Genetic Determinants Of Susceptibility Research Articles

Clinical and Genetic Characteristics of Coronaviruses with Particular Emphasis on SARS-CoV-2 Virus.

The rapidly spreading Coronavirus Disease 2019 (COVID-19) pandemic has led to a global health crisis and has left a deep mark on society, culture, and the global economy. Despite considerable efforts made to contain the disease, SARS-CoV-2 still poses a threat on a global scale. The current epidemiological situation caused an urgent need to understand the basic mechanisms of the virus transmission and COVID-19 severe course. This review summarizes current knowledge on clinical courses, diagnostics, treatment, and prevention of COVID-19. Moreover, we have included the latest research results on the genetic characterization of SARS-CoV-2 and genetic determinants of susceptibility and severity to infection.

Complement C4 Gene Copy Number Variation Genotyping by High Resolution Melting PCR.

Background: Complement C4 gene copy number variation plays an important role as a determinant of genetic susceptibility to common diseases, such as systemic lupus erythematosus, schizophrenia, rheumatoid arthritis, and infectious diseases. This study aimed to develop an assay for the quantification of copy number variations in the C4 locus. Methods: the assay was based on a gene ratio analysis copy enumeration (GRACE) PCR combined with high resolution melting (HRM) PCR. The test was optimized using samples of a known genotype and validated with 72 DNA samples from healthy blood donors. Results: to validate the assay, standard curves were generated by plotting the C4/RP1 ratio values against copy number variation (CNV) for each gene, using genomic DNA with known C4 CNV. The range of copy numbers in control individuals was comparable to distributions observed in previous studies of European descent. Conclusions: the method herein described significantly simplifies C4 CNV diagnosis to validate the assay.

SNP Association with Risk for Sporadic Papillary Thyroid Carcinoma in Kazakh Population

Background: The recent genome-wide association studies (GWAS) including FOXE1 and NKX2-1 genes have represent associations for well differentiated thyroid carcinoma. Replication studies in geographically distinct populations identified strong associations of rs965513 (9q22.33) and rs944289 (14q13.3) SNPs with papillary thyroid cancer. This work is the first to characterise the associations of SNPs in a population-based Kazakh cohort.Aims: To study association of SNPs with risk for sporadic papillary thyroid carcinoma (PTC) in Kazakh population.Materials and methods: A total of 298 patients with histologically confirmed PTC and 742 controls of Kazakh origin were recruited. All participants donated a peripheral venous blood sample which was used to isolate genomic DNA. Genotyping was performed using TaqMan Genotyping on a Light Cycler 480 (Roche, Indianapolis, IN).Results: Significant associations: rs965513 (p=3.24 E-16; OR=2.05, 95% CI 1.82−2.11) and rs944289 (p=1.38 E-06; OR=1.39, 95% CI 1.21−1.52) were found in the multiplicative model of inheritance adjusted for age and sex.Conclusions: Our study unambiguously confirms the existence of genetic determinants of susceptibility to PTC in Kazakh population.

Rat models of 17β-estradiol-induced mammary cancer reveal novel insights into breast cancer etiology and prevention

Numerous laboratory and epidemiologic studies strongly implicate endogenous and exogenous estrogens in the etiology of breast cancer. Data summarized herein suggest that the ACI rat model of 17β-estradiol (E2)-induced mammary cancer is unique among rodent models in the extent to which it faithfully reflects the etiology and biology of luminal types of breast cancer, which together constitute ~70% of all breast cancers. E2 drives cancer development in this model through mechanisms that are largely dependent upon estrogen receptors and require progesterone and its receptors. Moreover, mammary cancer development appears to be associated with generation of oxidative stress and can be modified by multiple dietary factors, several of which may attenuate the actions of reactive oxygen species. Studies of susceptible ACI rats and resistant COP or BN rats provide novel insights into the genetic bases of susceptibility and the biological processes regulated by genetic determinants of susceptibility. This review summarizes research progress resulting from use of these physiologically relevant rat models to advance understanding of breast cancer etiology and prevention.

