DNA repair gene polymorphism is associated with the genetic basis of atherosclerotic coronary artery disease

Background: Atherosclerotic coronary artery disease (CAD) is a multifactorial process that appears to be caused by the interaction of environmental risk factors with multiple predisposing genes. It is nowadays accepted that increased levels of DNA damage induced by xenobiotics play an important role in the early phases of atherogenesis. Therefore, in this study, we focus on determining whether genetic variations in xenobiotic-metabolizing [glutathione-S-transferase theta 1 (GSTT1), glutathione-S-transferase mu 1 (GSTM1), cytochrome P450 IIEI (CYP2E1)] and DNA repair [X-ray cross-complementing group 1 (XRCC1)] genes might be associated with increased risk for CAD. Methods: A case-control study was conducted with 400 individuals who underwent subjected to coronary angiography. A total of 299 were patients diagnosed with effective coronary atherosclerosis (case group; >20% obstructive lesion), and 101 (control group) were individuals diagnosed as negative for CAD (<20% obstructive lesions). The polymorphism identifications for GSTM1 and GSTT1, and for CYP2E1 and XRCC1 genes were performed by polymerase chain reaction (PCR) amplification and by PCR-RFLP, respectively. Results and conclusions: The XRCC1 homozygous wild-type genotype Arg/Arg for codon 399 was statistically less pronounced in the case subjects (21.4%) than in controls (38.5%); individuals with the variant XRCC1 genotype had a 2.3-fold increased risk for coronary atherosclerosis than individuals with the wild-type genotype (OR=2.3, 95% CI=1.13-4.69). Conversely, no association between GSTM1, GSTT1, and CYP2E1gene polymorphisms and coronary atherosclerosis was detected. The results provide evidence of the role of DNA damage and repair in cardiovascular disease. © 2011 Elsevier Inc. All rights reserved.

The genetic polymorphism of diabetic nephropathy

Introduction: The Diabetic Nephropathy (DN) affects approximately 40% of patients diagnosed with DM is associated with increased mortality from cardiovascular phenomena and is considered the main cause of Chronic Renal Failure (CRF) in patients dialectics. Methods: Searches were performed on Medline, SciELO, Lilacs and Cochrane databases using the crossing between the key-words: “genetic polymorphism” and “diabetic nephropathy”. Results: The selected studies indicated that diabetic nephropathy is the leading cause of chronic renal failure, which significantly reduces the life expectancy of diabetics. Currently, some factors may have connection with DN. They are: genetic predisposition based on family history, hypertension, and cardiovascular events, quality of glycemic control and lipid levels and blood pressure and smoking. Conclusion: Studies constants are essential to add new elements in the literature for the definition (s) of factor (s) gene (s) specific (s) of diabetic nephropathy.

Comparative expression profiling of E. coli and S. aureus inoculated primary mammary gland cells sampled from cows with different genetic predispositions for somatic cell score

BACKGROUND: During the past ten years many quantitative trait loci (QTL) affecting mastitis incidence and mastitis related traits like somatic cell score (SCS) were identified in cattle. However, little is known about the molecular architecture of QTL affecting mastitis susceptibility and the underlying physiological mechanisms and genes causing mastitis susceptibility. Here, a genome-wide expression analysis was conducted to analyze molecular mechanisms of mastitis susceptibility that are affected by a specific QTL for SCS on Bos taurus autosome 18 (BTA18). Thereby, some first insights were sought into the genetically determined mechanisms of mammary gland epithelial cells influencing the course of infection. METHODS: Primary bovine mammary gland epithelial cells (pbMEC) were sampled from the udder parenchyma of cows selected for high and low mastitis susceptibility by applying a marker-assisted selection strategy considering QTL and molecular marker information of a confirmed QTL for SCS in the telomeric region of BTA18. The cells were cultured and subsequently inoculated with heat-inactivated mastitis pathogens Escherichia coli and Staphylococcus aureus, respectively. After 1, 6 and 24 h, the cells were harvested and analyzed using the microarray expression chip technology to identify differences in mRNA expression profiles attributed to genetic predisposition, inoculation and cell culture. RESULTS: Comparative analysis of co-expression profiles clearly showed a faster and stronger response after pathogen challenge in pbMEC from less susceptible animals that inherited the favorable QTL allele 'Q' than in pbMEC from more susceptible animals that inherited the unfavorable QTL allele 'q'. Furthermore, the results highlighted RELB as a functional and positional candidate gene and related non-canonical Nf-kappaB signaling as a functional mechanism affected by the QTL. However, in both groups, inoculation resulted in up-regulation of genes associated with the Ingenuity pathways 'dendritic cell maturation' and 'acute phase response signaling', whereas cell culture affected biological processes involved in 'cellular development'. CONCLUSIONS: The results indicate that the complex expression profiling of pathogen challenged pbMEC sampled from cows inheriting alternative QTL alleles is suitable to study genetically determined molecular mechanisms of mastitis susceptibility in mammary epithelial cells in vitro and to highlight the most likely functional pathways and candidate genes underlying the QTL effect.

