Publications by authors named "Josephine Hoh"

61 Publications

Cadmium Induces Glomerular Endothelial Cell-Specific Expression of Complement Factor H via the -1635 AP-1 Binding Site.

J Immunol 2019 02 14;202(4):1210-1218. Epub 2019 Jan 14.

Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong 250014, China;

Cadmium (Cd) is an environmental toxin that induces nephrotoxicity. Complement factor H (CFH), an inhibitor of complement activation, is involved in the pathogenesis of various renal diseases. In this study, we investigated the effects of Cd on CFH production by the kidney. In C57B6/J mice, an increased CFH level was found in renal blood and glomerular endothelial cells after Cd treatment. In vitro, Cd induces an increased CFH secretion and mRNA expression in human renal glomerular endothelial cells but not in human podocytes or human mesangial cells. Cd activates the JNK pathway and increases c-Jun and c-Fos in human renal glomerular endothelial cells. A JNK inhibitor, SP600125, specifically abolishes Cd-induced CFH production. By chromatin immunoprecipitation assay and EMSA, the -1635 AP-1 motif on human promoter was identified as the binding element for c-Jun and c-Fos. In a luciferase activity assay, mutation of the AP1 site eliminates Cd-induced increase of promoter activity. Thus, the -1635 AP-1 motif on the promoter region mediates Cd-inducible gene expression.
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http://dx.doi.org/10.4049/jimmunol.1800081DOI Listing
February 2019

Müller cells in pathological retinal angiogenesis.

Transl Res 2019 05 27;207:96-106. Epub 2018 Dec 27.

Medical Research Center, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China. Electronic address:

Müller cells are the major glial cells spanning the entire layer of the retina and maintaining retinal structure. Under pathological conditions, Müller cells are involved in retinal angiogenesis, a process of growing new blood vessels from pre-existing capillaries. In response to hypoxia, high glucose, and inflammation conditions, multiple signaling pathways are activated in Müller cells, followed by the increased production of proangiogenic factors including vascular endothelial growth factor, basic fibroblast growth factor, matrix metalloproteinases, Netrin-4, and angiopoietin-like 4. Expression of antiangiogenic factors is also downregulated in Müller cells. Besides, proliferation and dedifferentiation of Müller cells facilitates retinal angiogenesis. In this review, we summarized molecular mechanisms of Müller cells-related retinal angiogenesis. The potential of Müller cells as a therapeutic target for retinal angiogenesis was also discussed.
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http://dx.doi.org/10.1016/j.trsl.2018.12.006DOI Listing
May 2019

Gene-Centric Analysis of Preeclampsia Identifies Maternal Association at .

Hypertension 2018 08 2;72(2):408-416. Epub 2018 Jul 2.

Brigham and Women's Hospital, Boston, MA; Department of Anesthesia, Critical Care and Pain Medicine (H.M., B.T.B., R.S.).

The genetic susceptibility to preeclampsia, a pregnancy-specific complication with significant maternal and fetal morbidity, has been poorly characterized. To identify maternal genes associated with preeclampsia risk, we assembled 498 cases and 1864 controls of European ancestry from preeclampsia case-control collections in 5 different US sites (with additional matched population controls), genotyped samples on a cardiovascular gene-centric array composed of variants from ≈2000 genes selected based on prior genetic studies of cardiovascular and metabolic diseases and performed case-control genetic association analysis on 27 429 variants passing quality control. In silico replication testing of 9 lead signals with <10 was performed in independent European samples from the SOPHIA (Study of Pregnancy Hypertension in Iowa) and Inova cohorts (212 cases, 456 controls). Multiethnic assessment of lead signals was then performed in samples of black (26 cases, 136 controls), Hispanic (132 cases, 468 controls), and East Asian (9 cases, 80 controls) ancestry. Multiethnic meta-analysis (877 cases, 3004 controls) revealed a study-wide statistically significant association of the rs9478812 variant in the pleiotropic gene (odds ratio, 1.40 [1.23-1.60]; =5.90×10). The rs9478812 effect was even stronger in the subset of European cases with known early-onset preeclampsia (236 cases diagnosed <37 weeks, 1864 controls; odds ratio, 1.59 [1.27-1.98]; =4.01×10). variants have previously been implicated in genome-wide association studies of blood pressure, body weight, and neurological disorders. Although larger studies are required to further define maternal preeclampsia heritability, this study identifies a novel maternal risk locus for further investigation.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.10688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043396PMC
August 2018

BMI1 enhancer polymorphism underlies chromosome 10p12.31 association with childhood acute lymphoblastic leukemia.

Int J Cancer 2018 12 3;143(11):2647-2658. Epub 2018 Oct 3.

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.