OC-031 A Genome-Wide Association Study Identifies PNPLA3 and SLC38A4 as Risk Loci for Alcoholic Hepatitis

Introduction The clinical spectrum of alcohol-related liver disease varies widely but the majority of patients with evolving disease are asymptomatic. However, a small minority of patients develop severe alcoholic hepatitis (SAH), a clinical syndrome manifest as profound hepatocellular failure, often superimposed on cirrhosis. As only a relative minority of patients develop SAH genetic determination of susceptibility has been proposed. A genome-wide association study (GWAS) approach was used to identify potential risk loci for SAH. Methods Cases with SAH, of self-reported white British ancestry, were recruited prospectively through the Steroids or Pentoxifylline for Alcoholic Hepatitis trial (n = 860). Ancestry-matched controls with alcohol dependence but without alcohol-related liver injury were recruited from the Centre for Hepatology, Royal Free Hospital, London (n = 1191). A two-stage GWAS was performed. DNA samples from an exploratory cohort (332 cases, 318 controls) were genotyped on Illumina CoreExome BeadChips (Illumina, San Diego, USA) at the Wellcome Trust Sanger Institute, Cambridge, UK. The most significantly associated SNPs were genotyped in DNA samples from an independent replication cohort (528 cases, 873 controls) using KASPar chemistry (LGC Genomics, Hoddesdon, UK). Data were analysed in PLINK1.9. Results The variant rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3) was associated at genome-wide significance level (PTHRESHOLD Conclusion This first analysis of data from a GWAS of severe alcoholic hepatitis confirms significant risk association with PNPLA3, consistent with the phenotypic overlap with alcohol-related cirrhosis. It also identified SLC38A4 as a potential, novel risk locus for development of alcoholic hepatitis per se; this gene is predominantly expressed in the liver and is involved in amino acid transport. Disclosure of Interest None Declared

HLA Class II Differentiates Between Thyroid and Polyglandular Autoimmunity.

The HLA class II genes are susceptibility genes for autoimmune endocrine diseases; however, scarce data are available pertaining to the determinants of genetic susceptibility to polyglandular autoimmunity (PGA). A total of 300 consecutive and unselected patients with either PGA or monoglandular autoimmune thyroid disease (AITD) and 100 healthy control subjects were genotyped for the HLA class II DRB1, -DQA1, and -DQB1 alleles. Compared to patients with AITD and controls, the HLA-DRB1*03 (pc =0.001), *04 (pc<0.001), -DQA1*03 (pc<0.001), and -DQB1*02 (pc =0.001) alleles were increased in patients with PGA. When dividing patients with Hashimoto's thyroiditis (HT) into those with PGA (PGA-HT) vs. those with HT as monoglandular disease, significant differences for the DRB1*03 (pc=0.001) and DQA1*03 (pc=0.001) alleles were observed. In contrast, the DQB1*02 allele was more prevalent in PGA patients with Graves' disease (PGA-GD) vs. those with monoglandular GD (pc=0.002). The HLA-DRB1*15 (pc =0.001), -DQA1*01 (pc =0.001), -DQB1*05 (pc =0.002) and -DQB1*06 (pc =0.002) alleles were significantly less present in PGA compared to monoglandular AITD and controls, thus indicating protective alleles. The HLA class II alleles differentiate between mono- and polyglandular autoimmunity in patients with autoimmune thyroid disease.

Impact of VEGF gene polymorphisms in elderly cancer patients: clinical outcome and toxicity.

Vascular endothelial growth factors (VEGFs) are the key regulators in angiogenesis and have been shown to play a significant role in the progression and prognosis of angiogenesis-related diseases, such as cancer. VEGF inhibitors are a current pharmacological tumoral strategy. However, despite the strong association between aging and cancer incidence and progression, recent findings suggest impaired angiogenesis accompanied by a reduced expression of VEGF in cells derived from aging subjects. Specific variations of VEGF genes have been demonstrated to be genetic determinants for susceptibility, outcome and therapy response, especially for the solid tumors. Considering the complications present in frail elderly patients, analysis of VEGF genetic polymorphisms in these subjects may further help in tailoring an angiogenic pharmacological strategy, and in improving our ability to better understand prognosis during therapy-related to cancer.