Genetic variations in IL28B and allergic disease in children

Environmental changes affecting the relationship between the developing immune system and microbial exposure have been implicated in the epidemic rise of allergic disease in developed countries. While early developmental differences in T cell function are well-recognised, there is now emerging evidence that this is related to developmental differences in innate immune function. In this study we sought to examine if differences associated with innate immunity contribute to the altered immune programming recognised in allergic children. Here, we describe for the first time, the association of carriage of the T allele of the tagging single nucleotide polymorphism rs12979860 3 kb upstream of IL28B, encoding the potent innate immune modulator type III interferon lambda (IFN-λ3), and allergy in children (p = 0.004; OR 4.56). Strikingly, the association between rs12979860 genotype and allergic disease is enhanced in girls. Furthermore, carriage of the T allele at rs12979860 correlates with differences in the pro-inflammatory profile during the first five years of life suggesting this contributes to the key differences in subsequent innate immune development in children who develop allergic disease. In the context of rising rates of disease, these immunologic differences already present at birth imply very early interaction between genetic predisposition and prenatal environmental influences.

Alcohol dehydrogenase 1C*1 allele is a genetic marker for alcohol-associated cancer in heavy drinkers

Chronic alcohol consumption is associated with an increased risk for upper aerodigestive tract cancer and hepatocellular carcinoma. Increased acetaldehyde production via alcohol dehydrogenase (ADH) has been implicated in the pathogenesis. The allele ADH1C*1 of ADH1C encodes for an enzyme with a high capacity to generate acetaldehyde. So far, the association between the ADH1C*1 allele and alcohol-related cancers among heavy drinkers is controversial. ADH1C genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism in a total of 818 patients with alcohol-associated esophageal (n=123), head and neck (n=84) and hepatocellular cancer (n=86) as well as in patients with alcoholic pancreatitis (n=117), alcoholic liver cirrhosis (n=217), combined liver cirrhosis and pancreatitis (n=17) and in alcoholics without gastrointestinal organ damage (n=174). The ADH1C*1 allele and genotype ADH1C*1/1 were significantly more frequent in patients with alcohol-related cancers than that in individuals with nonmalignant alcohol-related organ damage. Using multivariate analysis, ADH1C*1 allele frequency and rate of homozygosity were significantly associated with an increased risk for alcohol-related cancers (p<0.001 in all instances). The odds ratio for genotype ADH1C*1/1 regarding the development of esophageal, hepatocellular and head and neck cancer were 2.93 (CI, 1.84-4.67), 3.56 (CI, 1.33-9.53) and 2.2 (CI, 1.11-4.36), respectively. The data identify genotype ADH1C*1/1 as an independent risk factor for the development of alcohol-associated tumors among heavy drinkers, indicating a genetic predisposition of individuals carrying this genotype.

Effects of genetic and environmental factors on chronic lower airway disease in horses

BACKGROUND: Environment and genetics influence the manifestation of recurrent airway obstruction (RAO), but the associations of specific factors with mild, moderate, and severe clinical signs are unknown. HYPOTHESIS: We hypothesized that sire, feed, bedding, time outdoors, sex, and age are associated with clinical manifestations of mild, moderate, and severe lower airway disease. ANIMALS: Direct offspring of 2 RAO-affected Warmblood stallions (F1S1, n = 172; F1S2, n = 135); maternal half-siblings of F1S1 (mHSS1, n = 66); and an age-matched, randomly chosen control group (CG, n = 33). METHODS: A standardized questionnaire was used to assess potential risk factors and to establish a horse owner assessed respiratory signs index (HOARSI 1-4, from healthy to severe) according to clinical signs of lower airway disease. RESULTS: More F1S1 and F1S2 horses showed moderate to severe clinical signs (HOARSI 3 and HOARSI 4 combined, 29.6 and 27.3%, respectively) compared with CG and mHSS1 horses (9.1 and 6.2%, respectively; contingency table overall test, P < .001). Sire, hay feeding, and age (in decreasing order of strength) were associated with more severe clinical signs (higher HOARSI), more frequent coughing, and nasal discharge. CONCLUSIONS AND CLINICAL RELEVANCE: There is a genetic predisposition and lesser but also marked effects of hay feeding and age on the manifestation of moderate to severe clinical signs, most markedly on coughing frequency. In contrast, mild clinical signs were not associated with sire or hay feeding in our populations.

