Genetic Variation In Susceptibility Research Articles

Nasopharyngeal Bacterial Colonization and Gene Polymorphisms of Mannose-Binding Lectin and Toll-Like Receptors 2 and 4 in Infants

BackgroundHuman nasopharynx is often colonized by potentially pathogenic bacteria. Gene polymorphisms in mannose-binding lectin (MBL), toll-like receptor (TLR) 2 and TLR4 have been reported. The present study aimed to investigate possible association between nasopharyngeal bacterial colonization and gene polymorphisms of MBL, TLR2 and TLR4 in healthy infants.Methodology/Principal FindingsFrom August 2008 to June 2010, 489 nasopharyngeal swabs and 412 blood samples were taken from 3-month-old healthy Finnish infants. Semi-quantitative culture was performed and pyrosequencing was used for detection of polymorphisms in MBL structural gene at codons 52, 54, and 57, TLR2 Arg753Gln and TLR4 Asp299Gly. Fifty-nine percent of subjects were culture positive for at least one of the four species: 11% for Streptococcus pneumoniae, 23% for Moraxella catarrhalis, 1% for Haemophilus influenzae and 25% for Staphylococcus aureus. Thirty-two percent of subjects had variant types in MBL, 5% had polymorphism of TLR2, and 18% had polymorphism of TLR4. Colonization rates of S. pneumoniae and S. aureus were significantly higher in infants with variant types of MBL than those with wild type (p = .011 and p = .024). Colonization rates of S. aureus and M. catarrhalis were significantly higher in infants with polymorphisms of TLR2 and of TLR4 than those without (p = .027 and p = .002).ConclusionsOur study suggests that there is an association between nasopharyngeal bacterial colonization and genetic variation of MBL, TLR2 and TLR4 in young infants. This finding supports a role for these genetic variations in susceptibility of children to respiratory infections.

Screening of Maritime pine (Pinus pinaster) for resistance to Fusarium circinatum, the causal agent of Pitch Canker disease

Pitch canker, caused by the fungus Fusarium circinatum, is an introduced non-native disease on pines in natural and planted stands of Europe. Research has not been conducted to test whether a European native pine species shows genetic variation in susceptibility to this disease. Half-sib families from 39 Pinus pinaster clones and seedlings from one unimproved seed source (control) were evaluated for resistance. Pitch canker resistance was not genetically related to tree growth, but seed weight and germination rates were predictive of time-to-death. Heritabilities and associated genetic gains calculated from the greenhouse experiment were consistent, hi2 = 0.18 and 0.45 for time-to-death and for tree mortality, respectively. These heritabilities are high enough to allow pitch canker to be reduced through appropriate genetic strategies. Results indicated that selection for growth of P. pinaster trees in breeding programs would not necessarily imply an increase of susceptibility to F. circinatum. This research may allow the use of native pine individuals as breeding stock or as sources to produce seeds with moderate levels of tolerance to F. circinatum.

Genetic variation in virulence among chalkbrood strains infecting honeybees.

Ascosphaera apis causes chalkbrood in honeybees, a chronic disease that reduces the number of viable offspring in the nest. Although lethal for larvae, the disease normally has relatively low virulence at the colony level. A recent study showed that there is genetic variation for host susceptibility, but whether Ascosphaera apis strains differ in virulence is unknown. We exploited a recently modified in vitro rearing technique to infect honeybee larvae from three colonies with naturally mated queens under strictly controlled laboratory conditions, using four strains from two distinct A. apis clades. We found that both strain and colony of larval origin affected mortality rates. The strains from one clade caused 12–14% mortality while those from the other clade induced 71–92% mortality. Larvae from one colony showed significantly higher susceptibility to chalkbrood infection than larvae from the other two colonies, confirming the existence of genetic variation in susceptibility across colonies. Our results are consistent with antagonistic coevolution between a specialized fungal pathogen and its host, and suggest that beekeeping industries would benefit from more systematic monitoring of this chronic stress factor of their colonies.