ADIPOQ +45T&gt;G, +712A&gt;G and +4545C&gt;G variants are associated with dyslipidemia in Chinese pre-eclampsia women

The pathogenesis of pre-eclampsia, the most common complication in obstetrics, is unclear. Family based studies have shown that the incidence of pre-eclampsia is related to genetic factors. Lipid profile indicated that pre-eclampsia were also accompanied by dyslipidemia. We would like to evaluate the influence of common polymorphisms of the adipose most abundant gene transcript-1, adiponectin (ADIPOQ) gene on the lipid metabolism, and pre-eclampsia in Chinese Han women of pregnancy. Clinically defined pre-eclampsia patients (n = 221) and healthy pregnant women (n = 271) were recruited. PCR-RFLP was used to genotype ADIPOQ +45T/G, +712A/G, and +4545C/G single-nucleotide polymorphisms (SNPs). Changes in metabolic and clinical data were analyzed according to SNPs and groups. +45TT genotype had a relatively lower ApoA1 level than G-allele carrier in case group (p = 0.002). In the controls, systolic blood pressure (SBP) levels were higher in +712AA genotype group than G-allele carriers’ (p = 0.009), +4545CC were higher than G-allele carriers’ (p = 0.009). No significant association between the ADIPOQ genotype or the alleles and pre-eclampsia had been observed. There is a strong linkage disequilibrium between polymorphic loci +45T>G and +712A>G, +45T>G and +4545T>G, and +712A>G and +4545T>G, respectively. ADIPOQ gene might affect SBP and lipid metabolism of pre-eclampsia, although the three polymorphic sites on ADIPOQ gene are not the major genetic determinants of susceptibility to pre-eclampsia in Chinese women.

Transcriptional Profiling of the Circulating Immune Response to Lassa Virus in an Aerosol Model of Exposure

Lassa virus (LASV) is a significant human pathogen that is endemic to several countries in West Africa. Infection with LASV leads to the development of hemorrhagic fever in a significant number of cases, and it is estimated that thousands die each year from the disease. Little is known about the complex immune mechanisms governing the response to LASV or the genetic determinants of susceptibility and resistance to infection. In the study presented here, we have used a whole-genome, microarray-based approach to determine the temporal host response in the peripheral blood mononuclear cells (PBMCs) of non-human primates (NHP) following aerosol exposure to LASV. Sequential sampling over the entire disease course showed that there are strong transcriptional changes of the immune response to LASV exposure, including the early induction of interferon-responsive genes and Toll-like receptor signaling pathways. However, this increase in early innate responses was coupled with a lack of pro-inflammatory cytokine response in LASV exposed NHPs. There was a distinct lack of cytokines such as IL1β and IL23α, while immunosuppressive cytokines such as IL27 and IL6 were upregulated. Comparison of IRF/STAT1-stimulated gene expression with the viral load in LASV exposed NHPs suggests that mRNA expression significantly precedes viremia, and thus might be used for early diagnostics of the disease. Our results provide a transcriptomic survey of the circulating immune response to hemorrhagic LASV exposure and provide a foundation for biomarker identification to allow clinical diagnosis of LASV infection through analysis of the host response.

Abstract 1393: Fine mapping and characterization of Emca8.2, a genetic determinant of susceptibility to estrogen-induced mammary cancer on chromosome 5 in the rat.

Abstract Although estrogens have long been implicated in the etiology of breast cancer, the mechanisms through which estrogens contribute to breast cancer development remain poorly defined. Furthermore, many of the genes that influence the risk of developing breast cancer also remain to be determined. The ACI rat model of 17β-estradiol (E2)-induced mammary cancer is being used to elucidate the mechanisms through which estrogens contribute to breast cancer development and to identify novel genetic determinants of breast cancer susceptibility. Female ACI rats develop mammary cancer at an incidence nearing 100% when treated with physiological levels of E2. In contrast, the Brown Norway (BN) rat strain is resistant to E2-induced mammary cancer. A total of seven quantitative trait loci (QTL), designated Emca3 (Estrogen-induced mammary cancer) through Emca9, have been mapped in reciprocal intercrosses between ACI and BN rats. The purpose of the current study is to fine map the Emca8 genetic determinants of mammary cancer susceptibility, which was mapped to rat chromosome 5 (RNO5). ACI alleles at this QTL act to increase the number of mammary cancers per rat and to decrease the latency to the appearance of the first palpable mammary cancer. A series of congenic rat strains have been generated by introgressing defined segments of RNO5 from the resistant BN rat strain onto the genetic background of the susceptible ACI strain. By defining the susceptibility of these congenic rat strains relative to that of the parental ACI strain, a locus determining susceptibility to E2-induced mammary cancer, designated Emca8.2, has now been localized to a 1.1 megabase (Mb) region of distal RNO5 containing approximately 1200 genetic sequence variants. To help identify the mechanisms through which Emca8.2 determines susceptibility to mammary cancer, the expression levels of the candidate genes within the fine-mapped region have been investigated. The mapping and expression data that define the genomic architecture of Emca8.2 will be presented and discussed. Citation Format: John A. Colletti, Nicole L. Seiler, Maureen P. Hickman, Nyssa B. Samanas, Chrsitopher L. Warren, James D. Shull. Fine mapping and characterization of Emca8.2, a genetic determinant of susceptibility to estrogen-induced mammary cancer on chromosome 5 in the rat. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1393. doi:10.1158/1538-7445.AM2013-1393

