Germline Mutations in CIDEB and Protection against Liver Disease.

BACKGROUND: Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets. METHODS: We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations. RESULTS: The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased aminotransferase levels and an increased risk of liver disease. We also found that variants in CIDEB, which encodes a structural protein found in hepatic lipid droplets, had a protective effect. The burden of rare predicted loss-of-function variants plus missense variants in CIDEB (combined carrier frequency, 0.7%) was associated with decreased alanine aminotransferase levels (beta per allele, -1.24 U per liter; 95% confidence interval [CI], -1.66 to -0.83; P = 4.8×10-9) and with 33% lower odds of liver disease of any cause (odds ratio per allele, 0.67; 95% CI, 0.57 to 0.79; P = 9.9×10-7). Rare coding variants in CIDEB were associated with a decreased risk of liver disease across different underlying causes and different degrees of severity, including cirrhosis of any cause (odds ratio per allele, 0.50; 95% CI, 0.36 to 0.70). Among 3599 patients who had undergone bariatric surgery, rare coding variants in CIDEB were associated with a decreased nonalcoholic fatty liver disease activity score (beta per allele in score units, -0.98; 95% CI, -1.54 to -0.41 [scores range from 0 to 8, with higher scores indicating more severe disease]). In human hepatoma cell lines challenged with oleate, CIDEB small interfering RNA knockdown prevented the buildup of large lipid droplets. CONCLUSIONS: Rare germline mutations in CIDEB conferred substantial protection from liver disease. (Funded by Regeneron Pharmaceuticals.).

Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism.

Less than half of human zygotes survive to birth, primarily due to aneuploidies of meiotic or mitotic origin. Mitotic errors generate chromosomal mosaicism, defined by multiple cell lineages with distinct chromosome complements. The incidence and impacts of mosaicism in human embryos remain controversial, with most previous studies based on bulk DNA assays or comparisons of multiple biopsies of few embryonic cells. Single-cell genomic data provide an opportunity to quantify mosaicism on an embryo-wide scale. To this end, we extended an approach to infer aneuploidies based on dosage-associated changes in gene expression by integrating signatures of allelic imbalance. We applied this method to published single-cell RNA sequencing data from 74 human embryos, spanning the morula to blastocyst stages. Our analysis revealed widespread mosaic aneuploidies, with 59 of 74 (80%) embryos harboring at least one putative aneuploid cell (1% FDR). By clustering copy number calls, we reconstructed histories of chromosome segregation, inferring that 55 (74%) embryos possessed mitotic aneuploidies and 23 (31%) embryos possessed meiotic aneuploidies. We found no significant enrichment of aneuploid cells in the trophectoderm compared to the inner cell mass, although we do detect such enrichment in data from later postimplantation stages. Finally, we observed that aneuploid cells up-regulate immune response genes and down-regulate genes involved in proliferation, metabolism, and protein processing, consistent with stress responses documented in other stages and systems. Together, our work provides a high-resolution view of aneuploidy in preimplantation embryos, and supports the conclusion that low-level mosaicism is a common feature of early human development.

The outcomes of nurse practitioner (NP)-Provided home visits: A systematic review.