Genome-wide association studies of childhood acute lymphoblastic leukemia (ALL) have identified regions of association at PIP4K2A and upstream of BMI1 at chromosome 10p12.31-12.2. The contribution of both loci to ALL risk and underlying functional variants remain to be elucidated. We carried out single nucleotide polymorphism (SNP) imputation across chromosome 10p12.31-12.2 in Latino and non-Latino white ALL cases and controls from two independent California childhood leukemia studies, and additional Genetic Epidemiology Research on Aging study controls. Ethnicity-stratified association analyses were performed using logistic regression, with meta-analysis including 3,133 cases (1,949 Latino, 1,184 non-Latino white) and 12,135 controls (8,584 Latino, 3,551 non-Latino white). SNP associations were identified at both BMI1 and PIP4K2A. After adjusting for the lead PIP4K2A SNP, genome-wide significant associations remained at BMI1, and vice-versa (p < 10 ), supporting independent effects. Lead SNPs differed by ethnicity at both peaks. We sought functional variants in tight linkage disequilibrium with both the lead Latino SNP among Admixed Americans and lead non-Latino white SNP among Europeans. This pinpointed rs11591377 (p = 2.1 x 10 ) upstream of BMI1, residing within a hematopoietic stem cell enhancer of BMI1, and which showed significant preferential binding of the risk allele to MYBL2 (p = 1.73 x 10 ) and p300 (p = 1.55 x 10 ) transcription factors using binomial tests on ChIP-Seq data from a SNP heterozygote. At PIP4K2A, we identified rs4748812 (p = 1.3 x 10 ), which alters a RUNX1 binding motif and demonstrated chromosomal looping to the PIP4K2A promoter. Fine-mapping chromosome 10p12 in a multi-ethnic ALL GWAS confirmed independent associations and identified putative functional variants upstream of BMI1 and at PIP4K2A.
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http://dx.doi.org/10.1002/ijc.31622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235695PMC
December 2018

GWAS in childhood acute lymphoblastic leukemia reveals novel genetic associations at chromosomes 17q12 and 8q24.21.

Nat Commun 2018 01 18;9(1):286. Epub 2018 Jan 18.

Department of Chronic Diseases Epidemiology, School of Public Health, Yale University, 60 College Street, New Haven, CT, 06520, USA.

Childhood acute lymphoblastic leukemia (ALL) (age 0-14 years) is 20% more common in Latino Americans than non-Latino whites. We conduct a genome-wide association study in a large sample of 3263 Californian children with ALL (including 1949 of Latino heritage) and 3506 controls matched on month and year of birth, sex, and ethnicity, and an additional 12,471 controls from the Kaiser Resource for Genetic Epidemiology Research on Aging Cohort. Replication of the strongest genetic associations is performed in two independent datasets from the Children's Oncology Group and the California Childhood Leukemia Study. Here we identify new risk loci on 17q12 near IKZF3/ZPBP2/GSDMB/ORMDL3, a locus encompassing a transcription factor important for lymphocyte development (IKZF3), and at an 8q24 region known for structural contacts with the MYC oncogene. These new risk loci may impact gene expression via local (four 17q12 genes) or long-range (8q24) interactions, affecting function of well-characterized hematopoietic and growth-regulation pathways.
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http://dx.doi.org/10.1038/s41467-017-02596-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773513PMC
January 2018

Loss of Complement Factor H in Plasma Increases Endothelial Cell Migration.

J Cancer 2017 15;8(12):2184-2190. Epub 2017 Jul 15.

Department of Epidemiology and Public Health, Yale University, 60 College Street, New Haven, CT 06520, USA.

Tumor growth depends on angiogenesis, the growth of new blood vessels. Complement factor H (CFH) is a plasma glycoprotein that functions as a regulator of the complement system. The aim of this study is to delineate the role of CFH in angiogenesis. A conditional null allele of the gene was generated in C57BL/6J mice by flanking the exon 3 with sites. The mice were crossed with mice to obtain the mice homozygotes of deletion (). The mice were examined by angiogenesis assays. Mouse endothelial cells were treated with media containing 5% of mouse plasma from the wildtype or mice and assayed for proliferation, viability and migration. The mice did not display any obvious abnormalities. They demonstrated a pro-angiogenic phenotype in matrigel plug assay, but not in aorta ring assay. loss of Cfh in plasma does not affect proliferation or viability, but significantly increases migration of mouse endothelial cells. Our findings suggest that plasma CFH inhibits angiogenesis by reduction of endothelial cell migration. Thus the mutation of CFH might lead to excessive tumor angiogenesis.
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http://dx.doi.org/10.7150/jca.19452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560135PMC
July 2017

Genetic predisposition to elevated levels of C-reactive protein is associated with a decreased risk for preeclampsia.

Hypertens Pregnancy 2017 Feb 22;36(1):30-35. Epub 2016 Sep 22.

a Department of Epidemiology , University of Iowa College of Public Health , Iowa City , Iowa , USA.

Objective: To examine the association between genetic predisposition to elevated C-reactive protein (CRP)and risk for preeclampsia using validated genetic loci for C-reactive protein.

Methods: Preeclampsia cases (n = 177) and normotensive controls (n = 116) were selected from live birth certificates to nulliparous Iowa women during the period August 2002-May 2005. Disease status was verified by the medical chart review. Genetic predisposition to CRP was estimated by a genetic risk score on the basis of established loci for CRP levels. Logistic regression analyses were used to evaluate the relationships between the genotype score and preeclampsia. Replication analyses were performed in an independent, US population of preeclampsia cases (n = 516) and controls (n = 1,097) of European ancestry.