Abstract 3624: Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau.

Abstract Epidemiological studies of underground miners suggest that occupational exposure to radon causes lung cancer with squamous cell carcinoma (SCC) as the predominant histological type. However, the genetic determinants for susceptibility of radon-induced SCC in miners are unclear. Double-strand breaks (DSBs) induced by radioactive radon daughters are repaired primarily by non-homologous end joining (NHEJ) that is accompanied by the dynamic changes in surrounding chromatin, including nucleosome repositioning and histone modifications. Thus, a molecular epidemiological study was conducted to assess whether genetic variation in 16 genes involved in NHEJ and related histone modification affected susceptibility for SCC in radon-exposed former miners (267 SCC cases and 383 controls) from the Colorado plateau. A global association between genetic variation in the haplotype block where SIRT1 resides and the risk for SCC in miners (P=0.003) was identified. Haplotype alleles tagged by the A allele of SIRT1 rs7097008 were associated with increased risk for SCC (Odds Ratio = 1.69, P = 8.2×10−5) and greater survival in SCC cases (Hazard Ratio = 0.79, P = 0.03) in miners. Functional validation of rs7097008 demonstrated that the A allele was associated with reduced gene expression in bronchial epithelial cells and compromised DNA repair capacity in peripheral lymphocytes. Together, these findings substantiate genetic variation in SIRT1 as a risk modifier for developing SCC in miners and suggested that SIRT1 may also play a tumor suppressor role in radon-induced cancer in miners. Citation Format: Shuguang Leng, Maria A. Picchi, Yushi Liu, Yong Lin, Christine A. Stidley, Frank D. Gilliland, Marty R. Jacobson, Steven A. Belinsky. Genetic variation in SIRT1 affects susceptibility of lung squamous cell carcinomas in former uranium miners from the Colorado plateau. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3624. doi:10.1158/1538-7445.AM2013-3624

Nutrient Modulation of Autophagy

During nutrient deprivation, autophagy provides the constituents required to maintain the metabolism essential for survival. Recently, genome-wide association studies have identified genetic determinants for susceptibility to Crohn's disease (CD) such as ATG16L1 and IRGM that are involved in the autophagy pathway. Both disease-carrying NOD2 mutations and ATG16L1 mutations may result in impairment of autophagy. Impairment in autophagy results in impaired clearance of microbes. Ileal CD is associated with Paneth cell loss of function such as decreased production of α-defensins, which may arise from mutations in NOD2 or autophagy genes. Nutrients are able to modify several cellular pathways and in particular autophagy. We summarize the contribution of a variety of dietary components to activate autophagy. Understanding the crosstalk between nutrients and autophagy in the intestine may provide novel targets that have therapeutics potential in intestinal inflammation. Nutrient activation of autophagy may contribute to restoring the Paneth cell loss of function in ileal CD.