Genetics of Type 2 diabetes in Asian Indians

Type 2 diabetes (T2D) is a polygenic disorder with multiple genes located on different chromosomes contributing to its susceptibility. Analysis of the genetic factors is further complicated by the fact that numerous environmental factors interact with genes to produce the disorder. Only a minority of cases of T2D such as maturity-onset diabetes of the young are caused by single gene defects. As Asian Indians have an increased susceptibility to diabetes and have increased insulin resistance, they are a unique population for carrying out genetic studies. Asian Indians develop T2D at lower levels of BMI, one to two decades earlier and have stronger heritability factors compared with Europeans. All these factors point to the role of possible ethnic variations in genetic susceptibility. Recent genetic studies on Asian Indians indicate that certain genes appear to predispose Indians to diabetes while other genes, which afford protection against diabetes and insulin resistance to Caucasians, do not appear to protect Indians. In addition, there are several genes (e.g., TCF7L2), which are similar in Asian Indians and in Europeans, that contribute to susceptibility to T2D. Advances in genotyping techniques and the availability of large patient cohorts have made it possible to identify common genetic variants associated with T2D through genome-wide association studies. Recent studies have shown that common genetic variations contribute to T2D risk within populations but do not explain the difference between populations. In this context, the risk allele evaluation of T2D in Asian Indians could help provide better understanding of increased susceptibility to T2D within this ethnic group.

Genetics of animal health and disease in cattle

There have been considerable recent advancements in animal breeding and genetics relevant to disease control in cattle, which can now be utilised as part of an overall programme for improved cattle health. This review summarises the contribution of genetic makeup to differences in resistance to many diseases affecting cattle. Significant genetic variation in susceptibility to disease does exist among cattle suggesting that genetic selection for improved resistance to disease will be fruitful. Deficiencies in accurately recorded data on individual animal susceptibility to disease are, however, currently hindering the inclusion of health and disease resistance traits in national breeding goals. Developments in 'omics' technologies, such as genomic selection, may help overcome some of the limitations of traditional breeding programmes and will be especially beneficial in breeding for lowly heritable disease traits that only manifest themselves following exposure to pathogens or environmental stressors in adulthood. However, access to large databases of phenotypes on health and disease will still be necessary. This review clearly shows that genetics make a significant contribution to the overall health and resistance to disease in cattle. Therefore, breeding programmes for improved animal health and disease resistance should be seen as an integral part of any overall national disease control strategy.

Quantitative genetics of taura syndrome resistance in pacific white shrimp (penaeus vannamei): a cure model approach

BackgroundIn aquaculture breeding, resistance against infectious diseases is commonly assessed as time until death under exposure to a pathogen. For some diseases, a fraction of the individuals may appear as "cured" (non-susceptible), and the resulting survival time may thus be a result of two confounded underlying traits, i.e., endurance (individual hazard) and susceptibility (whether at risk or not), which may be accounted for by fitting a cure survival model. We applied a cure model to survival data of Pacific white shrimp (Penaeus vannamei) challenged with the Taura syndrome virus, which is one of the major pathogens of Panaeid shrimp species.MethodsIn total, 15,261 individuals of 513 full-sib families from three generations were challenge-tested in 21 separate tests (tanks). All challenge-tests were run until mortality naturally ceased. Time-until-event data were analyzed with a mixed cure survival model using Gibbs sampling, treating susceptibility and endurance as separate genetic traits.ResultsOverall mortality at the end of test was 28%, while 38% of the population was considered susceptible to the disease. The estimated underlying heritability was high for susceptibility (0.41 ± 0.07), but low for endurance (0.07 ± 0.03). Furthermore, endurance and susceptibility were distinct genetic traits (rg = 0.22 ± 0.25). Estimated breeding values for endurance and susceptibility were only moderately correlated (0.50), while estimated breeding values from classical models for analysis of challenge-test survival (ignoring the cured fraction) were closely correlated with estimated breeding values for susceptibility, but less correlated with estimated breeding values for endurance.ConclusionsFor Taura syndrome resistance, endurance and susceptibility are apparently distinct genetic traits. However, genetic evaluation of susceptibility based on the cure model showed clear associations with standard genetic evaluations that ignore the cure fraction for these data. Using the current testing design, genetic variation in observed survival time and absolute survival at the end of test were most likely dominated by genetic variation in susceptibility. If the aim is to reduce susceptibility, earlier termination of the challenge-test or back-truncation of the follow-up period should be avoided, as this may shift focus of selection towards endurance rather than susceptibility.