Results: The genetic risk score (GRS) related to higher levels of CRP demonstrated a significantly decreased risk of preeclampsia (OR 0.89, 95% CI 0.82-0.96). When the GRS was analyzed by quartile, an inverse linear trend was observed (p = 0.0006). The results were similar after adjustments for the body mass index (BMI), smoking, and leisure-time physical activity. In the independent replication population, the association with the CRP GRS was also marginally significant (OR 0.97, 95% CI 0.92, 1.02). Meta-analysis of the two studies was statistically significant (OR 0.95, 95% CI 0.90, 0.99).

Conclusion: Our data suggest an inverse, counterintuitive association between the genetic predisposition to elevated levels of CRP and a decreased risk of preeclampsia. This suggests that the blood CRP level is a marker of preeclampsia, but it does not appear to be a factor on the causal pathway.
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http://dx.doi.org/10.1080/10641955.2016.1223303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538572PMC
February 2017

A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging.

J Vis Exp 2016 07 14(113). Epub 2016 Jul 14.

Department of Environmental Health Sciences, Yale University School of Medicine; Department of Ophthalmology, Yale University School of Medicine;

Age-related diseases are becoming increasingly prevalent and the burden continues to grow as our population ages. Effective treatments are necessary to lessen the impact of debilitating conditions but remain elusive in many cases. Only by understanding the causes and pathology of diseases associated with aging, can scientists begin to identify potential therapeutic targets and develop strategies for intervention. The most common age-related conditions are neurodegenerative disorders such as Parkinson's disease and blindness. Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly. Genome wide association studies have previously identified loci that are associated with increased susceptibility to this disease and identified two regions of interest: complement factor H (CFH) and the 10q26 locus, where the age-related maculopathy susceptibility 2 (ARMS2) and high-temperature requirement factor A1 (HtrA1) genes are located. CFH acts as a negative regulator of the alternative pathway (AP) of the complement system while HtrA1 is an extracellular serine protease. ARMS2 is located upstream of HtrA1 in the primate genome, although the gene is absent in mice. To study the effects of these genes, humanized knock-in mouse lines of Cfh and ARMS2, knockouts of Cfh, HtrA1, HtrA2, HtrA3 and HtrA4 as well as a conditional neural deletion of HtrA2 were generated. Of all the genetically engineered mice produced only mice lacking HtrA2, either systemically or in neural tissues, displayed clear phenotypes. In order to examine these mice thoroughly and systematically, an initial phenotyping schedule was established, consisting of a series of tests related to two main diseases of interest: AMD and Parkinson's. Genetically modified mice can be subjected to appropriate experiments to identify phenotypes that may be related to the associated diseases in humans. A phenotyping regimen with a mitochondrial focus is presented here alongside representative results from the tests of interest.
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http://dx.doi.org/10.3791/54136DOI Listing
July 2016

2016: A 'Mitochondria' Odyssey.

Trends Mol Med 2016 May 14;22(5):391-403. Epub 2016 Apr 14.

School of Medicine, Departments of Environmental Health Science and Ophthalmology, Yale University, New Haven, CT, USA. Electronic address:

The integration of the many roles of mitochondria in cellular function and the contribution of mitochondrial dysfunction to disease are major areas of research. Within this realm, the roles of mitochondria in immune defense, epigenetics, and stem cell (SC) development have recently come into the spotlight. With new understanding, mitochondria may bring together these seemingly unrelated fields, a crucial process in treatment and prevention for various diseases. In this review we describe novel findings in these three arenas, discussing the significance of the interplay between mitochondria and the cell nucleus in response to environmental cues. While we optimistically anticipate that further research in these areas can have a profound impact on disease management, we also bring forth some of the key questions and challenges that remain.
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http://dx.doi.org/10.1016/j.molmed.2016.03.009DOI Listing
May 2016

Generation and characterization of mice with a conditional null allele of the HtrA4 gene.

Mol Med Rep 2015 Nov 3;12(5):6768-74. Epub 2015 Sep 3.

Department of Epidemiology and Public Health, Yale University, New Haven, CT 06520, USA.

High temperature requirement factor A4 (HtrA4) is a member of the HtrA family of serine peptidases involved in regulating protein‑protein interactions. Little is known regarding the function of HtrA4 in humans and in mouse models. To gain insights into the role of HtrA4 in vivo, mice were generated with a conditional null allele of HtrA4 by flanking exons 4, 5 and 6 with loxP sites. Cre‑mediated recombination, using a ubiquitously active Rosa26‑Cre line, resulted in the deletion of the floxed region in the mouse genome. Mice homozygous for the recombinant allele (HtrA4‑/‑) were viable, fertile and appeared to be normal. The HtrA4 protein was detectable in coronary vessels and in the placenta. However, the loss of HtrA4 affected neither the basic heart nor placental functions. These mice, featuring a conditional null allele of HtrA4, may provide a valuable tool to investigate the role of HtrA4 in development and pathogenesis of coronary heart disease and preeclampsia.
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http://dx.doi.org/10.3892/mmr.2015.4291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626166PMC
November 2015

Genetic Risk Score for Essential Hypertension and Risk of Preeclampsia.

