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PubMed2003

Genes expressed by the kidney, but not by bone marrow-derived cells, underlie the genetic predisposition to progressive glomerulosclerosis after mesangial injury.

Progressive renal failure is accompanied by uncontrolled accumulation of extracellular matrix in glomeruli and tubulointerstitium, eventually resulting in glomerulosclerosis. Although glomerulosclerosis occurs secondary to various renal diseases, the fact that not all patients develop progressive glomerulosclerosis suggests that genetic factors may underlie the tendency to progress, or not to progress. Identified were two Lewis rat substrains with small genetic differences but with considerable difference in resolution of glomerulonephritis after anti-Thy-1 administration. In the Lewis/Møllegard rat strain, anti-Thy-1 glomerulonephritis spontaneously resolves within 4 wk. In contrast, Lewis/Maastricht rats develop progressive glomerulosclerosis after induction of this disease. The involvement of bone marrow-derived cells and kidney cells in the development of glomerulosclerosis was determined. In the first study, exchange of bone marrow between these substrains did not affect the course of anti-Thy-1 nephritis. Lewis/Møllegard rats recovered rapidly, but Lewis/Maastricht rats showed progressive disease regardless of the genotype of the bone marrow they received. In the second study, kidneys were exchanged between the substrains. After transplantation, anti-Thy-1 nephritis was induced and glomerular damage assessed at day 21. Severe damage was observed in Lewis/Maastricht glomeruli independent of whether the kidney had been transplanted or not. Similarly, Lewis/Møllegard glomeruli, whether transplanted or not, revealed no residual histopathologic abnormalities. The inherited differences between the two substrains with regard to their insusceptibility to develop progressive glomerulosclerosis after mesangial injury are governed by genes expressed by the kidney, but not by bone marrow-derived cells.

Animals↗
PubMed1999

Altered NGF regulation may link a genetic predisposition for hypertension with hyperactive voiding.

PURPOSE: Hyperactive voiding and elevated smooth muscle NGF output are traits of the spontaneously hypertensive rat (SHR). Elevated target-derived NGF is associated with hypertension and hyperactive voiding in SHRs. In the present study, we tested for possible genetic links between hypertension, hyperactive voiding and augmented bladder smooth muscle cell (BSMC) NGF secretion. MATERIALS AND METHODS: We crossed SHRs with WKYs to produce a gene segregating F2 population. We measured F2 mean arterial blood pressure (BP) and six-hour voiding frequency. BSMCs were cultured from 'Low BP F2s' (95+/-2) and 'High BP F2s' (141+/-3 mm. Hg) and conditioned medium tested for NGF with a two-site ELISA. The NGF regulators isoproterenol, platelet-derived growth factor (PDGF) and phorbol-12-myristate-13-acetate were tested in F2 BSMC cultures. RESULTS: A positive correlation (r = 0.75) between blood pressure and voiding frequency existed in this F2 population. As BP rose voiding frequency increased and volume per void decreased such that there were no significant changes in total urine voided (Low BP F2s: 1.0+/-0.5; High BP F2s: 6.2+/-0.5 voids/6 hours). Low BP F2s (2.0+/-0.2) secreted NGF at a higher basal rate than High BP F2s (0.7+/-0.1 fg NGF/hr/100 cells). However, High BP F2s (1,620 and 3,850) were oversensitive to isoproterenol and PDGF-induced increases in NGF output, compared with Low BP F2s (219 and 1,282% control, respectively). CONCLUSIONS: Elevated tissue NGF due to a hypersensitivity to NGF regulating stimuli, rather than alterations in basal NGF, may genetically link hypertension and hyperactive voiding.

Animals↗
PubMed2001

Nucleotide excision repair gene XPD polymorphisms and genetic predisposition to melanoma.

The nucleotide excision repair pathway has evolved to deal with UV light-induced DNA damage. Individuals with the rare inherited nucleotide excision repair deficiency disease xeroderma pigmentosum have a 1000-fold increased incidence of skin cancer. We are interested in the possibility that more subtle changes in nucleotide excision repair genes, resulting in either a reduced capacity for repair or in altered interactions between repair proteins and components of the cell cycle control machinery, might constitute important genetic risk factors for the development of skin cancer in the general population. To investigate this hypothesis we have compared the frequency of polymorphisms in exons 6, 22 and 23 of the XPD gene in melanoma patients and a control group. For each of these two allele polymorphisms one of the alleles was over-represented in the melanoma group and there was a significant association with melanoma. Importantly, this association did not extend to markers immediately flanking the XPD gene, thus providing evidence that XPD gene polymorphisms might predispose to melanoma in the general population. There is a report that one of the polymorphic XPD alleles (exon 23 Lys), which is over-represented in the melanoma group, has reduced repair proficiency and we discuss the possibility that this is the causal change to the XPD gene that predisposes to melanoma.

Alleles↗
PubMed2007

Genetic predisposition to asthma and atopy.