Abstract 2387: Fine mapping and characterization of a genetic determinant of susceptibility to estrogen-induced mammary cancer on chromosome 5 in the rat

Abstract Although estrogens have long been implicated in the etiology of breast cancer, the mechanisms through which estrogens contribute to breast cancer development remain poorly defined. Furthermore many of the genes that influence the risk of developing breast cancer also remain to be determined. The ACI rat model of 17β-estradiol (E2)-induced mammary cancer is being used to elucidate the mechanisms through which estrogens contribute to breast cancer development and to identify novel genetic determinants of breast cancer susceptibility. Female ACI rats develop mammary cancer at an incidence nearing 100% when treated with physiological levels of E2. In contrast, both the Brown Norway (BN) and Copenhagen (COP) rat strains are resistant to E2-induced mammary cancer. A total of nine quantitative trait loci (QTL), designated Emca1 (Estrogen-induced mammary cancer) through Emca9, have been mapped in a series of intercrosses between ACI and COP rats (Emca1-2) or ACI and BN rats (Emca3-9). The purpose of the current study is to fine map the Emca1 and Emca8 genetic determinants of mammary cancer susceptibility, which were mapped to rat chromosome 5 (RNO5). ACI alleles at these QTL act to increase the number of mammary cancers per rat and to decrease the latency to the appearance of the first palpable mammary cancer. A series of congenic rat strains have been generated by introgressing defined segments of RNO5 from the resistant COP or BN rat strains onto the genetic background of the susceptible ACI strain. By defining the susceptibility of these congenic rat strains relative to that of the parental ACI strain, Emca8 has now been localized to an approximate 10 megabase (Mb) region of distal RNO5. Similar studies are underway to determine whether or not Emca1 maps to the same region of RNO5 as Emca8. As currently defined, Emca8 harbors approximately 200 known and predicted genes as well as a copy number variant (CNV) that differs between the ACI, COP and BN rat strains based on array comparative genomic hybridization (aCGH). To help identify the mechanisms through which Emca1 and Emca8 determine susceptibility to mammary cancer, we have defined gene expression profiles for normal mammary gland from E2 treated ACI, COP and BN rats and identified those genes that reside within Emca1 and Emca8 and are differentially expressed between ACI and COP or BN rats. Gene expression profiles were also defined for mammary cancers induced by E2 in ACI rats to identify those genes that reside within these QTL and are differentially expressed between normal and neoplastic mammary tissues. The mapping and expression data that define the genomic architecture of Emca1 and Emca8 will be presented and discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2387. doi:10.1158/1538-7445.AM2011-2387

Genetic determinants of susceptibility and severity in nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) in most patients involves only simple hepatic steatosis; however, a minority develop progressive steatohepatitis. Family studies and inter-ethnic differences in susceptibility suggest that genetic factors may be important risk determinants for progressive disease. Polymorphisms in genes affecting lipid metabolism, cytokines, fibrotic mediators and oxidative stress may be associated with steatohepatitis and/or fibrosis, but most of these findings require replication. A recent finding that a nonsynonymous polymorphism in the PNPLA3 gene predicts the extent of steatosis in NAFLD has been replicated in at least eight studies, with several studies also demonstrating an association with fibrosis. A new genome-wide association study has identified several additional novel associations with NAFLD severity. Other disease genes may be identified by similar approaches in the future.

Detecting two-locus associations allowing for interactions in genome-wide association studies

Genome-wide association studies (GWASs) aim to identify genetic susceptibility to complex diseases by assaying and analyzing hundreds of thousands of single nucleotide polymorphisms (SNPs). Although traditional single-locus statistical tests have identified many genetic determinants of susceptibility, those findings cannot completely explain genetic contributions to complex diseases. Marchini and coauthors demonstrated the importance of testing two-locus associations allowing for interactions through a wide range of simulation studies. However, such a test is computationally demanding as we need to test hundreds of billions of SNP pairs in GWAS. Here, we provide a method to address this computational burden for dichotomous phenotypes. We have applied our method on nine datasets from GWAS, including the aged-related macular degeneration (AMD) dataset, the Parkinson's disease dataset and seven datasets from the Wellcome Trust Case Control Consortium (WTCCC). Our method has discovered many associations that were not identified before. The running time for the AMD dataset, the Parkinson's disease dataset and each of seven WTCCC datasets are 2.5, 82 and 90 h on a standard 3.0 GHz desktop with 4 G memory running Windows XP system. Our experiment results demonstrate that our method is feasible for the full-scale analyses of both single- and two-locus associations allowing for interactions in GWAS. http://bioinformatics.ust.hk/SNPAssociation.zip nelsontang@cuhk.edu.hk; eeyu@ust.hk; Supplementary data are available at Bioinformatics online.