Am J Hypertens 2016 Jan 23;29(1):17-24. Epub 2015 May 23.

Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa, USA;

Background: Preeclampsia is a hypertensive complication of pregnancy characterized by novel onset of hypertension after 20 weeks gestation, accompanied by proteinuria. Epidemiological evidence suggests that genetic susceptibility exists for preeclampsia; however, whether preeclampsia is the result of underlying genetic risk for essential hypertension has yet to be investigated. Based on the hypertensive state that is characteristic of preeclampsia, we aimed to determine if established genetic risk scores (GRSs) for hypertension and blood pressure are associated with preeclampsia.

Methods: Subjects consisted of 162 preeclamptic cases and 108 normotensive pregnant controls, all of Iowa residence. Subjects' DNA was extracted from buccal swab samples and genotyped on the Affymetrix Genome-wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA). Missing genotypes were imputed using MaCH and Minimac software. GRSs were calculated for hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) using established genetic risk loci for each outcome. Regression analyses were performed to determine the association between GRS and risk of preeclampsia. These analyses were replicated in an independent US population of 516 cases and 1,097 controls of European ancestry.

Results: GRSs for hypertension, SBP, DBP, and MAP were not significantly associated with risk for preeclampsia (P > 0.189). The results of the replication analysis also yielded nonsignificant associations.

Conclusions: GRSs for hypertension and blood pressure are not associated with preeclampsia, suggesting that an underlying predisposition to essential hypertension is not on the causal pathway of preeclampsia.
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http://dx.doi.org/10.1093/ajh/hpv069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4692983PMC
January 2016

Loss of HtrA1-induced attenuation of TGF-β signaling in fibroblasts might not be the main mechanism of CARASIL pathogenesis.

Proc Natl Acad Sci U S A 2015 Apr 13;112(14):E1693. Epub 2015 Mar 13.

Department of Epidemiology and Public Health, Yale University, New Haven, CT 06520.

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http://dx.doi.org/10.1073/pnas.1500911112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4394265PMC
April 2015

Postnatal overexpression of the human ARMS2 gene does not induce abnormalities in retina and choroid in transgenic mouse models.

Invest Ophthalmol Vis Sci 2015 Feb 25;56(2):1387-8. Epub 2015 Feb 25.

Department of Epidemiology and Public Health, Yale University, New Haven, Connecticut, United States; and.

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http://dx.doi.org/10.1167/iovs.14-15914DOI Listing
February 2015

Neural-specific deletion of Htra2 causes cerebellar neurodegeneration and defective processing of mitochondrial OPA1.

PLoS One 2014 22;9(12):e115789. Epub 2014 Dec 22.

Department of Environmental Health Sciences, Yale University School of Medicine, New Haven, Connecticut, United States of America.

HTRA2, a serine protease in the intermembrane space, has important functions in mitochondrial stress signaling while its abnormal activity may contribute to the development of Parkinson's disease. Mice with a missense or null mutation of Htra2 fail to thrive, suffer striatal neuronal loss, and a parkinsonian phenotype that leads to death at 30-40 days of age. While informative, these mouse models cannot separate neural contributions from systemic effects due to the complex phenotypes of HTRA2 deficiency. Hence, we developed mice carrying a Htra2-floxed allele to query the consequences of tissue-specific HTRA2 deficiency. We found that mice with neural-specific deletion of Htra2 exhibited atrophy of the thymus and spleen, cessation to gain weight past postnatal (P) day 18, neurological symptoms including ataxia and complete penetrance of premature death by P40. Histologically, increased apoptosis was detected in the cerebellum, and to a lesser degree in the striatum and the entorhinal cortex, from P25. Even earlier at P20, mitochondria in the cerebella already exhibited abnormal morphology, including swelling, vesiculation, and fragmentation of the cristae. Furthermore, the onset of these structural anomalies was accompanied by defective processing of OPA1, a key molecule for mitochondrial fusion and cristae remodeling, leading to depletion of the L-isoform. Together, these findings suggest that HTRA2 is essential for maintenance of the mitochondrial integrity in neurons. Without functional HTRA2, a lifespan as short as 40 days accumulates a large quantity of dysfunctional mitochondria that contributes to the demise of mutant mice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0115789PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274161PMC
December 2015

Genetic Predisposition to Dyslipidemia and Risk of Preeclampsia.

Am J Hypertens 2015 Jul 17;28(7):915-23. Epub 2014 Dec 17.

Department of Epidemiology, University of Iowa College of Public Health, Iowa City, Iowa, USA;

Background: Large epidemiologic studies support the role of dyslipidemia in preeclampsia; however, the etiology of preeclampsia or whether dyslipidemia plays a causal role remains unclear. We examined the association between the genetic predisposition to dyslipidemia and risk of preeclampsia using validated genetic markers of dyslipidemia.