No role of matrixmetalloproteinase-3 genetic promoter polymorphism 1171 as a risk factor for cirrhosis in alcoholic liver disease

BACKGROUND: As only a minority of alcoholics develop cirrhosis, polymorphic genes, whose products are involved in fibrosis development were suggested to confer individual susceptibility. We tested whether a functional promoter polymorphism in the gene encoding matrix metalloproteinase-3 (MMP-3; 1171 5A/6A) was associated liver cirrhosis in alcoholics. METHODS: Independent cohorts from the UK and Germany were studied. (i) UK cohort: 320 alcoholic cirrhotics and 183 heavy drinkers without liver damage and (ii) German cohort: 149 alcoholic cirrhotics, 220 alcoholic cirrhotics who underwent liver transplantation and 151 alcoholics without liver disease. Patients were genotyped for MMP-3 variants by restriction fragment length polymorphism, single strand confirmation polymorphism, and direct sequencing. In addition, MMP-3 transcript levels were correlated with MMP-3 genotype in normal liver tissues. RESULTS: Matrix metalloproteinase-3 genotype and allele distribution in all 1023 alcoholic patients were in Hardy-Weinberg equilibrium. No significant differences in MMP-3 genotype and allele frequencies were observed either between alcoholics with or without cirrhosis. There were no differences in hepatic mRNA transcription levels according to MMP-3 genotype. CONCLUSIONS: Matrix metalloproteinase-3 1171 promoter polymorphism plays no role in the genetic predisposition for liver cirrhosis in alcoholics. Stringently designed candidate gene association studies are required to exclude chance observations.

Influence of age and genetic risk on anti-tissue transglutaminase IgA titers

OBJECTIVES: False-positive results of anti-tissue-transglutaminase (tTG) IgA autoantibodies have been reported in subjects with a genetic risk for celiac disease (CD). The aims of this retrospective study were to assess the prevalence of false-positive tTG titers in patients at risk of CD compared with symptomatic children and to evaluate the influence of age and indication for testing on tTG titers. PATIENTS AND METHODS: All tTG results measured in our institution during a 33-month period were evaluated. Patients with known CD were excluded. Indications for testing were either symptoms suggestive of CD (group 1) or history of being at risk for CD (group 2). Duodenal biopsies were recommended if titers were positive (> or =10 U/mL) and offered if borderline (> or =4 to <10 U/mL). RESULTS: The final analysis included 2056 patients, 1707 belonged to group 1, and 349 to group 2. All 65 patients with positive tTG results underwent biopsy (group 1: 57, group 2: 8). Celiac disease was confirmed in 61 subjects (median titer: 107.8 U/mL, range 12.0-1748 mL, NS between group 1 and 2), whereas 4 had normal histology (10.2-25.2 U/mL). Three out of 16 patients with borderline results underwent biopsy and had normal histology. Borderline titers were more common in group 2 patients (2.6% vs 0.4%, P<0.001). Multiple regression analysis in patients with negative tTG results (n=1975) revealed that titers were independently related to age (P<0.05) and indication for testing (P<0.001). CONCLUSIONS: The influence of age and genetic predisposition/risk has to be taken into account when interpreting tTG results.

Genetic variation in genes for the xenobiotic-metabolizing enzymes CYP1A1, EPHX1, GSTM1, GSTT1, and GSTP1 and susceptibility to colorectal cancer in Lynch syndrome.