Host genetic variation in susceptibility to Punta Toro virus

Infection of small laboratory animals by Punta Toro virus (PTV), family Bunyaviridae, genus Phlebovirus, is a model for the study of the human pathogen Rift Valley fever virus (RVFV). We have identified inbred mouse strains with significant differences in host response to the Adames strain of PTV. Nine inbred strains of mice representing major branches in the Mus musculus phylogeny were inoculated subcutaneously with a high dose of PTV in survival experiments. Two inbred strains of mice, NZW/LacJ and 129S1/SvImJ, died ∼4days after PTV infection, whereas 7 other strains survived the challenge and showed no clinical signs of disease. Histologically, 129S1/SvImJ mice showed massive hepatocellular necrosis and had additional lesions in lung, brain, and spleen, whereas NZW/LacJ mice had mild piecemeal hepatocellular necrosis. PTV viral loads in the livers of infected mice were determined by reverse transcriptase quantitative PCR. Inbred mice from strains that showed clinical signs and succumbed to PTV infection had higher liver viral loads than did mice of resistant strains. Hybrid F1 mice were generated by crossing susceptible 129S1 and resistant FVB/N mice and tested for susceptibility. The hybrid F1 mice showed significantly higher viral loads in the liver than the resistant parental FVB/N mice, suggesting that susceptibility is dominant. These findings will enable an unbiased genetic approach to identify host genes mediating susceptibility to PTV.

Obesity, Cancer and Epigenetics

Obesity, Cancer and Epigenetics

Presence of natural genetic resistance in Fraxinus excelsior (Oleraceae) to Chalara fraxinea (Ascomycota): an emerging infectious disease.

Fraxinus excelsior, common ash native to Europe, is threatened by a recently identified pathogenic fungus Chalara fraxinea, which causes extensive damage on ash trees across Europe. In Denmark, most stands are severely affected leaving many trees with dead crowns. However, single trees show notably fewer symptoms. In this study, the impact of the emerging infectious disease on native Danish ash trees is assessed by estimating presence of inherent resistance in natural populations. Disease symptoms were assessed from 2007 to 2009 at two different sites with grafted ramets of 39 selected clones representing native F. excelsior trees. A strong genetic variation in susceptibility to C. fraxinea infections was observed. No genetic or geographic structure can explain the differences, but strong genetic correlations to leaf senescence were observed. The results suggest that a small fraction of trees in the Danish population of ash possess substantial resistance against the damage. Though this fraction is probably too low to avoid population collapse in most natural or managed ash forests, the observed presence of putative resistance against the emerging infectious disease in natural stands is likely to be of evolutionary importance. This provides prospects of future maintenance of the species through natural or artificial selection in favour of remaining healthy individuals.

Effect of Genetic Variation in the Human Fatty Acid Synthase Gene (FASN) on Obesity and Fat Depot‐Specific mRNA Expression

Inhibition of fatty acid synthase (FASN) induces a rapid decline in fat stores in mice, suggesting a role for this enzyme in energy homeostasis. To investigate the potential role of FASN in the pathophysiology of human obesity, the FASN gene was sequenced in 48 German whites. Thirty-five single-nucleotide polymorphisms (SNPs) were identified. Eight SNPs representative for their linkage disequilibrium groups and the Val1483Ile (rs2228305) substitution were genotyped for subsequent association analyses in 1,311 adults from Germany. Further, the tagging SNPs were genotyped also in German childhood cohorts (738 schoolchildren, 205 obese children). Effects of genetic variation on FASN mRNA expression in visceral and subcutaneous adipose tissue from a subgroup of 172 subjects were analyzed. Several polymorphisms in the FASN (rs62078748, rs2229422, rs2229425, and rs17848939) were nominally associated with obesity in case-control studies including 446 obese subjects (BMI >or=30 kg/m(2)) and 389 lean controls (BMI <or=25 kg/m(2)) (adjusted P < 0.05). The strongest significant effect was found for rs2229422 (P = 1.3 x 10(-5) adjusted for age, sex, type 2 diabetes status), which was supported by associations with BMI, waist-to-hip ratio (WHR), fasting plasma insulin and glucose infusion rate (adjusted P < 0.05). Subjects with the Val1483Ile substitution appeared to be protected against obesity. In addition, rs17848939 was nominally significantly associated with the ratio of visceral/subcutaneous FASN mRNA expression (adjusted P = 0.04). No effect of genetic variation in FASN on obesity was found in children. In conclusion, our data indicate a role of FASN genetic variation in susceptibility to obesity in adults.