BACKGROUND: With the shortage of primary care providers to provide home-based care to the growing number of homebound older adults in the U.S. Nurse Practitioners (NPs) are increasingly utilized to meet the growing demand for home-based care and are now the largest type of primary care providers delivering home-visits. PURPOSE: The purpose of this study was to systematically examine the current state of the evidence on health and healthcare utilization outcomes associated with NP-home visits. METHOD: Five Databases (PubMed, EMBASE, Cumulative Index to Nursing and Allied Health Literature and the Cochrane Library) were systematically searched to identify studies examining NP-home visits. The search focused on English language studies that were published before April 2019 and sought to describe the outcomes associated with NP-home visits. We included experimental and observational studies.  Quality appraisal was performed with the Kmet, Lee & Cook tool, and results summarized qualitatively. The impact of NP-home visits on clinical (functional status, quality of life [QOL]), and healthcare utilization (hospitalization, Emergency department(ED) visits) outcomes was evaluated. RESULTS/DISCUSSION: A total of 566 citations were identified; 7 met eligibility criteria and were included in the review. The most commonly reported outcomes were emergency department (ED) visits and readmissions. Given the limited number of articles generated by our search and wide variation in intervention and outcomes measures. NP-home visits were associated with reductions in ED visits in 2 out of 3 studies and with reduction in readmissions in 2 out of 4 studies. CONCLUSION: Published studies evaluating the outcomes associated with NP-home visits are limited and of mixed quality. Limitations include small sample size, and variation in duration and frequency of NP-home visits. Future studies should investigate the independent effect of NP-home visits on the health outcomes of older adults using large and nationally representative data with more rigorous study design.

Converging evidence from exome sequencing and common variants implicates target genes for osteoporosis.

In this study, we leveraged the combined evidence of rare coding variants and common alleles to identify therapeutic targets for osteoporosis. We undertook a large-scale multiancestry exome-wide association study for estimated bone mineral density, which showed that the burden of rare coding alleles in 19 genes was associated with estimated bone mineral density (P < 3.6 × 10-7). These genes were highly enriched for a set of known causal genes for osteoporosis (65-fold; P = 2.5 × 10-5). Exome-wide significant genes had 96-fold increased odds of being the top ranked effector gene at a given GWAS locus (P = 1.8 × 10-10). By integrating proteomics Mendelian randomization evidence, we prioritized CD109 (cluster of differentiation 109) as a gene for which heterozygous loss of function is associated with higher bone density. CRISPR-Cas9 editing of CD109 in SaOS-2 osteoblast-like cell lines showed that partial CD109 knockdown led to increased mineralization. This study demonstrates that the convergence of common and rare variants, proteomics and CRISPR can highlight new bone biology to guide therapeutic development.

Economic Empowerment and Tolerance of Domestic Violence Among Married Women: A Cross-Sectional Study.

We evaluated whether markers of economic empowerment are associated with a tolerant attitude toward spousal physical violence (SPV) among employed married women in Nigeria. Cross-sectional analyses of responses to the 2013 Nigeria Demographic Health Survey by a nationally representative sample of 3,999 women aged 15 to 49 years who reported being employed and married. Tolerance for SPV was defined as supporting statements with justifications for wife-beating. Logistic regression assessed the associations of reporting tolerance for SPV with educational attainment and interspousal equivalency in income, controlling for previous exposure to domestic abuse. The prevalence of tolerance for SPV among the sample was 37%. Women with tertiary education had lower odds of tolerance for SPV relative to their counterparts without formal education (adjusted odds ratio [aOR] = 0.22, 95% confidence interval [CI] = [0.12, 0.40], p < .0001). Compared with women with similar income levels as their partners, women who either earned more (aOR = 2.77, 95% CI = [1.36, 5.62], p = .005) or earned less income relative to their spouses (aOR = 1.93, 95% CI = [1.14, 3.26], p = .02) had higher odds of tolerance for SPV. Odds of tolerance for SPV were also higher among women reporting previous spousal abuse than among their counterparts without such a history (aOR = 1.55, 95% CI = [1.14, 2.12], p = .006). A history of nonspousal abuse was associated with lower odds of tolerance for SPV (aOR = 0.56, 95% CI = [0.37, 0.84], p = .005). Lower educational attainment and interspousal differences in income may contribute to tolerance of SPV. Efforts to increase economic empowerment should be combined with education to recognize cultural norms that foster SPV and build skills to exit violent relationships.

Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes.

Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10-09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin ßE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.

Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity.