Methods: Preeclampsia cases (n = 164) and normotensive controls (n = 110) were selected from live birth certificates to nulliparous Iowa women during the period August 2002 to May 2005. Disease status was verified by medical chart review. Genetic predisposition to dyslipidemia was estimated by 4 genetic risk scores (GRS) (total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), and triglycerides) on the basis of established loci for blood lipids. Logistic regression analyses were used to evaluate the relationships between each of the 4 genotype scores and preeclampsia. Replication analyses were performed in an independent, US population of preeclampsia cases (n = 516) and controls (n = 1,097) of European ancestry.

Results: The GRS related to higher levels of TC, LDL-C, and triglycerides demonstrated no association with the risk of preeclampsia in either the Iowa or replication population. The GRS related to lower HDL-C was marginally associated with an increased risk for preeclampsia (odds ratio (OR) = 1.03, 95% confidence interval (CI) = 0.99-1.07; P = 0.10). In the independent replication population, the association with the HDL-C GRS was also marginally significant (OR = 1.03, 95% CI: 1.00-1.06; P = 0.04).

Conclusions: Our data suggest a potential effect between the genetic predisposition to dyslipidemic levels of HDL-C and an increased risk of preeclampsia, and, as such, suggest that dyslipidemia may be a component along the causal pathway to preeclampsia.
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http://dx.doi.org/10.1093/ajh/hpu242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542907PMC
July 2015

Protoporphyrins enhance oligomerization and enzymatic activity of HtrA1 serine protease.

PLoS One 2014 15;9(12):e115362. Epub 2014 Dec 15.

Department of Environmental Health Science, Yale University School of Public Health, New Haven, Connecticut, United States of America; Department of Ophthalmology and Visual Sciences, Yale University School of Medicine, New Haven, Connecticut, United States of America.

High temperature requirement protein A1 (HtrA1), a secreted serine protease of the HtrA family, is associated with a multitude of human diseases. However, the exact functions of HtrA1 in these diseases remain poorly understood. We seek to unravel the mechanisms of HtrA1 by elucidating its interactions with chemical or biological modulators. To this end, we screened a small molecule library of 500 bioactive compounds to identify those that alter the formation of extracellular HtrA1 complexes in the cell culture medium. An initial characterization of two novel hits from this screen showed that protoporphyrin IX (PPP-IX), a precursor in the heme biosynthetic pathway, and its metalloporphyrin (MPP) derivatives fostered the oligomerization of HtrA1 by binding to the protease domain. As a result of the interaction with MPPs, the proteolytic activity of HtrA1 against Fibulin-5, a specific HtrA1 substrate in age-related macular degeneration (AMD), was increased. This physical interaction could be abolished by the missense mutations of HtrA1 found in patients with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Furthermore, knockdown of HtrA1 attenuated apoptosis induced by PPP-IX. These results suggest that PPP-IX, or its derivatives, and HtrA1 may function as co-factors whereby porphyrins enhance oligomerization and the protease activity of HtrA1, while active HtrA1 elevates the pro-apoptotic actions of porphyrin derivatives. Further analysis of this interplay may shed insights into the pathogenesis of diseases such as AMD, CARASIL and protoporphyria, as well as effective therapeutic development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0115362PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266670PMC
May 2016

Scan statistics in human gene mapping.

Am J Hum Genet 2012 Nov;91(5):970; author reply 970-1

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http://dx.doi.org/10.1016/j.ajhg.2012.07.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487129PMC
November 2012

Stage and gene specific signatures defined by histones H3K4me2 and H3K27me3 accompany mammalian retina maturation in vivo.

PLoS One 2012 9;7(10):e46867. Epub 2012 Oct 9.

Department of Neural and Behavioral Sciences, Penn State University College of Medicine, Hershey, Pennsylvania, United States of America.

The epigenetic contribution to neurogenesis is largely unknown. There is, however, growing evidence that posttranslational modification of histones is a dynamic process that shows many correlations with gene expression. Here we have followed the genome-wide distribution of two important histone H3 modifications, H3K4me2 and H3K27me3 during late mouse retina development. The retina provides an ideal model for these studies because of its well-characterized structure and development and also the extensive studies of the retinal transcriptome and its development. We found that a group of genes expressed only in mature rod photoreceptors have a unique signature consisting of de-novo accumulation of H3K4me2, both at the transcription start site (TSS) and over the whole gene, that correlates with the increase in transcription, but no accumulation of H3K27me3 at any stage. By in silico analysis of this unique signature we have identified a larger group of genes that may be selectively expressed in mature rod photoreceptors. We also found that the distribution of H3K4me2 and H3K27me3 on the genes widely expressed is not always associated with their transcriptional levels. Different histone signatures for retinal genes with the same gene expression pattern suggest the diversities of epigenetic regulation. Genes without H3K4me2 and H3K27me3 accumulation at any stage represent a large group of transcripts never expressed in retina. The epigenetic signatures defined by H3K4me2 and H3K27me3 can distinguish cell-type specific genes from widespread transcripts and may be reflective of cell specificity during retina maturation. In addition to the developmental patterns seen in wild type retina, the dramatic changes of histone modification in the retinas of mutant animals lacking rod photoreceptors provide a tool to study the epigenetic changes in other cell types and thus describe a broad range of epigenetic events in a solid tissue in vivo.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0046867PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467275PMC
May 2013

Genome-wide association study identifies a maternal copy-number deletion in PSG11 enriched among preeclampsia patients.