A large number of studies have tried to identify heritable components in the susceptibility to asthma and atopy phenotypes. This review examines the evidence of multigenetic inheritance for these conditions. We identified in the literature at least 372 gene-disease association studies for asthma and 124 for atopy published in the last 6 years. Gene-environment analyses were performed in 41 and 14 articles, respectively, in the same time period. Many postulated associations have been probed with limited sample sizes and will require more extensive replication and large-scale evidence. Meta-analyses have been performed for polymorphisms in 5 genes and provide modest evidence for genetic association of asthma with ADAM33 and TNFA gene polymorphisms. Meta-analyses of linkage studies show that it is unlikely to detect strong linkage peaks for asthma susceptibility. However, linkage was claimed between loci on chromosomes 2, 4, 6, 9, 10, 11 and 15 and total serum IgE levels. Careful definitions and standardization of phenotypes across teams of investigators are important to endorse. New large-scale testing platforms may offer new opportunities for discovering susceptibility gene variants, but they need to be coupled with careful study design, international collaboration, and possibly also dissection of gene-environment interactions.

Asthma↗
PubMed1997

[Genetic predisposition to infectious diseases].

At the present time more is known about barriers to transmission of infectious agents between species than barriers to transmission within the same species. However differences in resistance to infection have been well-established within given species of various plants and domestic farm animals. Unsurprisingly several similar mechanisms have been observed in humans. A well-known human example of genetic protection is resistance to malaria in endemic areas which has been associated with polymorphism in alpha and beta chain globulin genes, cytoskeleton proteins, and protein/receptors on the surface of red blood cells. Studies regarding infection by Schistosoma mansoni show that the extent of infection depends largely on each individual's intrinsic resistance under the control of a single major gene which has now been located on q31-33 locus of the long arm of chromosome 5. This locus harbors several genes involved in differentiation of auxiliary T lymphocytes. With regard to HIV infection it has been known for several years that a small but significant number of individuals are relatively resistant. This resistance has been attributed to deletion of the gene coding for the chemokine receptor used by the virus as a co-receptor to infect macrophage.

Agriculture↗
PubMed2005

CTLA-4 and the genetic predisposition to autoimmunity.

Due to the wide spectrum of clinical manifestations and their epidemiological dimensions, autoimmune diseases represent an important medical issue. They are the consequence of the loss of immune tolerance to autoantigens, which in turn is a result of the interaction of environmental, as well as genetic factors. The predisposing role of HLA antigens is widely accepted; nonetheless, it does not fully explain the occurrence of autoimmune disorders. In this topical review, we present the current knowledge on the role of some non-HLA genes (ICOS, CD28 and CTLA-4 in particular) in the development of autoimmunity. (Fig. 1, Ref: 106.)

Antigens, CD↗
PubMed2005

HLA associated genetic predisposition to autoimmune diseases: Genes involved and possible mechanisms.

Autoimmune diseases are the result of an interplay between predisposing genes and triggering environmental factors, leading to loss of self-tolerance and an immune-mediated destruction of autologous cells and/or tissues. Genes in the HLA complex are among the strongest predisposing genetic factors. The HLA complex genes primarily involved are most often those encoding the peptide-presenting HLA class I or II molecules. A probable mechanism is preferential presentation by the disease-associated HLA molecules of peptides from autoantigens to T cells. Recent studies have shown, however, that other genes in the HLA complex also contribute. Taken together, available evidence suggests that the HLA complex harbour both disease predisposing genes which are quite specific for some autoimmune diseases (e.g. HLA-B27 for ankylosing spondylitis) and others which may be more common for several diseases. This will be briefly reviewed in the following.

Animals↗
PubMed1997

Genetic predisposition to multiple sclerosis as revealed by immunoprinting.

This study was designed to examine the immunogenetic background predisposing to multiple sclerosis (MS). Three hundred fifty-eight clinically well-characterized MS patients from Germany were investigated and compared to 395 healthy control subjects. Each individual was genotyped for 22 polymorphic markers located within or close to immunorelevant candidate genes including HLA-DRB1*, T-cell receptor (TCR), cell interaction molecules, cytokines, and cytokine receptor genes. Altogether, approximately 17,000 genetic analyses were performed. Patients were grouped according to the course of MS-relapsing-remitting or chronic progressive. Most of the genetic markers were not associated with increased risk or their exact contribution was not clear (e.g., tumor necrosis factor). The relative risks for HLA-DRB1*15+ and DRB1*03+ individuals were 3.64 and 1.42, respectively. In both groups of patients, certain TCRB gene polymorphisms were risk factors. In DRB1*03+ individuals the relative risk was increased (> 22) when a specific TCRBV6S3 allele was also inherited. Furthermore, distinct linkage disequilibria of TCRBV6S1/TCRBV6S3 elements in patients and control subjects strongly suggested an additional risk factor in the TCRBV region for DRB1*15+ individuals. These findings are discussed with respect to the pathogenesis and rational approaches to the therapy of MS.

Adolescent↗
PubMed2003

Genetic predisposition to external apical root resorption.