Abstract ED3-2: Understanding melanoma using GWAS and systems biology

Abstract In this review I will discuss progress made in understanding the genetic determinants of susceptibility to melanoma and outcome from melanoma using genome wide association studies (GWAS) and approaches based more upon systems biology. In very recent years the first GWAS identifying hereditary susceptibility genes have been published as have the first larger scale gene expression studies. In the next few years, bioinformatics developments will allow integration of data from these and other system-wide approaches, in a multi-disciplinary fashion to better understand complex interactions between biological pathways and both the cellular environment and that of the organism. Family studies are usually the first approach to identifying high penetrance susceptibility genes for cancer in general and for melanoma these lead to the identification of germline mutations in CDKN2A and CDK4 as the most common genes underlying susceptibility in families with 4 or more cases of melanoma. The melanoma genetics consortium GenoMEL at www.genomel.org is directed towards understanding the clinical relevance of these mutations. More recently, GWAS studies confirmed the role of MC1R variants as the most common low risk susceptibility genes (1), although this was previously recognised as a result of a small candidate gene study in 1996 (2) perhaps showing the value of taking multiple approaches. Other pigment genes have been identified as low risk susceptibility genes using a combination of agnostic and candidate gene approaches (3) and the evolution of new techniques was demonstrated by Brown et al who developed DNA pooling in GWAS which identified a locus near to the agouti signalling protein gene as a melanoma susceptibility gene (4). These GWAS have therefore identified susceptibility loci in genes predicted from epidemiological studies, which identified sun-sensitive phenotypes as associated with melanoma risk. Epidemiological studies also identified large numbers of melanocytic nevi as associated with increased risk and GWAS studies designed to identify nevus genes were therefore carried out to identify both nevus and melanoma susceptibility genes (5). Thus the melanoma field has benefitted from GWAS technology in conjunction with epidemiology to identify pathways involved in susceptibility. It is perhaps disappointing that so far the agnostic approach has failed to identify new biological pathways of note but there are some interesting clues and the GWAS data existing already are being interrogated using newer informatics approaches. It is likely that new relevant biological pathways will be identified in the very near future. It is crucial to increase our understanding of the genetic determinants of outcome for melanoma patients not least to improve the response to therapies for stage IV melanoma. In recent years genomics has lead to major progress in understanding the biological pathways important to tumour progression, which has lead to the clinical trials with the most hopeful chemotherapeutic agent for melanoma, a specific inhibitor of mutant Braf. Biological complexity is evident however and it seems likely that we require a quantum leap in understanding to provide therapeutic options for all patients. Systems biological approaches will be of fundamental importance here aided by new technologies/platforms which allow us to work with small paraffin embedded melanoma tumours such as the Illumina DASL platform (6). Citation Information: Clin Cancer Res 2010;16(7 Suppl):ED3-2

Hereditary influences in oxygen-induced retinopathy in the rat

Rodent models of oxygen-induced retinopathy (OIR) provide important insights into the pathogenesis of human retinopathy of prematurity. Herein, we present an overview of our work with rat OIR to date. We have identified marked and consistent variations in susceptibility to OIR amongst different inbred rat strains and provide strong evidence for a genetic determinant of susceptibility to OIR. Furthermore, we have characterised differences in retinal angiogenic factor gene expression amongst different inbred rat strains exposed to cyclic hyperoxia. A key determinant of susceptibility to OIR appears to be the extent to which pro-angiogenic factor genes, such as vascular endothelial growth factor and erythropoietin, are expressed during the period of hyperoxic exposure. Those strains in which expression is relatively well maintained are less susceptible to retinopathy than are those in which expression is reduced. In addition, we identify an association between ocular pigmentation and OIR susceptibility.