BMC Pregnancy Childbirth 2012 Jun 29;12:61. Epub 2012 Jun 29.

Center for Perinatal, Pediatric and Environmental Epidemiology, Yale School of Public Health, New Haven, CT 06520, USA.

Background: Specific genetic contributions for preeclampsia (PE) are currently unknown. This genome-wide association study (GWAS) aims to identify maternal single nucleotide polymorphisms (SNPs) and copy-number variants (CNVs) involved in the etiology of PE.

Methods: A genome-wide scan was performed on 177 PE cases (diagnosed according to National Heart, Lung and Blood Institute guidelines) and 116 normotensive controls. White female study subjects from Iowa were genotyped on Affymetrix SNP 6.0 microarrays. CNV calls made using a combination of four detection algorithms (Birdseye, Canary, PennCNV, and QuantiSNP) were merged using CNVision and screened with stringent prioritization criteria. Due to limited DNA quantities and the deleterious nature of copy-number deletions, it was decided a priori that only deletions would be selected for assay on the entire case-control dataset using quantitative real-time PCR.

Results: The top four SNP candidates had an allelic or genotypic p-value between 10(-5) and 10(-6), however, none surpassed the Bonferroni-corrected significance threshold. Three recurrent rare deletions meeting prioritization criteria detected in multiple cases were selected for targeted genotyping. A locus of particular interest was found showing an enrichment of case deletions in 19q13.31 (5/169 cases and 1/114 controls), which encompasses the PSG11 gene contiguous to a highly plastic genomic region. All algorithm calls for these regions were assay confirmed.

Conclusions: CNVs may confer risk for PE and represent interesting regions that warrant further investigation. Top SNP candidates identified from the GWAS, although not genome-wide significant, may be useful to inform future studies in PE genetics.
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http://dx.doi.org/10.1186/1471-2393-12-61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3476390PMC
June 2012

Disease risk prediction with rare and common variants.

BMC Proc 2011 Nov 29;5 Suppl 9:S61. Epub 2011 Nov 29.

Department of Epidemiology and Public Health, Yale University, 60 College Street, New Haven, CT 06510, USA.

A number of studies have been conducted to investigate the predictive value of common genetic variants for complex diseases. To date, these studies have generally shown that common variants have no appreciable added predictive value over classical risk factors. New sequencing technology has enhanced the ability to identify rare variants that may have larger functional effects than common variants. One would expect rare variants to improve the discrimination power for disease risk by permitting more detailed quantification of genetic risk. Using the Genetic Analysis Workshop 17 simulated data sets for unrelated individuals, we evaluate the predictive value of rare variants by comparing prediction models built using the support vector machine algorithm with or without rare variants. Empirical results suggest that rare variants have appreciable effects on disease risk prediction.
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http://dx.doi.org/10.1186/1753-6561-5-S9-S61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3287900PMC
November 2011

Genetic signatures of exceptional longevity in humans.

PLoS One 2012 18;7(1):e29848. Epub 2012 Jan 18.

Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, United States of America.

Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different "genetic signatures" of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0029848PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3261167PMC
July 2012

A comparison of association methods correcting for population stratification in case-control studies.

Ann Hum Genet 2011 May 31;75(3):418-27. Epub 2011 Jan 31.

Department of Epidemiology and Public Health, Yale University, New Haven, CT 06510, USA.

Population stratification is an important issue in case-control studies of disease-marker association. Failure to properly account for population structure can lead to spurious association or reduced power. In this article, we compare the performance of six methods correcting for population stratification in case-control association studies. These methods include genomic control (GC), EIGENSTRAT, principal component-based logistic regression (PCA-L), LAPSTRUCT, ROADTRIPS, and EMMAX. We also include the uncorrected Armitage test for comparison. In the simulation studies, we consider a wide range of population structure models for unrelated samples, including admixture. Our simulation results suggest that PCA-L and LAPSTRUCT perform well over all the scenarios studied, whereas GC, ROADTRIPS, and EMMAX fail to correct for population structure at single nucleotide polymorphisms (SNPs) that show strong differentiation across ancestral populations. The Armitage test does not adjust for confounding due to stratification thus has inflated type I error. Among all correction methods, EMMAX has the greatest power, based on the population structure settings considered for samples with unrelated individuals. The three methods, EIGENSTRAT, PCA-L, and LAPSTRUCT, are comparable, and outperform both GC and ROADTRIPS in almost all situations.
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http://dx.doi.org/10.1111/j.1469-1809.2010.00639.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215268PMC
May 2011

A pilot genome-wide association study shows genomic variants enriched in the non-tumor cells of patients with well-differentiated neuroendocrine tumors of the ileum.

Endocr Relat Cancer 2011 Feb 13;18(1):171-80. Epub 2011 Jan 13.

Department of Epidemiology and Public Health, Yale University, 60 College Street, New Haven, Connecticut 06520, USA.