Large-scale human exome sequencing can identify rare protein-coding variants with a large impact on complex traits such as body adiposity. We sequenced the exomes of 645,626 individuals from the United Kingdom, the United States, and Mexico and estimated associations of rare coding variants with body mass index (BMI). We identified 16 genes with an exome-wide significant association with BMI, including those encoding five brain-expressed G protein-coupled receptors (CALCR, MC4R, GIPR, GPR151, and GPR75). Protein-truncating variants in GPR75 were observed in ~4/10,000 sequenced individuals and were associated with 1.8 kilograms per square meter lower BMI and 54% lower odds of obesity in the heterozygous state. Knock out of Gpr75 in mice resulted in resistance to weight gain and improved glycemic control in a high-fat diet model. Inhibition of GPR75 may provide a therapeutic strategy for obesity.

Home Health Agency Factors Associated With Acute Care Hospitalization and Emergency Department Use.

We linked the Medicare Provider Utilization and Payment Data for Home Health and the Home Health Compare data for the year 2016 to identify home healthcare agency (HHA) characteristics associated with acute care hospitalization (ACH) or emergency department (ED) use. The study cohort consisted of 9,800 HHAs. Beta regression was used to examine the association between average age, race/ethnic composition, number of skilled nursing visits, number of therapy visits, percentage of dual eligible patients, HHA ownership, HHA location, Medicare tenure, proportion of patients with a diagnosis of schizophrenia, stroke, diabetes, depression, chronic obstructive pulmonary disease (COPD), heart failure, cancer and Alzheimer disease, and ACH or ED use. After controlling for HHA-level characteristics, variations in HHAs' ACH and unplanned ED visits were found. For-profit HHAs were significantly less likely to have patients with ACH. (Odds ratio = -0.05, p = 0.020), HHAs in the Midwest, South, and West had lower odds of ACH. HHAs that serve more than 50% Black patients had significantly decreased odds (ß = -0.16, p < 0.001) of ACH. A 1-unit increase in the proportion of patients with a diagnosis of schizophrenia, COPD, stroke, heart failure, and Alzheimer disease was associated with increased odds of hospitalization. For each unit increase in the number of skilled nursing visits, the odds of ACH increased by 0.02 (p = 0.001). For-profit and nonprofit HHAs had a significant decrease in the odds of unplanned ED visits (p < 0.05). An increase in the proportion of patients with COPD was associated with increased odds of unplanned ED visits (p < 0.001). HHA characteristics are associated with hospitalization and ED use without hospitalization. These characteristics point to variation in quality of care measured by ACH and ED use.

Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes.

We determined differential gene expression in response to high glucose in lymphoblastoid cell lines derived from matched individuals with type 1 diabetes with and without retinopathy. Those genes exhibiting the largest difference in glucose response were assessed for association with diabetic retinopathy in a genome-wide association study meta-analysis. Expression quantitative trait loci (eQTLs) of the glucose response genes were tested for association with diabetic retinopathy. We detected an enrichment of the eQTLs from the glucose response genes among small association p-values and identified folliculin (FLCN) as a susceptibility gene for diabetic retinopathy. Expression of FLCN in response to glucose was greater in individuals with diabetic retinopathy. Independent cohorts of individuals with diabetes revealed an association of FLCN eQTLs with diabetic retinopathy. Mendelian randomization confirmed a direct positive effect of increased FLCN expression on retinopathy. Integrating genetic association with gene expression implicated FLCN as a disease gene for diabetic retinopathy.

