Statistical analysis of haplotypes, untyped SNPs, and CNVs in genome-wide association studies

Missing data arise in genetic association studies when one is interested in assessing the effects of haplotypes, untyped single nucleotide polymorphisms (SNPs) or copy number variants (CNVs). Haplotypes are combinations of nucleotides at multiple loci along individual homologous chromosomes, and the use of haplotypes tends to yield more efficient analysis of disease association than SNPs. Untyped SNPs are SNPs that are not on the genotyping chips used in the study (i.e., missing on all study subjects), and the analysis of untyped SNPs can facilitate localization of disease-causing variants and permit meta-analysis of association studies with different genotyping platforms. A CNV refers to the duplication or deletion of a segment of DNA sequence compared to a reference genome assembly, and can play a causal role in genetic diseases. In the first part of the proposal, we provide a general likelihood-based framework for making inference on the effects of haplotypes or untyped SNPs and their interactions with environmental variables. Unlike most of the existing methods, we allow genetic and environmental variables to be correlated. We show that the maximum likelihood estimators are consistent, asymptotically normal, and asymptotically efficient and we develop EM algorithms to implement the corresponding inference procedures. We conduct extensive simulation studies and apply the methods to a genome-wide association study (GWAS) of lung cancer. In the second part, we focus on comparing two approaches in the analysis of untyped SNPs. The maximum likelihood approach integrates prediction of untyped genotypes and estimation of association parameters into a single framework and yields consistent and efficient estimators of genetic effects and gene-environment interactions with proper variance estimators. The imputation approach is a two-stage strategy which first imputes the untyped genotypes by either the most likely genotypes or the expected genotype counts and then uses the imputed values in downstream association analysis. We conduct extensive simulation studies to compare the bias, type I error, power, and confidence interval coverage between the two methods under various situations. In addition, we provide an illustration with genome-wide data from the Wellcome Trust Case-Control Consortium (WTCCC). In the third part, we present a general framework for the integrated analysis of CNVs and SNPs in association studies, including the analysis of total copy number as a special case. We use allele-specific copy numbers (ASCNs) to describe both the copy number and allelic variations of a locus. %The joint effects of CNVs and SNPs on the disease are formulated in terms of allele-specific copy numbers (ASCNs). Our approach combines the ASCN calling and association analysis into a single step while allowing for differential errors. We construct likelihood functions that properly account for the case-control sampling and measurement errors. We establish the asymptotic properties of the maximum likelihood estimators and develop EM algorithms to implement the proposed inference procedures. The advantages of the proposed methods over the existing ones are demonstrated through realistic simulation studies and an application to a GWAS of schizophrenia

Evaluation of population impact of candidate polymorphisms for coronary heart disease in the Framingham Heart Study Offspring Cohort

In order to evaluate the population impact of putative causal genetic variants over the life course of disease, we extended the static estimation of population-attributable risk fraction and developed a novel tool to evaluate how the population impact changes over time using the Framingham Heart Study Offspring Cohort data provided to the Genetic Analysis Workshop 16, Problem 2. A set of population-attributable risk fractions based on survival functions were estimated under the proportional hazards models. The development of this novel measure of population impact creates a more comprehensive estimate of population impact over the life course of disease, which may help us to better understand genetic susceptibility at the population level

Prospective associations of coronary heart disease loci in African Americans using the MetaboChip: The PAGE study

