introns as connecting lines. The locations of the genotyped SNPs relative to the exons are indicated. The linkage disequilibrium (LD) plot at the bottom displays D' values (%) for each pair of SNPs in the box at the intersection of the diagonals from each SNP. The solid blocks indicate D' = 1 for the corresponding pair of variants. The darker solid blocks indicate a logarithm of the odds (LOD) score ≥2 for the corresponding pair of variants; lighter solid blocks indicate a LOD score <2. Within each gene, SNPs were considered together in one haplotype block as indicated.</p