Genetic studies of midgut carcinoid cancer have exclusively focused on genomic changes of the tumor cells. We investigated the role of constitutional genetic polymorphisms in predisposing individuals to ileal carcinoids. In all, 239 cases and 110 controls were collected from three institutions: the Uppsala University Hospital; the Dana-Farber Cancer Institute; and the MD Anderson Cancer Center, and were genotyped using microarrays assaying >300 000 single nucleotide polymorphisms. Association with rs2208059 in KIF16B approached statistical significance (Mantel-Haenszel odds ratio=2.42, P=4.16×10(-7)) at a Bonferroni-corrected level (<1.62×10(-7)). Using two computational algorithms, four copy-number variants (CNVs) were identified in multiple cases that were absent in study controls and markedly less frequent in ∼1500 population-based controls. Of these four constitutional CNVs identified in blood-derived DNA, a 40 kb heterozygous deletion in Chr18q22.1 corresponded with a region frequently showing loss of heterozygosity (LOH) in ileal carcinoid tumor cells based on our meta-analysis of previously published cytogenetic studies (69.7% LOH, 95% confidence interval=60.0-77.9%). We analyzed the constitutional 40 kb deletion on chr18 in our study samples with a real-time quantitative PCR assay; 14/226 cases (6.19%) and 2/97 controls (2.06%) carried the CNV, although the exact boundaries of each deletion have not been determined. Given the small sample size, our findings warrant an independent cohort for a replication study. Owing to the rarity of this disease, we believe these results will provide a valuable resource for future work on this serious condition by allowing others to make efficient use of their samples in targeted studies.
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http://dx.doi.org/10.1677/ERC-10-0248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3221459PMC
February 2011

Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma.

Nat Genet 2010 Oct 12;42(10):906-9. Epub 2010 Sep 12.

deCODE genetics Inc, Reykjavik, Iceland.

We conducted a genome-wide association study for primary open-angle glaucoma (POAG) in 1,263 affected individuals (cases) and 34,877 controls from Iceland. We identified a common sequence variant at 7q31 (rs4236601[A], odds ratio (OR) = 1.36, P = 5.0 × 10⁻¹⁰). We then replicated the association in sample sets of 2,175 POAG cases and 2,064 controls from Sweden, the UK and Australia (combined OR = 1.18, P = 0.0015) and in 299 POAG cases and 580 unaffected controls from Hong Kong and Shantou, China (combined OR = 5.42, P = 0.0021). The risk variant identified here is located close to CAV1 and CAV2, both of which are expressed in the trabecular meshwork and retinal ganglion cells that are involved in the pathogenesis of POAG.
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http://dx.doi.org/10.1038/ng.661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3222888PMC
October 2010

Association between reduced copy-number at T-cell receptor gamma (TCRgamma) and childhood allergic asthma: A possible role for somatic mosaicism.

Mutat Res 2010 Aug 27;690(1-2):89-94. Epub 2010 May 27.

Center for Perinatal Pediatric and Environmental Epidemiology, Yale School of Public Health, New Haven, CT 06510, USA.

Asthma is a chronic inflammatory disease of the lungs which affects more than 6.5 million American children. A family-based genome-wide association study of copy-number variation identified an association between decreased copy-number at TCRgamma and childhood allergic asthma. TCRgamma encodes the T-cell receptor gamma glycoprotein, a cell-surface protein found on T-cells and involved in cell-mediated immunity. Using quantitative real-time PCR, we sought to determine if copy-number variation at TCRalpha, TCRbeta or TCRgamma was associated with childhood allergic asthma in an independent cohort of 94 cases and 455 controls using DNA from buccal swabs. Copy-number variation at these loci is well-known, but appears to be dominated by somatic mutations. Genotyping results indicated that copy-number variants at these genes are largely somatic mutations, as inheritance did not show Mendelian consistency. In these mosaic cell populations, copy-number was significantly reduced among asthmatic children at TCRgamma (p=0.0199), but was not associated at TCRalpha or TCRbeta (p=0.7972 and 0.8585, respectively). These findings support the association between reduced copy-number at TCRgamma and childhood allergic asthma. Further work is needed to resolve whether reduced copy-number at TCRgamma predisposes individuals to asthma, or whether deletion of this gene is a somatic response to the disease.
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http://dx.doi.org/10.1016/j.mrfmmm.2010.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2914201PMC
August 2010

A genome-wide association study on African-ancestry populations for asthma.

J Allergy Clin Immunol 2010 Feb 11;125(2):336-346.e4. Epub 2009 Nov 11.

Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA.

Background: Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed.

Objectives: We sought to test the hypothesis that some genes might contribute to the profound disparities in asthma.

Methods: We performed a genome-wide association study in 2 independent populations of African ancestry (935 African American asthmatic cases and control subjects from the Baltimore-Washington, DC, area and 929 African Caribbean asthmatic subjects and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma.

Results: A meta-analysis combining these 2 African-ancestry populations yielded 3 SNPs with a combined P value of less than 10(-5) in genes of potential biologic relevance to asthma and allergic disease: rs10515807, mapping to the alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 x 10(-6)); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 x 10(-6)); and rs1435879, mapping to the dipeptidyl peptidase 10 (DPP10) gene on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of United Kingdom and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Evidence for association was also examined in 4 additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated.