Individuals with Lynch syndrome are predisposed to cancer due to an inherited DNA mismatch repair gene mutation. However, there is significant variability observed in disease expression likely due to the influence of other environmental, lifestyle, or genetic factors. Polymorphisms in genes encoding xenobiotic-metabolizing enzymes may modify cancer risk by influencing the metabolism and clearance of potential carcinogens from the body. In this retrospective analysis, we examined key candidate gene polymorphisms in CYP1A1, EPHX1, GSTT1, GSTM1, and GSTP1 as modifiers of age at onset of colorectal cancer among 257 individuals with Lynch syndrome. We found that subjects heterozygous for CYP1A1 I462V (c.1384A>G) developed colorectal cancer 4 years earlier than those with the homozygous wild-type genotype (median ages, 39 and 43 years, respectively; log-rank test P = 0.018). Furthermore, being heterozygous for the CYP1A1 polymorphisms, I462V and Msp1 (g.6235T>C), was associated with an increased risk for developing colorectal cancer [adjusted hazard ratio for AG relative to AA, 1.78; 95% confidence interval, 1.16-2.74; P = 0.008; hazard ratio for TC relative to TT, 1.53; 95% confidence interval, 1.06-2.22; P = 0.02]. Because homozygous variants for both CYP1A1 polymorphisms were rare, risk estimates were imprecise. None of the other gene polymorphisms examined were associated with an earlier onset age for colorectal cancer. Our results suggest that the I462V and Msp1 polymorphisms in CYP1A1 may be an additional susceptibility factor for disease expression in Lynch syndrome because they modify the age of colorectal cancer onset by up to 4 years.

HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis: a genome-wide association study in Koreans with replication in North Americans.

OBJECTIVE: To identify systemic sclerosis (SSc) susceptibility loci via a genome-wide association study. METHODS: A genome-wide association study was performed in 137 patients with SSc and 564 controls from Korea using the Affymetrix Human SNP Array 5.0. After fine-mapping studies, the results were replicated in 1,107 SSc patients and 2,747 controls from a US Caucasian population. RESULTS: The single-nucleotide polymorphisms (SNPs) (rs3128930, rs7763822, rs7764491, rs3117230, and rs3128965) of HLA-DPB1 and DPB2 on chromosome 6 formed a distinctive peak with log P values for association with SSc susceptibility (P=8.16x10(-13)). Subtyping analysis of HLA-DPB1 showed that DPB1*1301 (P=7.61x10(-8)) and DPB1*0901 (P=2.55x10(-5)) were the subtypes most susceptible to SSc in Korean subjects. In US Caucasians, 2 pairs of SNPs, rs7763822/rs7764491 and rs3117230/rs3128965, showed strong association with SSc patients who had either circulating anti-DNA topoisomerase I (P=7.58x10(-17)/4.84x10(-16)) or anticentromere autoantibodies (P=1.12x10(-3)/3.2x10(-5)), respectively. CONCLUSION: The results of our genome-wide association study in Korean subjects indicate that the region of HLA-DPB1 and DPB2 contains the loci most susceptible to SSc in a Korean population. The confirmatory studies in US Caucasians indicate that specific SNPs of HLA-DPB1 and/or DPB2 are strongly associated with US Caucasian patients with SSc who are positive for anti-DNA topoisomerase I or anticentromere autoantibodies.

Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1.

Familial hemiplegic migraine type 1 (FHM1) is an autosomal dominant subtype of migraine with aura that is associated with hemiparesis. As with other types of migraine, it affects women more frequently than men. FHM1 is caused by mutations in the CACNA1A gene, which encodes the alpha1A subunit of Cav2.1 channels; the R192Q mutation in CACNA1A causes a mild form of FHM1, whereas the S218L mutation causes a severe, often lethal phenotype. Spreading depression (SD), a slowly propagating neuronal and glial cell depolarization that leads to depression of neuronal activity, is the most likely cause of migraine aura. Here, we have shown that transgenic mice expressing R192Q or S218L FHM1 mutations have increased SD frequency and propagation speed; enhanced corticostriatal propagation; and, similar to the human FHM1 phenotype, more severe and prolonged post-SD neurological deficits. The susceptibility to SD and neurological deficits is affected by allele dosage and is higher in S218L than R192Q mutants. Further, female S218L and R192Q mutant mice were more susceptible to SD and neurological deficits than males. This sex difference was abrogated by ovariectomy and senescence and was partially restored by estrogen replacement, implicating ovarian hormones in the observed sex differences in humans with FHM1. These findings demonstrate that genetic and hormonal factors modulate susceptibility to SD and neurological deficits in FHM1 mutant mice, providing a potential mechanism for the phenotypic diversity of human migraine and aura.

