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Privacy protection is a core principle of genomic but not proteomic research. We identified independent single nucleotide polymorphism (SNP) quantitative trait loci (pQTL) from COPDGene and Jackson Heart Study (JHS), calculated continuous protein level genotype probabilities, and then applied a naïve Bayesian approach to match proteomes to genomes for 2,812 independent subjects from COPDGene, JHS, SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) and Multi-Ethnic Study of Atherosclerosis (MESA). We were able to correctly match 90%-95% of proteomes to their correct genome and for 95%-99% we could match the proteome to the 1% most likely genome. The accuracy of matching in subjects with African ancestry was lower (~ 60%) unless training included diverse subjects. With larger profiling (SomaScan 5K) in the Atherosclerosis Risk Communities (ARIC) correct identification was > 99% even in mixed ancestry populations. When serial proteomes are available, the matching algorithm can be used to identify and correct mislabeled samples. This work also demonstrates the importance of including diverse populations in omics research and that large proteomic datasets (> 1,000 proteins) can be accurately linked to a specific genome through pQTL knowledge and should not be considered unidentifiable.

In the medical management of obesity, treating physicians observe significant heterogeneity in responses to pharmacotherapy. Indeed one of the most important clinical questions in obesity medicine is whether we can predict how an individual will respond to a particular pharmacotherapeutic agent. The present study examines patterns and predictors of weight loss among overweight and obese women who demonstrated early robust response to twice daily exenatide treatment.182 women were assigned using single-blind randomization to either treatment with twice daily exenatide injections or to matched placebo injections with dietary counseling. Women who demonstrated > 5% weight loss after 12 weeks of treatment were deemed high responders and remained on study treatment for up to 52 weeks; women who lost < 5% body weight at 12 weeks were deemed low responders and stopped study treatment. We additionally characterized individuals who lost > 10% of body weight as super responders. Our primary outcome was change in body weight; secondary outcomes included changes in metabolic parameters including lipids, waist circumference, resting energy expenditure, and response to a meal tolerance test. We also performed an exploratory metabolomic analysis.Consistent with published literature, we observed individual heterogeneity in the weight loss response to exenatide and diet/placebo. Although there was no significant difference between treatment groups in the percentage of participants who achieved > 5% weight loss (56% of exenatide group and 76% of diet/placebo group), or those who achieved > 10% weight loss (43% of exenatide group and 55% of diet/placebo group), in both cases there was a trend toward a higher response rate in the group that received placebo with dietary counseling. In addition to achieving similar average weight loss, both treatment groups also demonstrated similar maximum weight loss. The range of maximum weight loss was greater in the diet/placebo group and there was more weight regain among individuals in the exenatide group compared to the diet/placebo group. In our exploratory metabolomic analysis, we observed lower baseline circulating cysteine concentrations in the exenatide responder group and we also found a trend toward higher baseline levels of serotonin, aminoisobutyric acid, anandamide, and sarcosine in the exenatide super responder group. We did not identify any metabolic predictors of weight loss in either the exenatide or the diet/placebo treatment group.

The vascular endothelium plays a critical role in vascular homeostasis. Inflammatory cytokines and non-laminar blood flow induce endothelial dysfunction and confer a pro-adhesive and pro-thrombotic phenotype. Therefore, identification of factors that mediate the effects of these stimuli on endothelial function is of considerable interest. Kruppel-like factor 4 expression has been documented in endothelial cells, but a function has not been described. In this communication we describe the expression in vitro and in vivo of Kruppel-like factor 4 in human and mouse endothelial cells. Furthermore, we demonstrate that endothelial Kruppel-like factor 4 is induced by pro-inflammatory stimuli and shear stress. Overexpression of Kruppel-like factor 4 induces expression of multiple anti-inflammatory and anti-thrombotic factors including endothelial nitric-oxide synthase and thrombomodulin, whereas knockdown of Kruppellike factor 4 leads to enhancement of tumor necrosis factor alpha-induced vascular cell adhesion molecule-1 and tissue factor expression. The functional importance of Kruppel-like factor 4 is verified by demonstrating that Kruppel-like factor 4 expression markedly decreases inflammatory cell adhesion to the endothelial surface and prolongs clotting time under inflammatory states. Kruppel-like factor 4 differentially regulates the promoter activity of pro- and anti-inflammatory genes in a manner consistent with its anti-inflammatory function. These data implicate Kruppel-like factor 4 as a novel regulator of endothelial activation in response to pro-inflammatory stimuli.