Conclusions: This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease, such as asthma, in admixed populations, especially populations of African descent.
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http://dx.doi.org/10.1016/j.jaci.2009.08.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606015PMC
February 2010

Common variants on chromosome 2 and risk of primary open-angle glaucoma in the Afro-Caribbean population of Barbados.

Proc Natl Acad Sci U S A 2009 Oct 24;106(40):17105-10. Epub 2009 Sep 24.

Ophthalmic Genetics and Visual Function Branch, National Eye Institute, and Barbados Family Study Group, National Institutes of Health, Bethesda, MD 20892, USA.

Primary open-angle glaucoma (POAG) is the second leading cause of blindness worldwide. Although a number of genetic loci have shown association or genetic linkage to monogenic forms of POAG, the identified genes and loci do not appear to have a major role in the common POAG phenotype. We seek to identify genetic loci that appear to be major risk factors for POAG in the Afro-Caribbean population of Barbados, West Indies. We performed linkage analyses in 146 multiplex families ascertained through the Barbados Family Study of Glaucoma (BFSG) and identified a strong linkage signal on chromosome 2p (logarithm of odds score = 6.64 at = 0 with marker D2S2156). We subsequently performed case-control analyses using unrelated affected individuals and unaffected controls. A set of SNPs on chromosome 2p was evaluated in two independent groups of BFSG participants, a discovery group (130 POAG cases, 65 controls) and a replication group (122 POAG cases, 65 controls), and a strong association was identified with POAG and rs12994401 in both groups (P < 3.34 E-09 and P < 1.21E-12, respectively). The associated SNPs form a common disease haplotype. In summary, we have identified a locus with a major impact on susceptibility to the common POAG phenotype in an Afro-Caribbean population in Barbados. Our approach illustrates the merit of using an isolated population enriched with common disease variants as an efficient method to identify genetic underpinning of POAG.
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http://dx.doi.org/10.1073/pnas.0907564106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761374PMC
October 2009

CCR3: Shedding new light on a dark problem?

J Mol Cell Biol 2009 Oct 14;1(1):17-9. Epub 2009 Aug 14.

Yale University School of Medicine, New Haven, CT 06510, USA.

A recent work by Ambati et al. represents a bold step towards a more effective diagnosis and treatment of age-related macular degeneration, with the new evidence showing that CCR3, a chemokine receptor, is an early marker of and potential therapeutic target for choroidal neovascularization development. In the wake of such a novel and significant finding, additional illumination to confirm and consolidate the promise shown by CCR3 will soon follow.
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http://dx.doi.org/10.1093/jmcb/mjp011DOI Listing
October 2009

Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: a meta-analysis.

JAMA 2009 Jun;301(23):2462-71

Institute for Human Genetics, University of California at San Francisco, and Kaiser Permanente Northern California Division of Research, Oakland, USA.

Context: Substantial resources are being devoted to identify candidate genes for complex mental and behavioral disorders through inclusion of environmental exposures following the report of an interaction between the serotonin transporter linked polymorphic region (5-HTTLPR) and stressful life events on an increased risk of major depression.

Objective: To conduct a meta-analysis of the interaction between the serotonin transporter gene and stressful life events on depression using both published data and individual-level original data.

Data Sources: Search of PubMed, EMBASE, and PsycINFO databases through March 2009 yielded 26 studies of which 14 met criteria for the meta-analysis.

Study Selection: Criteria for studies for the meta-analyses included published data on the association between 5-HTTLPR genotype (SS, SL, or LL), number of stressful life events (0, 1, 2, > or = 3) or equivalent, and a categorical measure of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) or the International Statistical Classification of Diseases, 10th Revision (ICD-10) or use of a cut point to define depression from standardized rating scales. To maximize our ability to use a common framework for variable definition, we also requested original data from all studies published prior to 2008 that met inclusion criteria. Of the 14 studies included in the meta-analysis, 10 were also included in a second sex-specific meta-analysis of original individual-level data.

Data Extraction: Logistic regression was used to estimate the effects of the number of short alleles at 5-HTTLPR, the number of stressful life events, and their interaction on depression. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated separately for each study and then weighted averages of the individual estimates were obtained using random-effects meta-analysis. Both sex-combined and sex-specific meta-analyses were conducted. Of a total of 14,250 participants, 1769 were classified as having depression; 12,481 as not having depression.

Results: In the meta-analysis of published data, the number of stressful life events was significantly associated with depression (OR, 1.41; 95% CI,1.25-1.57). No association was found between 5-HTTLPR genotype and depression in any of the individual studies nor in the weighted average (OR, 1.05; 95% CI, 0.98-1.13) and no interaction effect between genotype and stressful life events on depression was observed (OR, 1.01; 95% CI, 0.94-1.10). Comparable results were found in the sex-specific meta-analysis of individual-level data.

Conclusion: This meta-analysis yielded no evidence that the serotonin transporter genotype alone or in interaction with stressful life events is associated with an elevated risk of depression in men alone, women alone, or in both sexes combined.
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http://dx.doi.org/10.1001/jama.2009.878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2938776PMC
June 2009