Red oak responses to nitrogen addition depend on herbivory type, tree family, and site

Elevated atmospheric N deposition is predicted to increase plant growth and C storage in N-limited systems, but this assumes that no mitigating ecological factors are influenced by N deposition. Many herbivores are also N-limited and so increased herbivore damage in response to N deposition may moderate, or even eliminate, gains in plant growth under elevated N. Thus the response of herbivores to N deposition could influence the onset and magnitude of N saturation resulting in expedited decreases in C storage. Since tree susceptibility to herbivores is partially under genetic control and will be influenced by site characteristics, we tested whether the interaction between N deposition, tree growth, and herbivore damage depends on tree genetic variation in susceptibility to herbivores at different locations. By monitoring 12 half-sib families of northern red oak ( Quercus rubra) saplings at two common garden sites in south-central Pennsylvania, we found that herbivores were pervasive at both sites, resulting in 13% chewing damage, 16% galling damage and 28% browsing damage. N addition significantly affected browsing damage (8% overall increase) and chewing damage (19% overall increase) but did not affect galling damage. However, this effect was strongly dependent on the Q. rubra family and location, both of which influenced oak susceptibility to herbivore damage independent of N additions. Greater browsing damage on trees under N addition caused reductions in relative height growth, and this effect also depended on tree family and location. Our result suggests that herbivory, mediated by tree genetic lineage and site-specific conditions, may represent an important component of C sinks and N saturation under elevated N deposition.

Advances in Understanding Benzene Health Effects and Susceptibility

Benzene is a ubiquitous chemical in our environment that causes acute leukemia and probably other hematological cancers. Evidence for an association with childhood leukemia is growing. Exposure to benzene can lead to multiple alterations that contribute to the leukemogenic process, indicating a multimodal mechanism of action. Research is needed to elucidate the different roles of multiple metabolites in benzene toxicity and the pathways that lead to their formation. Studies to date have identified a number of polymorphisms in candidate genes that confer susceptibility to benzene hematotoxicity. However, a genome-wide study is needed to truly assess the role of genetic variation in susceptibility. Benzene affects the blood-forming system at low levels of occupational exposure, and there is no evidence of a threshold. There is probably no safe level of exposure to benzene, and all exposures constitute some risk in a linear, if not supralinear, and additive fashion.

Malignant mesothelioma

Mesothelioma is a malignant tumour of the pleura or peritoneum caused by asbestos. It is increasing in frequency and the prognosis remains grim, with average survival around 1 year. Medical literature and personal experience. Amphibole fibres are far more potent than chrysotile in causing mesothelioma. A minority view suggests that mesotheliomas in those exposed to chrysotile are caused only by tremolite (an amphibole) which contaminates chrysotile. There is a hypothesis, for which evidence is weakening, that Simian virus 40 may cause mesothelioma. There is emerging evidence of genetic variation in susceptibility to fibre carcinogenesis. There are developments in treatment, particularly chemotherapy with pemetrexed and cisplatin which prolongs survival and helps symptoms. Targeted agents for treatment are under investigation and may improve the outlook. The role of radical and palliative surgery requires clarification.

Contributions of three‐site mutations in acetylcholinesterase and cytochrome P450 to genetic variation in susceptibility to organophosphate insecticides within a natural population of Drosophila melanogaster

In this study, we attempted to elucidate the two resistance factors conferring resistance to organophosphates within the Katsunuma population of Drosophila melanogaster (Meigen), one of which has been mapped on the second chromosome and the other on the third chromosome. With regard to the second chromosome factor, we tested susceptibility to malathion of 54 recombinant inbred lines with recombination between ltd and vg. Analyses of variance (ANOVAs) showed highly significant variation in susceptibility to malathion between recombinant lines. In addition, susceptibility of the second-chromosome resistant line to malathion was increased with additional application of piperonyl butoxide, suggesting a member of the Cyp gene family located between ltd and vg. With regard to the third-chromosome factor, we conducted inhibition assays of acetylcholinesterase (AChE) with respect to fenitroxon and carbaryl, to evaluate the contribution of mutated AChE to organophosphate resistance within the Katsunuma population. I50 values of resistant lines, isolated from this population, were about 15 times higher for fenitroxon, and about two times higher for carbaryl, than those of susceptible lines, suggesting the contribution of mutated AChE to organophosphate resistance within the Katsunuma population. We further investigated the genetic variation in the acetylcholinesterase (Ace) gene within the newly collected Katsunuma population, by using the allele-specific polymerase chain reaction (PCR) approach, and revealed that within this population there were high frequencies of resistant-type mutations at three sites in the Ace gene, which play critical roles in altering sensitivity of AChE to organophosphate and carbamate insecticides.

