A genetic basis for atopic dermatitis (AD) has long been recognized. Historic documents allude to family history of disease as a risk factor. Before characterization of the human genome, heritability ...studies combined with family-based linkage studies supported the definition of AD as a complex trait in that interactions between genes and environmental factors and the interplay between multiple genes contribute to disease manifestation. A summary of more than 100 published reports on genetic association studies through mid-2009 implicates 81 genes, in 46 of which at least 1 positive association with AD has been demonstrated. Of these, the gene encoding filaggrin (FLG) has been most consistently replicated. Most candidate gene studies to date have focused on adaptive and innate immune response genes, but there is increasing interest in skin barrier dysfunction genes. This review examines the methods that have been used to identify susceptibility genes for AD and how the underlying pathology of this disease has been used to select candidate genes. Current challenges and the potential effect of new technologies are discussed.
Identifying the ancestry of chromosomal segments of distinct ancestry has a wide range of applications from disease mapping to learning about history. Most methods require the use of unlinked ...markers; but, using all markers from genome-wide scanning arrays, it should in principle be possible to infer the ancestry of even very small segments with exquisite accuracy. We describe a method, HAPMIX, which employs an explicit population genetic model to perform such local ancestry inference based on fine-scale variation data. We show that HAPMIX outperforms other methods, and we explore its utility for inferring ancestry, learning about ancestral populations, and inferring dates of admixture. We validate the method empirically by applying it to populations that have experienced recent and ancient admixture: 935 African Americans from the United States and 29 Mozabites from North Africa. HAPMIX will be of particular utility for mapping disease genes in recently admixed populations, as its accurate estimates of local ancestry permit admixture and case-control association signals to be combined, enabling more powerful tests of association than with either signal alone.
Asthma and atopic dermatitis (AD) are complex diseases with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. Here we summarize current ...knowledge from asthma and AD genome-wide association studies (GWAS) and pharmacogenetic studies in African ancestry populations.
GWAS catalog; PUBMed.
GWAS catalog studies with trait annotations "asthma" and "atopic eczema" and African ancestry individuals in the discovery dataset; the recent CAAPA asthma GWAS; reports on pharmacogenetic studies in asthma and AD.
Although GWASs have revolutionized gene discovery for multiple complex traits, African Americans continue to be severely underrepresented in sufficiently powered genetics studies. Indeed, of the 16 asthma and 21 AD loci that reached genomewide significance in Europeans, very few have replicated in African ancestry populations. Challenges in comparing results from European vs African ancestry cohorts include modest sample size, differences in risk allele frequency, effect size, correlation between genetic variants, and environmental exposure in evolutionary history. African Americans also constitute a small percentage of dermatological and respiratory-focused clinical trials. Pharmacogenetic studies have similarly been focused largely on non-Hispanic whites, despite compelling evidence that genetic variation from different ancestral backgrounds may alter therapeutic efficacy of asthma and AD drugs.
Large-scale genetic studies of asthma and AD in African Americans are essential to reduce research and health disparities and empower scientific discoveries.
Background Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by a defective skin barrier function. Recent studies have reported mutations of the skin barrier gene ...encoding filaggrin in a subset of patients with AD. Objective We investigated whether reduced filaggrin expression was found in patients with AD who were not carriers of known filaggrin mutations and whether filaggrin expression was modulated by the atopic inflammatory response. Methods Filaggrin expression was measured in skin biopsies and cultured keratinocytes using real-time RT-PCR and immunohistochemistry. Filaggrin loss-of-function mutations were screened in a total of 69 subjects. Results Compared with normal skin, filaggrin expression was significantly reduced ( P < .05) in acute AD skin, with further reduction seen in acute lesions from 3 European American subjects with AD who were heterozygous for the 2282del4 mutation. This was confirmed by using immunohistochemistry. AD skin is characterized by the overexpression of IL-4 and IL-13. Keratinocytes differentiated in the presence of IL-4 and IL-13 exhibited significantly reduced filaggrin gene expression (0.04 ± 0.01 ng filaggrin/ng glyceraldehyde 3-phosphate dehydrogenase; P < .05) compared with media alone (0.16 ± 0.03). Conclusion Patients with AD have an acquired defect in filaggrin expression that can be modulated by the atopic inflammatory response. Clinical implications The atopic immune response contributes to the skin barrier defect in AD; therefore, neutralization of IL-4 and IL-13 could improve skin barrier integrity.