Analysis of prion protein genotypes in relation to reproduction traits in local and cosmopolitan German sheep breeds

Due to the genetic determination of susceptibility to scrapie and other forms of transmissible spongiform encephalopathy (TSE) in sheep breeding to the less susceptible prion protein (PrP) genotype ARR/ARR was advanced within EU. In 4961 ewes of nine German sheep breeds (Coburg Fox sheep, Gray Horned Heath sheep, Merinoland sheep, Rhoen sheep, German Blackheaded Mutton sheep, Shropshire, Suffolk, Texel and White East Friesian Milk sheep) representing local and cosmopolitan breeds the reproductive traits number of lambs born, dead (including abortion at the end of pregnancy, stillbirth and death during the first 56 days post natum), weaned and rearing rate at each lambing were recorded and in 1641 of these ewes the PrP genotype was determined. A linear model was used to evaluate associations between PrP genotype and reproduction traits including the effects of PrP genotype (four classes: ewes with two, one and no copy of the ARR allele and with unknown PrP genotype), breed, interaction of PrP genotype and breed, number of lambing, lambing season and stock. Significant associations were only observed between the PrP genotype and the number of dead lambs at each lambing in Shropshire and Merinoland sheep and the rearing rate at each lambing in Shropshire. These significant associations were mainly caused by differences between animals with unknown PrP genotype and animals of the other PrP classes. In conclusion, breeding for TSE resistant sheep will not lead to a reduction in economically important reproduction traits.

Genetic Bases of Estrogen-Induced Tumorigenesis in the Rat: Mapping of Loci Controlling Susceptibility to Mammary Cancer in a Brown Norway × ACI Intercross

Exposure to estrogens is associated with an increased risk of breast cancer. Our laboratory has shown that the ACI rat is uniquely susceptible to 17beta-estradiol (E2)-induced mammary cancer. We previously mapped two loci, Emca1 and Emca2 (estrogen-induced mammary cancer), that act independently to determine susceptibility to E2-induced mammary cancer in crosses between the susceptible ACI rat strain and the genetically related, but resistant, Copenhagen (COP) rat strain. In this study, we evaluate susceptibility to E2-induced mammary cancer in a cross between the ACI strain and the unrelated Brown Norway (BN) rat strain. Whereas nearly 100% of the ACI rats developed mammary cancer when treated continuously with E2, BN rats did not develop palpable mammary cancer during the 196-day course of E2 treatment. Susceptibility to E2-induced mammary cancer segregated as a dominant or incompletely dominant trait in a cross between BN females and ACI males. In a population of 251 female (BN x ACI)F(2) rats, we observed evidence for a total of five genetic determinants of susceptibility. Two loci, Emca4 and Emca5, were identified when mammary cancer status at sacrifice was evaluated as the phenotype, and three additional loci, Emca6, Emca7, and Emca8, were identified when mammary cancer number was evaluated as the phenotype. A total of three genetic interactions were identified. These data indicate that susceptibility to E2-induced mammary cancer in the BN x ACI cross behaves as a complex trait controlled by at least five loci and multiple gene-gene interactions.

Genetic determination of susceptibility and resistance in the pathogenesis of Candida albicans infection.

The concepts of susceptibility and resistance are central to both clinical and experimental studies of infectious diseases. In general, resistance implies survival rather than death, or at the very least, a marked reduction in the severity of symptoms when compared with susceptible individuals. It is usually associated with the presence in the host of particular alleles of one or more genes that contribute to the formation of a ‘resistant’ phenotype. Conversely, susceptibility is determined by the presence of the ‘susceptible’ alleles of these genes. Diseases associated with Candida albicans infection occur in two discrete forms, mucosal and systemic. Mild infections of the oral and vaginal mucosa are common in the general population, but they are seen most frequently, and in their most severe form, in individuals with defects in the cell-mediated immune response. On the other hand, systemic candidiasis is confined almost exclusively to debilitated or immunocompromised patients in the hospital environment. Although a propensity to exploit flaws in host defence mechanisms in order to establish infection is certainly not unique to C. albicans , these clinical correlations may not offer relevant insights into the disease process, as deficiencies in host defence mechanisms induced by drugs or disease will not necessarily reflect the effector pathways that determine susceptibility and resistance to infection in the unmodified host. The object of this review is to highlight various aspects of susceptibility to C. albicans infection in both humans and experimental animals, and by examining recent studies of genetic influences on host responses, to propose a new paradigm for the experimental analysis of the mechanisms of pathogenesis. Our understanding of the pathogenesis of C. albicans infection in humans is confused by the multitude of factors that can precipitate infections, and the different sites at which they can occur. In healthy men and women, ‘conversion’ …