Polymorphisms of HLA-A and HLA-B genes in genetic susceptibility to esophageal carcinoma in Chaoshan Han Chinese

Esophageal carcinoma (EC) occurs at high rate in Chaoshan region of southern China. Human leukocyte antigen (HLA) polymorphism has been implicated in risk for various cancers. To investigate the impact of HLA-A and HLA-B polymorphisms on susceptibility to EC, a case-control study was conducted among 206 patients with esophageal squamous cell carcinoma and 524 controls from Chaoshan Han population. HLA-A and HLA-B polymorphisms were genotyped by polymerase chain reaction-sequence-specific primers. Genotypic association tests for dominant, recessive, and additive models, and haplotypic association were calculated using unconditional logistic regression. A*11 was identified in a recessive model as an only allele strongly associated with EC risk (odds ratios [OR]=2.10, 95% confidence interval [CI]=1.33-3.31) even after correction for multiple test. The haplotypes A*02-B*46 (OR=1.53, 95% CI=1.04-2.24) and A*11-B*51 (OR=2.29, 95% CI=1.20-4.40) showed association with increased risk for EC, whereas A*11-B*58 (OR=0.00, 95% CI=0.00-0.82) was associated with decreased risk, though the significance of these haplotypes was lost after correction. This is a first association study at genetic level identifying HLA-A and HLA-B-related variations in genetic susceptibility to EC among Chaoshan population. The variation pattern is likely to be EC-specific because it is different from that observed for nasopharyngeal carcinoma in the same study population and might, at least in part, explain the high rate of EC in this ethnic group.

Susceptibility of Iberian trees to Phytophthora ramorum and P. cinnamomi

The capacity of Phytophthora ramorum to colonize the inner bark of 18 native and two exotic tree species from the Iberian Peninsula was tested. Living logs were wound‐inoculated in a growth chamber with three isolates belonging to the EU1 and two to the NA1 clonal lineages of P. ramorum. Most of the Quercus species ranked as highly susceptible in experiments carried out in summer, with mean lesion areas over 100 cm2 in Q. pubescens, Q. pyrenaica, Q. faginea and Q. suber and as large as 273 cm2 in Q. canariensis, ca. 40 days after inoculation. Quercus ilex ranked as moderately susceptible to P. ramorum, forming lesions up to 133 cm2 (average 17·2 cm2). Pinus halepensis and P. pinea were highly susceptible, exhibiting long, narrow lesions; but three other pine species, P. pinaster, P. nigra and P. sylvestris, were resistant to slightly susceptible. No significant difference in aggressiveness was found between the isolates of P. ramorum. In addition, there was evidence of genetic variation in susceptibility within host populations, and of significant seasonal variation in host susceptibility in some Quercus species. The results suggest a high risk of some Iberian oaks to P. ramorum, especially in forest ecosystems in southwestern Spain, where relict populations of Q. canariensis grow amongst susceptible understory species such as Rhododendron ponticum and Viburnum tinus. One isolate of P. cinnamomi used as positive control in all the inoculations was also highly aggressive to Iberian oaks and Eucalyptus dalrympleana.

Polimorfismos reguladores y su participación en la patogenia de enfermedades complejas en la era posgenómica

The genomic era is imparting a new impulse to the study of the role of genetic variation in susceptibility to disease. The most common type of genetic variation between individuals is single nucleotide polymorphisms (SNP). The association of SNPs with susceptibility to disease is the current focus of intense research. Recently, the study of SNPs that alter the regulatory mechanisms of gene expression (rSNP) has emerged as a promising field for understanding disease, since this type of variation can have a profound effect on human traits related to susceptibility to disease. The finding and functional characterization of biologically significant rSNPs is advancing our knowledge of genetic determinants for multifactorial disease.