One of the side effects of diabetes is loss of vision from diabetic retinopathy, which is caused by injury to the light sensing tissue in the eye, the retina. Almost all individuals with diabetes develop diabetic retinopathy to some extent, and it is the leading cause of irreversible vision loss in working-age adults in the United States. How long a person has been living with diabetes, the extent of increased blood sugars and genetics all contribute to the risk and severity of diabetic retinopathy. Unfortunately, virtually no genes associated with diabetic retinopathy have yet been identified. When a gene is activated, it produces messenger molecules known as mRNA that are used by cells as instructions to produce proteins. The analysis of mRNA molecules, as well as genes themselves, can reveal the role of certain genes in disease. The studies of all genes and their associated mRNAs are respectively called genomics and transcriptomics. Genomics reveals what genes are present, while transcriptomics shows how active genes are in different cells. Skol et al. developed methods to study genomics and transcriptomics together to help discover genes that cause diabetic retinopathy. Genes involved in how cells respond to high blood sugar were first identified using cells grown in the lab. By comparing the activity of these genes in people with and without retinopathy the study identified genes associated with an increased risk of retinopathy in diabetes. In people with retinopathy, the activity of the folliculin gene (FLCN) increased more in response to high blood sugar. This was further verified with independent groups of people and using computer models to estimate the effect of different versions of the folliculin gene. The methods used here could be applied to understand complex genetics in other diseases. The results provide new understanding of the effects of diabetes. They may also help in the development of new treatments for diabetic retinopathy, which are likely to improve on the current approach of using laser surgery or injections into the eye.

Author Correction: Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration.

In the version of this article initially published, in Supplementary Data 5, the logFC, FC, P value and adjusted P value for advanced AMD versus control (DE 4/1) without age correction did not correspond to the correct gene IDs. The errors have been corrected in the HTML version of the article.

Retinal transcriptome and eQTL analyses identify genes associated with age-related macular degeneration.

Genome-wide association studies (GWAS) have identified genetic variants at 34 loci contributing to age-related macular degeneration (AMD)1-3. We generated transcriptional profiles of postmortem retinas from 453 controls and cases at distinct stages of AMD and integrated retinal transcriptomes, covering 13,662 protein-coding and 1,462 noncoding genes, with genotypes at more than 9 million common SNPs for expression quantitative trait loci (eQTL) analysis of a tissue not included in Genotype-Tissue Expression (GTEx) and other large datasets4,5. Cis-eQTL analysis identified 10,474 genes under genetic regulation, including 4,541 eQTLs detected only in the retina. Integrated analysis of AMD-GWAS with eQTLs ascertained likely target genes at six reported loci. Using transcriptome-wide association analysis (TWAS), we identified three additional genes, RLBP1, HIC1 and PARP12, after Bonferroni correction. Our studies expand the genetic landscape of AMD and establish the Eye Genotype Expression (EyeGEx) database as a resource for post-GWAS interpretation of multifactorial ocular traits.

Ambulatory Medication Reconciliation and Frequency of Hospitalizations and Emergency Department Visits in Patients With Diabetes.

OBJECTIVE: To investigate the association between ambulatory medication reconciliation and health care utilization in patients with diabetes. RESEARCH DESIGN AND METHODS: In this retrospective cohort analysis, we studied adults taking at least one diabetes medication treated in primary care practices affiliated with two academic medical centers between 2000 and 2014. We assessed the relationship between the fraction of outpatient diabetes medications reconciled over a 6-month period and the composite primary outcome of combined frequency of emergency department (ED) visits and hospitalizations over the subsequent 6 months. RESULTS: Among 261,765 reconciliation assessment periods contributed by 31,689 patients, 176,274 (67.3%), 27,775 (10.6%), and 57,716 (22.1%) had all, some, or none of the diabetes medications reconciled, respectively. Patients with all, some, or no diabetes medications reconciled had 0.354, 0.377, and 0.384 primary outcome events per 6 months, respectively (P < 0.0001). In a multivariable analysis adjusted for demographics and comorbidities, having some or all versus no diabetes medications reconciled was associated with a lower risk of the primary outcome (rate ratio 0.94 [95% CI 0.90-0.98; P = 0.0046] vs. 0.92 [0.89-0.95; P < 0.0001], respectively). Introduction of feedback to individual providers was associated with a significant increase in the odds of all diabetes medications being reconciled (2.634 [2.524-2.749]; P < 0.0001). CONCLUSIONS: A higher fraction of reconciled outpatient diabetes medications was associated with a lower frequency of ED visits and hospitalizations. Individual performance feedback could help to achieve more comprehensive medication reconciliation.