Background Coronary heart disease (CHD) is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published variants in CHD loci with incident CHD, attempted to fine map these loci, and characterize novel variants influencing CHD risk in African Americans. Methods and Results Up to 8,201 African Americans (including 546 first CHD events) were genotyped using the MetaboChip array in the Atherosclerosis Risk in Communities (ARIC) study and Women\u27s Health Initiative (WHI). We tested associations using Cox proportional hazard models in sex- and study-stratified analyses and combined results using meta-analysis. Among 44 validated CHD loci available in the array, we replicated and fine-mapped the SORT1 locus, and showed same direction of effects as reported in studies of individuals of European ancestry for SNPs in 22 additional published loci. We also identified a SNP achieving array wide significance (MYC: rs2070583, allele frequency 0.02, P = 8.1×10−8), but the association did not replicate in an additional 8,059 African Americans (577 events) from the WHI, HealthABC and GeneSTAR studies, and in a meta-analysis of 5 cohort studies of European ancestry (24,024 individuals including 1,570 cases of MI and 2,406 cases of CHD) from the CHARGE Consortium. Conclusions Our findings suggest that some CHD loci previously identified in individuals of European ancestry may be relevant to incident CHD in African Americans

Comprehensive analysis of a NAD+ metabolism-derived gene signature to predict the prognosis and immune landscape in endometrial cancer

As a crucial regulator influencing tumor progression, nicotinamide adenine dinucleotide (NAD+) is widely acknowledged. However, its role in endometrial cancer (EC) is not completely understood. In this study, we aimed to develop an NAD+metabolic-related genes (NMRGs) risk signature that could reflect the prognosis of EC patients and their responsiveness to immunotherapy and chemotherapy. Data from The Cancer Genome Atlas (TCGA) databases and the Molecular Signatures Database (MSigDB) confirmed two distinct NMRG subtypes in EC patients using consensus clustering, and a risk score was constructed utilizing an NAD+-related prognostic signature depending on the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. Receiver operating characteristic (ROC) curves were employed to assess the model’s precision. Additionally, we used Gene Set Enrichment Analysis (GSEA) to predict the biological signaling pathways that might be involved. We also explored the role of the risk score in immune cell infiltration, tumor mutation burden (TMB), immunotherapy, and chemotherapy. Our study established a prognostic risk signature based on six NMRGs, and we observed that the high-risk group was associated with a poorer prognosis. Furthermore, we identified a strong correlation between the high-risk group and several pathways, including DNA replication, cell cycle, and mismatch repair. Lastly, our findings highlighted the influence of NMRGs on the regulation of immune infiltration in EC. Therefore, this signature holds potential value in predicting the prognosis of EC patients and guiding their management, including decisions regarding immunotherapy and chemotherapy, ultimately improving the accuracy of EC patient care

Recent Progress in Phage Therapy to Modulate Multidrug-Resistant Acinetobacter baumannii, Including in Human and Poultry

Acinetobacter baumannii is a multidrug-resistant and invasive pathogen associated with the etiopathology of both an increasing number of nosocomial infections and is of relevance to poultry production systems. Multidrug-resistant Acinetobacter baumannii has been reported in connection to severe challenges to clinical treatment, mostly due to an increased rate of resistance to carbapenems. Amid the possible strategies aiming to reduce the insurgence of antimicrobial resistance, phage therapy has gained particular importance for the treatment of bacterial infections. This review summarizes the different phage-therapy approaches currently in use for multiple-drug resistant Acinetobacter baumannii, including single phage therapy, phage cocktails, phage–antibiotic combination therapy, phage-derived enzymes active on Acinetobacter baumannii and some novel technologies based on phage interventions. Although phage therapy represents a potential treatment solution for multidrug-resistant Acinetobacter baumannii, further research is needed to unravel some unanswered questions, especially in regard to its in vivo applications, before possible routine clinical use

Carotid Intima-Media Thickness and Presence or Absence of Plaque Improves Prediction of Coronary Heart Disease Risk. The ARIC (Atherosclerosis Risk In Communities) Study

We evaluated whether carotid intima-media thickness (C-IMT) and the presence or absence of plaque improved coronary heart disease (CHD) risk prediction when added to traditional risk factors (TRF)

Activation of Human Stearoyl-Coenzyme A Desaturase 1 Contributes to the Lipogenic Effect of PXR in HepG2 Cells

