FTO and MC4R Gene Variants Are Associated with Obesity in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women. It is also associated with metabolic disturbances that place women at increased risk for obesity and type 2 diabetes. There is strong evidence for familial clustering of PCOS and a genetic predisposition. However, the gene(s) responsible for the PCOS phenotypes have not been elucidated. This two-phase family-based and case-control genetic study was designed to address the question of whether SNPs identified as susceptibility loci for obesity in genome-wide association studies (GWAS) are also associated with PCOS and elevated BMI. Members of 439 families having at least one offspring with PCOS were genotyped for 15 SNPs previously shown to be associated with obesity. Linkage and association with PCOS was assessed using the transmission/disequilibrium test (TDT). These SNPs were also analyzed in an independent case-control study involving 395 women with PCOS and 176 healthy women with regular menstrual cycles. Only one of these 15 SNPs (rs2815752 in NEGR1) was found to have a nominally significant association with PCOS (χ2 = 6.11, P = 0.013), but this association failed to replicate in the case-control study. While not associated with PCOS itself, five SNPs in FTO and two in MC4R were associated with BMI as assessed with a quantitative-TDT analysis, several of which replicated association with BMI in the case-control cohort. These findings demonstrate that certain SNPs associated with obesity contribute to elevated BMI in PCOS, but do not appear to play a major role in PCOS per se. These findings support the notion that PCOS phenotypes are a consequence of an oligogenic/polygenic mechanism

Novel inhibitors of α4β1 integrin receptor interactions through library synthesis and screening

A library of 2302 small molecule β-turn mimetics was screened for inhibition of the α4β1 integrin-CS1 splice variant binding interaction. Preliminary data revealed several active ligands, and validation with purified material culminated in the identification of some of the first small molecule ligands ( 1, IC 50 = 5 μM, and 2, IC 50 = 8 μM) to be reported for this class of integrins. Graphi

Obesity susceptibility loci identified in GWAS tested by logistic regression for association with PCOS in the case-control cohort (395 cases, 176 controls).

<p>Obesity susceptibility loci identified in GWAS tested by logistic regression for association with PCOS in the case-control cohort (395 cases, 176 controls).</p

Clinical characteristics of PCOS in probands and sisters in the family study, controls from the case-control cohort, and PCOS cases from the case-control cohort.

<p>Data are median (interquartile range).</p><p>*Nominal testosterone values based on different assays for the probands and sisters and the case-control cohort as described in text.</p>a<p>P<0.0001 compared to probands and sisters.</p>b<p>P<0.0001 compared to controls.</p>c<p>P = 0.002 compared to probands and sisters.</p

Obesity susceptibility loci identified in GWAS tested by linear regression for association with BMI in 395 women with PCOS.

<p>Obesity susceptibility loci identified in GWAS tested by linear regression for association with BMI in 395 women with PCOS.</p

Obesity susceptibility loci identified in GWAS tested by TDT and QTDT 439 PCOS families (N = 488 probands and sisters) for linkage and association with PCOS and BMI.

a<p>SNP alleles, minor allele appears second.</p>b<p>MAF, minor allele frequency for SNP.</p>c<p>T, number of transmissions to affected offspring in the TDT analysis.</p>d<p>P values are uncorrected.</p

Gene Expression and Genetic Variation in Response to Endoplasmic Reticulum Stress in Human Cells

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) results in the condition called “ER stress,” which induces the unfolded protein response (UPR), a complex cellular process that includes changes in expression of many genes. Failure to restore homeostasis in the ER is associated with human diseases. To identify the underlying changes in gene expression in response to ER stress, we induced ER stress in human B cells and then measured gene expression at ten time points. We followed up those results by studying cells from 60 unrelated people. We rediscovered genes that were known to play a role in the ER-stress response and uncovered several thousand genes that are not known to be involved. Two of these are VLDLR and INHBE, which showed significant increase in expression after ER stress in B cells and in primary fibroblasts. To study the links between UPR and disease susceptibility, we identified ER-stress-responsive genes that are associated with human diseases and assessed individual differences in the ER-stress response. Many of the UPR genes are associated with Mendelian disorders, such as Wolfram syndrome, and complex diseases, including amyotrophic lateral sclerosis and diabetes. Data from two independent samples showed extensive individual variability in ER-stress response. Additional analyses with monozygotic twins revealed significant correlations within twin pairs in their responses to ER stress, thus showing evidence for heritable variation among individuals. These results have implications for basic understanding of ER function and its role in disease susceptibility