Genotype-environment interactions and their translational implications

Organisms frequently encounter different environmental conditions. The physiological and behavioral responses to these conditions depend on the genetic make up of individuals. Genotype generally remains constant from one environment to another, although occasional spontaneous mutations may occur which cause it to change. However, when the same genotype is subjected to different environments, it can produce a wide range of phenotypes. These phenotypic variations are attributable to the effect of the environment on the expression and function of genes influencing the trait. Changes in the relative performance of genotypes across different environments are referred to as genotype-environment interactions (GEI). A general argument for research on the impact of GEI in common diseases is that it provides insights into disease processes at the population, individual and molecular levels. In humans, GEI is complicated by multiple factors including phenocopies, genocopies, epigenetics and imprinting. A better understanding of GEI is essential if patients are to make informed health choices guided by their genomic information. In this article, we clarify the role of the environment on phenotype, we describe how human population structure can obscure the resolution of GEI and we discuss how emerging biobanks across the globe can be coordinated to further our understanding of genotype-phenotype associations within the context of varying environment.     

2'-5' oligoadenylate synthetase 1 polymorphism is associated with prostate cancer

BACKGROUND:

The antiviral, proapoptotic, antiproliferative gene 2′‐5′ oligoadenylate synthetase (2‐5OAS1) converts adenosine triphosphate into a series of 2′‐5′ oligoadenylates (2‐5A). In turn, 2‐5A activates latent ribonuclease (RNaseL), a candidate hereditary prostate cancer gene. OAS1 polymorphism (reference single nucleotide polymorphism [SNP] 2660 [rs2660]) has been associated with increased susceptibility to infections and various diseases. In general, the low‐enzyme‐activity adenine‐adenine (AA) genotype promotes susceptibility, whereas the high‐enzyme‐activity guanosine‐guanosine (GG) genotype confers protection. In this study, the authors investigated the association of this functional OAS1 polymorphism (rs2660) with prostate cancer.

METHODS:

Sample size and power were calculated using a power calculation software program for case‐control genetic association analyses. Genomic DNA samples from a control group (n = 140) and from a case group of patients with prostate cancer (n = 164) were used for genotyping SNPs rs2660, rs1131454, and rs34137742 in all samples. Statistical analyses were performed using a logistic regression model.

RESULTS:

A significant association was observed between the rs2660 genotype (A/G) and prostate cancer. Genotype AA increased the risk, whereas genotype GG decreased the risk of prostate cancer. The GG genotype was not observed in the African American samples. The AA genotype also increased the risk of prostate cancer with age.

CONCLUSIONS:

The OAS1 SNP rs2660 AA genotype was associated significantly with prostate cancer, whereas the GG genotype protected against prostate cancer. OAS1 rs2660 may be a prostate cancer susceptibility polymorphism, which is a significant observation, especially in a context of the OAS1‐RNaseL pathway. Thus, a functional defect in OAS1 because of the rs2660 SNP not only can attenuate RNaseL function but also can alter cell growth and apoptosis independent of RNaseL. Cancer 2011;. © 2011 American Cancer Society.     

Neural distribution of vasotocin receptor mRNA in two species of songbird

The neurohypophyseal hormones vasopressin and oxytocin are produced and released within the mammalian brain, where they act via multiple receptor subtypes. The neural distributions of these receptors, for example, V1a and oxytocin receptors, have been well described in many mammals. In birds, the distribution of binding sites for the homologous neuropeptides, vasotocin (VT) and mesotocin, has been studied in several species by using synthetic radioligands designed to bind to mammalian receptors. Such binding studies, however, may not reveal the specific distributions of each receptor subtype. To identify and map the receptors likely to bind VT and mesotocin, we generated partial cDNA sequences for four VT receptor subtypes, VT1, VT2 (V1b), VT3 (oxytocin-like), and VT4 (V1a), in white-throated sparrow (Zonotrichia albicollis) and zebra finch (Taeniopygia guttata). These genes shared high sequence identity with the homologous avian and mammalian neurohypophyseal peptide receptors, and we found evidence for VT1, VT3, and VT4 receptor mRNA expression throughout the brains of both species. As has been described in rodents, there was striking interspecific and intraspecific variation in the densities and distribution of these receptors. For example, whereas the VT1 receptor mRNA was more widespread in zebra finch brain, the VT3 (oxytocin-like) receptor mRNA was more prevalent in the sparrow brain. Although VT2 (V1b) receptor mRNA was abundant in the pituitary, it was not found in the brain. Because of their association with brain regions implicated in social behavior, the VT1, VT3, and VT4 receptors are all likely candidates for mediating the behavioral effects of VT.     