NGS Nominated CELA1, HSPG2, and KCNK5 as Candidate Genes for Predisposition to Balkan Endemic Nephropathy

Balkan endemic nephropathy (BEN) is a familial chronic tubulointerstitial disease with insidious onset and slow progression leading to terminal renal failure. The results of molecular biological investigations propose that BEN is a multifactorial disease with genetic predisposition to environmental risk agents. Exome sequencing of 22 000 genes with Illumina Nextera Exome Enrichment Kit was performed on 22 DNA samples (11 Bulgarian patients and 11 Serbian patients). Software analysis was performed via NextGene, Provean, and PolyPhen. The frequency of all annotated genetic variants with deleterious/damaging effect was compared with those of European populations. Then we focused on nonannotated variants (with no data available about them and not found in healthy Bulgarian controls). There is no statistically significant difference between annotated variants in BEN patients and European populations. From nonannotated variants with more than 40% frequency in both patients' groups, we nominated 3 genes with possible deleterious/damaging variants-CELA1, HSPG2, and KCNK5. Mutant genes (CELA1, HSPG2, and KCNK5) in BEN patients encode proteins involved in basement membrane/extracellular matrix and vascular tone, tightly connected to process of angiogenesis. We suggest that an abnormal process of angiogenesis plays a key role in the molecular pathogenesis of BEN.

Disentangling the role of phenotypic plasticity and genetic divergence in contemporary ecotype formation during a biological invasion

The occurrence of contemporary ecotype formation through adaptive divergence of populations within the range of an invasive species typically requires standing genetic variation but can be facilitated by phenotypic plasticity. The relative contributions of both of these to adaptive trait differentiation have rarely been simultaneously quantified in recently diverging vertebrate populations. Here we study a case of intraspecific divergence into distinct lake and stream ecotypes of threespine stickleback that evolved in the past 140 years within the invasive range in Switzerland. Using a controlled laboratory experiment with full-sib crosses and treatments mimicking a key feature of ecotypic niche divergence, we test if the phenotypic divergence that we observe in the wild results from phenotypic plasticity or divergent genetic predisposition. Our experimental groups show qualitatively similar phenotypic divergence as those observed among wild adults. The relative contribution of plasticity and divergent genetic predisposition differs among the traits studied, with traits related to the biomechanics of feeding showing a stronger genetic predisposition, whereas traits related to locomotion are mainly plastic. These results implicate that phenotypic plasticity and standing genetic variation interacted during contemporary ecotype formation in this case.

The effects of cocaine self-administration on dendritic spine density in the rat hippocampus are dependent on genetic background

Chronic exposure to cocaine induces modifications to neurons in the brain regions involved in addiction. Hence, we evaluated cocaine-induced changes in the hippocampal CA1 field in Fischer 344 (F344) and Lewis (LEW) rats, 2 strains that have been widely used to study genetic predisposition to drug addiction, by combining intracellular Lucifer yellow injection with confocal microscopy reconstruction of labeled neurons. Specifically, we examined the effects of cocaine self-administration on the structure, size, and branching complexity of the apical dendrites of CA1 pyramidal neurons. In addition, we quantified spine density in the collaterals of the apical dendritic arbors of these neurons. We found differences between these strains in several morphological parameters. For example, CA1 apical dendrites were more branched and complex in LEW than in F344 rats, while the spine density in the collateral dendrites of the apical dendritic arbors was greater in F344 rats. Interestingly, cocaine self-administration in LEW rats augmented the spine density, an effect that was not observed in the F344 strain. These results reveal significant structural differences in CA1 pyramidal cells between these strains and indicate that cocaine self-administration has a distinct effect on neuron morphology in the hippocampus of rats with different genetic backgrounds.

Immune response of HLA-DQ8 transgenic mice to peptides from the third hypervariable region of HLA-DRB1 correlates with predisposition to rheumatoid arthritis.

The major histocompatibility complex class II genes play an important role in the genetic predisposition to many autoimmune diseases. In the case of rheumatoid arthritis (RA), the human leukocyte antigen (HLA)-DRB1 locus has been implicated in the disease predisposition. The "shared epitope" hypothesis predicts that similar motifs within the third hypervariable (HV3) regions of some HLA-DRB1 alleles are responsible for the class II-associated predisposition to RA. Using a line of transgenic mice expressing the DQB1*0302/DQA1*0301 (DQ8) genes in the absence of endogenous mouse class II molecules, we have analyzed the antigenicity of peptides covering the HV3 regions of RA-associated and nonassociated DRB1 molecules. Our results show that a correlation exists between proliferative response to peptides derived from the HV3 regions of DRB1 chains and nonassociation of the corresponding alleles with RA predisposition. While HV3 peptides derived from nonassociated DRB1 molecules are highly immunogenic in DQ8 transgenic mice, all the HV3 peptides derived from RA-associated DRB1 alleles fail to induce a DQ8-restricted T-cell response. These data suggest that the role of the "shared epitope" in RA predisposition may be through the shaping of the T-cell repertoire.