Background Atopic dermatitis (AD) is a chronic inflammatory skin disease that is characterized by a defective skin barrier function. Recent studies have reported mutations of the skin barrier gene ...encoding filaggrin in a subset of patients with AD. Objective We investigated whether reduced filaggrin expression was found in patients with AD who were not carriers of known filaggrin mutations and whether filaggrin expression was modulated by the atopic inflammatory response. Methods Filaggrin expression was measured in skin biopsies and cultured keratinocytes using real-time RT-PCR and immunohistochemistry. Filaggrin loss-of-function mutations were screened in a total of 69 subjects. Results Compared with normal skin, filaggrin expression was significantly reduced ( P < .05) in acute AD skin, with further reduction seen in acute lesions from 3 European American subjects with AD who were heterozygous for the 2282del4 mutation. This was confirmed by using immunohistochemistry. AD skin is characterized by the overexpression of IL-4 and IL-13. Keratinocytes differentiated in the presence of IL-4 and IL-13 exhibited significantly reduced filaggrin gene expression (0.04 ± 0.01 ng filaggrin/ng glyceraldehyde 3-phosphate dehydrogenase; P < .05) compared with media alone (0.16 ± 0.03). Conclusion Patients with AD have an acquired defect in filaggrin expression that can be modulated by the atopic inflammatory response. Clinical implications The atopic immune response contributes to the skin barrier defect in AD; therefore, neutralization of IL-4 and IL-13 could improve skin barrier integrity.
Long chain polyunsaturated fatty acids (LC-PUFAs) are essential for brain structure, development, and function, and adequate dietary quantities of LC-PUFAs are thought to have been necessary for both ...brain expansion and the increase in brain complexity observed during modern human evolution. Previous studies conducted in largely European populations suggest that humans have limited capacity to synthesize brain LC-PUFAs such as docosahexaenoic acid (DHA) from plant-based medium chain (MC) PUFAs due to limited desaturase activity. Population-based differences in LC-PUFA levels and their product-to-substrate ratios can, in part, be explained by polymorphisms in the fatty acid desaturase (FADS) gene cluster, which have been associated with increased conversion of MC-PUFAs to LC-PUFAs. Here, we show evidence that these high efficiency converter alleles in the FADS gene cluster were likely driven to near fixation in African populations by positive selection ∼85 kya. We hypothesize that selection at FADS variants, which increase LC-PUFA synthesis from plant-based MC-PUFAs, played an important role in allowing African populations obligatorily tethered to marine sources for LC-PUFAs in isolated geographic regions, to rapidly expand throughout the African continent 60-80 kya.
We propose in this paper a unified approach for testing the association between rare variants and phenotypes in sequencing association studies. This approach maximizes power by adaptively using the ...data to optimally combine the burden test and the nonburden sequence kernel association test (SKAT). Burden tests are more powerful when most variants in a region are causal and the effects are in the same direction, whereas SKAT is more powerful when a large fraction of the variants in a region are noncausal or the effects of causal variants are in different directions. The proposed unified test maintains the power in both scenarios. We show that the unified test corresponds to the optimal test in an extended family of SKAT tests, which we refer to as SKAT-O. The second goal of this paper is to develop a small-sample adjustment procedure for the proposed methods for the correction of conservative type I error rates of SKAT family tests when the trait of interest is dichotomous and the sample size is small. Both small-sample-adjusted SKAT and the optimal unified test (SKAT-O) are computationally efficient and can easily be applied to genome-wide sequencing association studies. We evaluate the finite sample performance of the proposed methods using extensive simulation studies and illustrate their application using the acute-lung-injury exome-sequencing data of the National Heart, Lung, and Blood Institute Exome Sequencing Project.
