Integrating multiple 'omics' analyses identifies serological protein biomarkers for preeclampsia.

BACKGROUND: Preeclampsia (PE) is a pregnancy-related vascular disorder which is the leading cause of maternal morbidity and mortality. We sought to identify novel serological protein markers to diagnose PE with a multi-'omics' based discovery approach. METHODS: Seven previous placental expression studies were combined for a multiplex analysis, and in parallel, two-dimensional gel electrophoresis was performed to compare serum proteomes in PE and control subjects. The combined biomarker candidates were validated with available ELISA assays using gestational age-matched PE (n=32) and control (n=32) samples. With the validated biomarkers, a genetic algorithm was then used to construct and optimize biomarker panels in PE assessment. RESULTS: In addition to the previously identified biomarkers, the angiogenic and antiangiogenic factors (soluble fms-like tyrosine kinase (sFlt-1) and placental growth factor (PIGF)), we found 3 up-regulated and 6 down-regulated biomakers in PE sera. Two optimal biomarker panels were developed for early and late onset PE assessment, respectively. CONCLUSIONS: Both early and late onset PE diagnostic panels, constructed with our PE biomarkers, were superior over sFlt-1/PIGF ratio in PE discrimination. The functional significance of these PE biomarkers and their associated pathways were analyzed which may provide new insights into the pathogenesis of PE.

Peptidomic Identification of Serum Peptides Diagnosing Preeclampsia.

We sought to identify serological markers capable of diagnosing preeclampsia (PE). We performed serum peptide analysis (liquid chromatography mass spectrometry) of 62 unique samples from 31 PE patients and 31 healthy pregnant controls, with two-thirds used as a training set and the other third as a testing set. Differential serum peptide profiling identified 52 significant serum peptides, and a 19-peptide panel collectively discriminating PE in training sets (n = 21 PE, n = 21 control; specificity = 85.7% and sensitivity = 100%) and testing sets (n = 10 PE, n = 10 control; specificity = 80% and sensitivity = 100%). The panel peptides were derived from 6 different protein precursors: 13 from fibrinogen alpha (FGA), 1 from alpha-1-antitrypsin (A1AT), 1 from apolipoprotein L1 (APO-L1), 1 from inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4), 2 from kininogen-1 (KNG1), and 1 from thymosin beta-4 (TMSB4). We concluded that serum peptides can accurately discriminate active PE. Measurement of a 19-peptide panel could be performed quickly and in a quantitative mass spectrometric platform available in clinical laboratories. This serum peptide panel quantification could provide clinical utility in predicting PE or differential diagnosis of PE from confounding chronic hypertension.

Sex differences in reported pain across 11,000 patients captured in electronic medical records.

UNLABELLED: Clinically recorded pain scores are abundant in patient health records but are rarely used in research. The use of this information could help improve clinical outcomes. For example, a recent report by the Institute of Medicine stated that ineffective use of clinical information contributes to undertreatment of patient subpopulations--especially women. This study used diagnosis-associated pain scores from a large hospital database to document sex differences in reported pain. We used de-identified electronic medical records from Stanford Hospital and Clinics for more than 72,000 patients. Each record contained at least 1 disease-associated pain score. We found over 160,000 pain scores in more than 250 primary diagnoses, and analyzed differences in disease-specific pain reported by men and women. After filtering for diagnoses with minimum encounter numbers, we found diagnosis-specific sex differences in reported pain. The most significant differences occurred in patients with disorders of the musculoskeletal, circulatory, respiratory and digestive systems, followed by infectious diseases, and injury and poisoning. We also discovered sex-specific differences in pain intensity in previously unreported diseases, including disorders of the cervical region, and acute sinusitis (P = .01, .017, respectively). Pain scores were collected during hospital encounters. No information about the use of pre-encounter over-the-counter medications was available. To our knowledge, this is the largest data-driven study documenting sex differences of disease-associated pain. It highlights the utility of electronic medical record data to corroborate and expand on results of smaller clinical studies. Our findings emphasize the need for future research examining the mechanisms underlying differences in pain. PERSPECTIVE: This article highlights the potential of electronic medical records to conduct large-scale pain studies. Our results are consistent with previous studies reporting pain differences between sexes and also suggest that clinicians should pay increased attention to this idea.

Transmission distortion in Crohn's disease risk gene ATG16L1 leads to sex difference in disease association.

BACKGROUND: Crohn's disease (CD), an inflammatory disease of the bowel, affects millions of people around the world. Evidence suggests that disease onset and pathogenesis differ between males and females. Yet no comprehensive efforts exist to assess the sex-specific genetic architecture of CD. METHODS: We used genotyping data from a cohort of 1748 CD cases and 2938 controls to investigate 71 meta-analysis-confirmed CD risk loci for sex differences in disease risk. We further validated the significant results in separate cohorts of 968 CD cases and 2809 controls, and performed a meta-analysis across datasets. RESULTS: The single nucleotide polymorphism (SNP) rs3792106 (C/T) in ATG16L1 showed a significant sex effect with P-value 6.9 × 10(-13) and allelic odds ratio 1.48 in females, and P-value 0.013 and odds ratio 1.22 in males (odds ratio heterogeneity P-value 0.037). Surprisingly, the difference was found to arise from a discrepancy in allele frequencies between male and female controls (P-value 0.0045) rather than cases. We found similar results for this SNP in the separate validation datasets. Using 155 HapMap 3 trios, we detected significant maternal overtransmission of the T allele at rs3792106 (P-value 0.027). CONCLUSIONS: Our results indicate that different transmission patterns between sexes may sustain the disparate allele frequencies at rs3792106 in healthy populations, and furthermore that a virus-risk variant mechanism implicated in CD alters the distribution in diseased patients. To our knowledge, this is the first report of sex-specific CD association in ATG16L1. The possible implications in CD and basic human biology present interesting areas for future investigation.

Sex differences in disease risk from reported genome-wide association study findings.

Men and women differ in susceptibility to many diseases and in responses to treatment. Recent advances in genome-wide association studies (GWAS) provide a wealth of data for associating genetic profiles with disease risk; however, in general, these data have not been systematically probed for sex differences in gene-disease associations. Incorporating sex into the analysis of GWAS results can elucidate new relationships between single nucleotide polymorphisms (SNPs) and human disease. In this study, we performed a sex-differentiated analysis on significant SNPs from GWAS data of the seven common diseases studied by the Wellcome Trust Case Control Consortium. We employed and compared three methods: logistic regression, Woolf's test of heterogeneity, and a novel statistical metric that we developed called permutation method to assess sex effects (PMASE). After correction for false discovery, PMASE finds SNPs that are significantly associated with disease in only one sex. These sexually dimorphic SNP-disease associations occur in Coronary Artery Disease and Crohn's Disease. GWAS analyses that fail to consider sex-specific effects may miss discovering sexual dimorphism in SNP-disease associations that give new insights into differences in disease mechanism between men and women.