Functional ENTPD1 polymorphisms in African Americans with diabetes and end-stage renal disease.

OBJECTIVEThe vascular ectonucleotidase ENTPD1 protects against renal injury and modulates glucose homeostasis in mouse models. We sought to determine whether human variation in ENTPD1 influences predisposition to diabetes or diabetic nephropathy.RESEARCH DESIGN AND METHODSWe analyzed ENTPD1 single nucleotide polymorphisms (SNPs) in 363 African American control subjects, 380 subjects with type 2 diabetes and end-stage renal disease (DM-ESRD), and 326 subjects with ESRD unrelated to diabetes (non–DM-ESRD). Using human cell lines, we correlated disease-associated ENTPD1 haplotypes with ENTPD1 gene expression. Finally, we studied consequences of ENTPD1 deletion in a mouse model of type 2 diabetes (db/db).RESULTSA common ENTPD1 two-SNP haplotype was associated with increased risk for DM-ESRD (P = 0.0027), and an uncommon four-SNP haplotype was associated with protection against DM-ESRD (P = 0.004). These haplotypes correlated with ENTPD1 gene expression levels in human cell lines in vitro. Subjects with high ENTPD1-expressing haplotypes were enriched in the DM-ESRD group. By crossing ENTPD1-null mice with db mice, we show that ENTPD1 deletion has prominent effects on metabolic syndrome traits. Specifically, deletion of ENTPD1 lowered glucose levels in control (db/−) mice with one functional leptin receptor and dramatically lowered weights in db/db mice with no functional leptin receptors. Similar effects were seen in aged ENTPD1-null mice with normal leptin receptors.CONCLUSIONSENTPD1 polymorphisms appear to influence susceptibility to type 2 diabetes and/or diabetic nephropathy in African Americans. Studies in human cell lines and in vivo mouse data support a potential role for ENTPD1 genetic variation in susceptibility to type 2 diabetes.

Rapid recruitment of innate immunity regulates variation of intracellular pathogen resistance in Drosophila

Genetic variation in susceptibility to pathogens is a central concern both to medicine and agriculture and to the evolution of animals. Here, we have investigated the link between such natural genetic variation and the immune response in wild-type Drosophila melanogaster, a major model organism for immunological research. We found that within nine wild-type strains, different Drosophila genotypes show wide-ranging variation in their ability to survive infection from the pathogenic bacteria Listeria monocytogenes. Canton-S, a resistant strain, showed increased capacity to induce stronger innate immune activities (antimicrobial peptides (AMPs), phenol oxidase activity, and phagocytosis) compared to the susceptible strain ( white) at early time points during bacterial infection. Moreover, PGRP-LE-induced innate immune activation immediately after infection greatly improves survival of the susceptible strain strongly suggesting a mechanism behind the natural genetic variation of these two strains. Taken together we provide the first experimental evidence to suggest that differences in innate immune activity at early time points during infection likely mediates infection susceptibility in Drosophila.

Organic Anion Transporter 3 Contributes to the Regulation of Blood Pressure

Renal organic anion transporters (OAT) are known to mediate the excretion of many drugs, but their function in normal physiology is not well understood. In this study, mice lacking organic anion transporter 3 (Oat3) had a 10 to 15% lower BP than wild-type mice, raising the possibility that Oat3 transports an endogenous regulator of BP. The aldosterone response to a low-salt diet was blunted in Oat3-null mice, but baseline aldosterone concentration was higher in these mice, suggesting that aldosterone dysregulation does not fully explain the lower BP in the basal state; therefore, both targeted and global metabolomic analyses of plasma and urine were performed, and several potential endogenous substrates of Oat3 were found to accumulate in the plasma of Oat3-null mice. One of these substrates, thymidine, was transported by Oat3 expressed in vitro. In vivo, thymidine, as well as two of the most potent Oat3 inhibitors that were characterized, reduced BP by 10 to 15%; therefore, Oat3 seems to regulate BP, and Oat3 inhibitors might be therapeutically useful antihypertensive agents. Moreover, polymorphisms in human OAT3 might contribute to the genetic variation in susceptibility to hypertension.