Studies in humans and animal models have demonstrated that acute kidney injury (AKI) has a significant effect on the function of extrarenal organs. The combination of AKI and lung dysfunction is ...associated with 80% mortality; the lung, because of its extensive capillary network, is a prime target for AKI-induced effects. The study presented here tested the hypothesis that AKI leads to a vigorous inflammatory response and produces distinct genomic signatures in the kidney and lung. In a murine model of ischemic AKI, prominent global transcriptomic changes and histologic injury in both kidney and lung tissues were identified. These changes were evident at both early (6 h) and late (36 h) timepoints after 60-min bilateral kidney ischemia and were more prominent than similar timepoints after sham surgery or 30 min of ischemia. The inflammatory transcriptome (109 genes) of both organs changed with marked similarity, including the innate immunity genes Cd14, Socs3, Saa3, Lcn2, and Il1r2. Functional genomic analysis of these genes suggested that IL-10 and IL-6 signaling was involved in the distant effects of local inflammation, and this was supported by increased serum levels of IL-10 and IL-6 after ischemia-reperfusion. In summary, this is the first comprehensive analysis of concomitant inflammation-associated transcriptional changes in the kidney and a remote organ during AKI. Functional genomic analysis identified potential mediators that connect local and systemic inflammation, suggesting that this type of analysis may be a useful discovery tool for novel biomarkers and therapeutic drug development.
Background The genetic determinants of the human innate immune response are poorly understood. Apolipoprotein (Apo) E, a lipid-trafficking protein that affects inflammation, has well-described ...wild-type (ε3) and disease-associated (ε2 and ε4) alleles, but its connection to human innate immunity is undefined. Objective We sought to define the relationship of APOε4 to the human innate immune response. Methods We evaluated APOε4 in several functional models of the human innate immune response, including intravenous LPS challenge in human subjects, and assessed APOε4 association to organ injury in patients with severe sepsis, a disease driven by dysregulated innate immunity. Results Whole blood from healthy APOε3 / APOε4 volunteers induced higher cytokine levels on ex vivo stimulation with Toll-like receptor (TLR) 2, TLR4, or TLR5 ligands than blood from APOε3 / APOε3 patients, whereas TLR7/8 responses were similar. This was associated with increased lipid rafts in APOε3/APOε4 monocytes. By contrast, APOε3 / APOε3 and APOε3 / APOε4 serum neutralized LPS equivalently and supported similar LPS responses in Apoe -deficient macrophages, arguing against a differential role for secretory APOE4 protein. After intravenous LPS, APOε3/APOε4 patients had higher hyperthermia and plasma TNF-α levels and earlier plasma IL-6 than APOε3/APOε3 patients. APOE4-targeted replacement mice displayed enhanced hypothermia, plasma cytokines, and hepatic injury and altered splenic lymphocyte apoptosis after systemic LPS compared with APOE3 counterparts. In a cohort of 828 patients with severe sepsis, APOε4 was associated with increased coagulation system failure among European American patients. Conclusions APOε4 is a determinant of the human innate immune response to multiple TLR ligands and associates with altered patterns of organ injury in human sepsis.
Smoking while pregnant is associated with a myriad of negative health outcomes in the child. Some of the detrimental effects may be due to epigenetic modifications, although few studies have ...investigated this hypothesis in detail.
To characterize site-specific epigenetic modifications conferred by prenatal smoking exposure within asthmatic children.
Using Illumina HumanMethylation27 microarrays, we estimated the degree of methylation at 27,578 distinct DNA sequences located primarily in gene promoters using whole blood DNA samples from the Childhood Asthma Management Program (CAMP) subset of Asthma BRIDGE childhood asthmatics (n = 527) ages 5-12 with prenatal smoking exposure data available. Using beta-regression, we screened loci for differential methylation related to prenatal smoke exposure, adjusting for gender, age and clinical site, and accounting for multiple comparisons by FDR.
Of 27,578 loci evaluated, 22,131 (80%) passed quality control assessment and were analyzed. Sixty-five children (12%) had a history of prenatal smoke exposure. At an FDR of 0.05, we identified 19 CpG loci significantly associated with prenatal smoke, of which two replicated in two independent populations. Exposure was associated with a 2% increase in mean CpG methylation in FRMD4A (p = 0.01) and Cllorf52 (p = 0.001) compared to no exposure. Four additional genes, XPNPEP1, PPEF2, SMPD3 and CRYGN, were nominally associated in at least one replication group.
These data suggest that prenatal exposure to tobacco smoke is associated with reproducible epigenetic changes that persist well into childhood. However, the biological significance of these altered loci remains unknown.
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