The pregnane X receptor (PXR) was previously known as a xenobiotic receptor. Several recent studies suggested that PXR also played an important role in lipid homeostasis but the underlying mechanism remains to be clearly defined. In this study, we found that rifampicin, an agonist of human PXR, induced lipid accumulation in HepG2 cells. Lipid analysis showed the total cholesterol level increased. However, the free cholesterol and triglyceride levels were not changed. Treatment of HepG2 cells with rifampicin induced the expression of the free fatty acid transporter CD36 and ABCG1, as well as several lipogenic enzymes, including stearoyl-CoA desaturase-1 (SCD1), long chain free fatty acid elongase (FAE), and lecithin-cholesterol acyltransferase (LCAT), while the expression of acyl:cholesterol acetyltransferase(ACAT1) was not affected. Moreover, in PXR over-expressing HepG2 cells (HepG2-PXR), the SCD1 expression was significantly higher than in HepG2-Vector cells, even in the absence of rifampicin. Down-regulation of PXR by shRNA abolished the rifampicin-induced SCD1 gene expression in HepG2 cells. Promoter analysis showed that the human SCD1 gene promoter is activated by PXR and a novel DR-7 type PXR response element (PXRE) response element was located at -338 bp of the SCD1 gene promoter. Taken together, these results indicated that PXR activation promoted lipid synthesis in HepG2 cells and SCD1 is a novel PXR target gene. © 2013 Zhang et al

Progressive Cognitive Deficit, Motor Impairment and Striatal Pathology in a Transgenic Huntington Disease Monkey Model from Infancy to Adulthood

One of the roadblocks to developing effective therapeutics for Huntington disease (HD) is the lack of animal models that develop progressive clinical traits comparable to those seen in patients. Here we report a longitudinal study that encompasses cognitive and motor assessment, and neuroimaging of a group of transgenic HD and control monkeys from infancy to adulthood. Along with progressive cognitive and motor impairment, neuroimaging revealed a progressive reduction in striatal volume. Magnetic resonance spectroscopy at 48 months of age revealed a decrease of N-acetylaspartate (NAA), further suggesting neuronal damage/loss in the striatum. Postmortem neuropathological analyses revealed significant neuronal loss in the striatum. Our results indicate that HD monkeys share similar disease patterns with HD patients, making them potentially suitable as a preclinical HD animal model

Genetic variation in estrogen and progesterone pathway genes and breast cancer risk: an exploration of tumor subtype-specific effects

To determine whether associations between estrogen pathway-related single nucleotide polymorphisms (SNPs) and breast cancer risk differ by molecular subtype, we evaluated associations between SNPs in cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1), estrogen receptor (ESR1), 3-beta hydroxysteroid dehydrogenase type I (HSD3B1), 17-beta hydroxysteroid dehydrogenase type II (HSD17B2), progesterone receptor (PGR), and sex hormone-binding globulin (SHBG) and breast cancer risk in a case-control study in North Carolina

Mouse Organ-Specific Proteins and Functions

Organ-specific proteins (OSPs) possess great medical potential both in clinics and in biomedical research. Applications of them—such as alanine transaminase, aspartate transaminase, and troponins—in clinics have raised certain concerns of their organ specificity. The dynamics and diversity of protein expression in heterogeneous human populations are well known, yet their effects on OSPs are less addressed. Here, we used mice as a model and implemented a breadth study to examine the panorgan proteome for potential variations in organ specificity in different genetic backgrounds. Using reasonable resources, we generated panorgan proteomes of four in-bred mouse strains. The results revealed a large diversity that was more profound among OSPs than among proteomes overall. We defined a robustness score to quantify such variation and derived three sets of OSPs with different stringencies. In the meantime, we found that the enriched biological functions of OSPs are also organ-specific and are sensitive and useful to assess the quality of OSPs. We hope our breadth study can open doors to explore the molecular diversity and dynamics of organ specificity at the protein level.&nbsp