Inhibition of experimental metastasis by targeting the HUIV26 cryptic epitope in collagen

Metastasis from the primary tumor to distant sites involves an array of molecules that function in an integrated manner. Proteolytic remodeling and subsequent tumor cell interactions with the extracellular matrix regulate tumor invasion. In previous studies, we have identified a cryptic epitope (HUIV26) that is specifically exposed after alterations in the triple helical structure of type IV collagen. Exposure of this cryptic epitope plays a fundamental role in the regulation of angiogenesis in vivo. However, little is known concerning the ability of tumor cells to interact with this cryptic site or whether this site regulates tumor cell metastasis in vivo. In this regard, many of the same cellular processes that regulate angiogenesis also contribute to tumor metastasis. Here we provide evidence that tumor cells such as B16F10 melanoma interact with denatured collagen type IV in part by recognizing the HUIV26 cryptic site. Systemic administration of a HUIV26 monoclonal antibody inhibited experimental metastasis of B16F10 melanoma in vivo. Taken together, our findings suggest that tumor cell interactions with the HUIV26 cryptic epitope play an important role in regulating experimental metastasis and that this cryptic element may represent a therapeutic target for controlling the spread of tumor cells to distant sites.     

Knowledge and perception of pulmonary tuberculosis in pastoral communities in the middle and Lower Awash Valley of Afar region,Ethiopia

Background  

Afar pastoralists live in the northeast of Ethiopia, confined to the most arid part of the country, where there is least access to educational, health and other social services. Tuberculosis (TB) is one of the major public health problems in Afar region. Lack of knowledge about TB could affect the health-seeking behaviour of patients and sustain the transmission of the disease within the community. In this study, we assessed the knowledge and perception of apparently healthy individuals about pulmonary tuberculosis (PTB) in pastoral communities of Afar.     

Nutritional status and cognitive performance of mother–child pairs in Sidama,Southern Ethiopia

The purpose of this study was to assess the nutritional status and cognitive performance of women and their 5‐year‐old children using a cross‐sectional design. Cognitive performance of mothers and children was assessed with Raven's Colored Progressive Matrices (CPM) and Kaufman Assessment Battery for Children‐II (KABC‐II). Demographic characteristics, food consumption patterns and anthropometry were also measured. Four rural districts in Sidama, southern Ethiopia served as the setting for this study. Subjects were one hundred women and their 5‐year‐old children. Mean ± standard deviation age of the mothers was 29 ± 6 years and family size was 7.0 ± 2.6. Maternal body mass index (BMI) ranged from 15.3 to 29.0 with 14% of the mothers having BMI < 18.5. Anthropometric assessment of children revealed 29% to be stunted (height‐for‐age z‐score < ?2) and 12% to be underweight (weight‐for‐age z‐score < ?2). Mothers' education significantly contributed to prediction of both mothers' and children's cognitive test scores. There were significant differences in mean cognitive test scores between stunted and non‐stunted, and between underweight and normal‐weight children. Height‐for‐age z‐scores were correlated with scores for short‐term memory (r = 0.42, P < 0.001), and visual processing (r = 0.42, P < 0.001) indices and weight‐for‐age z‐scores were also correlated with scores of short‐term memory (r = 0.41, P < 0.001) and visual processing (r = 0.43, P < 0.001) indices. Malnutrition in the community likely contributed to the cognitive performance of the subjects. Performance on memory and visual processing tasks was significantly lower in children with growth deficits suggesting that efficient and cost effective methods to alleviate malnutrition and food insecurity would impact not only child health but also cognitive function.     

Bacterial Profile and Antimicrobial Susceptibility Pattern of Isolates Among Burn Patients at Yekatit 12 Hospital Burn Center,Addis Ababa,Ethiopia

Background

Infection is a common cause of morbidity and mortality in burn patients. Clinical diagnosis of bacteremia and/or sepsis in burn patients is difficult for a number of reasons. It could be symptomatic and/or asymptomatic as a result of immune deficiency secondary to thermal injury.

Methods

A cross sectional study was conducted at Yekatit 12 Hospital Burn Center. Blood specimen and wound swab were collected from burn patients and were cultured by conventional method. Sensitivity/susceptibility pattern of the isolates was determined by disc diffusion method. Some of the risk factors of bacteremia like prior antibiotic use and total body surface area burn were also determined.

Results

Fifty patients were enrolled in the study of whom 21(42%) were found bacteremic. Five different bacteria were isolated from blood specimen. Coagulase negative Staphylococci, 9(42.8%), S. aureus, 8(38.2%), Bacillus spps, 2(9.52%), K. pneumoniae, 1(4.8%), and P. aeruginosa, 1(4.8%), were frequent isolates. From wound swab, S. aureus, (34.04%), and P. aeruginosa, (31.8%), were predominant. Antimicrobial resistance was observed for Ampicillin, (77.4%), Doxycycline, (74.0), Nalidixic acid, (70.5%), Penicillin G, (68.2%), and tetracycline, (67.5%). Total body surface area of burn ≥ 15% was found as a risk factor for bacteremia.

Conclusion

Bacteremia was detected at a rate of 42% among burn patients. Frequent isolates were S. aureus, (34.04%), and P. aeruginosa, (31.8%). About 82.16% of the isolates showed multiple resistances. In light of our findings, regular antibiotic resistance test has to be done for each patient in order to select an appropriate antimicrobial agent.