External apical root resorption (EARR) can be an undesirable sequela of orthodontic treatment. Previous studies have suggested that EARR has a substantial genetic component. Linkage and association were examined between polymorphisms of the interleukin IL-1 (IL-1A and IL-1B) genes and EARR in 35 white American families. Buccal swab cells were collected for DNA isolation and analysis. The EARR in the maxillary central incisors, the mandibular central incisors, and the mesial and distal roots of the mandibular first molar were analyzed separately and together by using both linkage and association methods of analysis. Highly significant (P =.0003) evidence of linkage disequilibrium of IL-1B polymorphism with the clinical manifestation of EARR was obtained. The analysis indicates that the IL-1B polymorphism accounts for 15% of the total variation of maxillary incisor EARR. Persons homozygous for the IL-1B allele 1 have a 5.6 fold (95% CI 1.9-21.2) increased risk of EARR greater than 2 mm as compared with those who are not homozygous for the IL-1 beta allele 1. Data indicate that allele 1 at the IL-1B gene, known to decrease the production of IL-1 cytokine in vivo, significantly increases the risk of EARR. These findings are consistent with an interpretation of EARR as a complex condition influenced by many factors, with the IL-1B gene contributing an important predisposition to this common problem. Defining genetic contributions to EARR is an important factor in understanding the contribution of environmental factors, such as habits and therapeutic biomechanics.

Alleles↗
PubMed1999

[Genetic predisposition in multiple metabolic syndrome. Part 2. Candidate genes in type II diabetes mellitus].

The author presents a review on candidate genes of proteins involved in the metabolism of glucose, lipids and other metabolites (glucose carriers, insulin receptors, proinsulin, glucokinase, amyline, glycogen synthase). One of the main causes of enhanced atherogenesis in patients with type II diabetes (NIDDM) are marked genetically conditioned deviations of the lipid, lipoprotein and apolipoprotein metabolism. In the metabolic dyshomeostasis of multiple metabolic syndrome participate in the process of atherogenesis also: isoforms of apolipoprotein E4, isoforms of apolipoprotein A-IV-1/1, hyperuricaemia, raised levels of the plasminogen activator inhibitor 1 (PAI-1), hyperfibrinogenaemia, hyperhomocysteinaemia and other metabolites (cytokines, endothelin etc.). Patients with a greated genetic sensitivity manifest diabetes sooner and more intensely and die at a younger age in particular from cardiovascular disease, but also on account of a higher incidence of tumours diseases.

Arteriosclerosis↗
PubMed2001

Comprehensive allelotype study of ovarian tumors of low malignant potential: potential differences in pathways between tumors with and without genetic predisposition to invasive carcinoma.

Ovarian tumors of low malignant potential (LMP) are intermediate between adenomas and ovarian carcinomas (OC); however, the relevance of LMP to ovarian carcinogenesis is not clear. We performed a comparative analysis of allelotypes in 50 cases of LMP (42 mucinous and 8 serous) and 23 cases of OC (15 mucinous and 8 serous) to investigate any differences in genetic changes. Analysis of loss of heterozygosity (LOH) using 25 microsatellite markers reportedly associated with OC revealed that the total LOH frequency at each marker was significantly lower in LMP than in OC (p < 0.01). However, 9 (36%) loci showed higher LOH frequency in mucinous LMP than in mucinous OC. A genome-wide scan for LOH using 91 microsatellite markers and fine mapping revealed that LOH at D7S1805 (7q35) is characteristic of mucinous LMP (19.4% in mucinous LMP, 8.3% in mucinous OC). We further studied LOH in 3 cases of mucinous OC that were accompanied by mucinous LMP lesions. In 2 cases, LOH frequency was higher in the carcinoma portion than in the morphologically LMP portion. The other case showed microsatellite instability in the morphologically LMP portion and LOH in the carcinoma portion. Our results suggest the presence of an LMP-to-OC developmental sequence and the existence of a subset of LMP that does not develop into OC in the mucinous subtype of ovarian tumors.

Adenoma↗
PubMed2006

Genetic predisposition of responsiveness to therapy for chronic hepatitis C.

BACKGROUND: A combination of interferon-alpha (IFN-alpha) and ribavirin has been the choice for treating chronic hepatitis C (CHC) patients. It achieves an overall sustained response rate of approximately 50%; however, the treatment takes 6-12 months and often brings significant adverse reactions to some patients. It would therefore be beneficial to include a pretreatment evaluation in order to maximize the efficacy. In addition to viral genotypes, we hypothesize that patient genotypes might also be useful for the prediction of treatment response. METHODS: We retrospectively analyzed the genetic differences of CHC patients that are associated with IFN/ribavirin responses. The DNA polymorphisms among 195 sustained responders and 122 nonresponders of CHC patients of Taiwanese origin were compared. Statistical and algorithmic methods were used to select the genes associated with drug response and single nucleotide polymorphisms (SNPs) that permitted the construction of a predictive model. RESULTS: Association studies and haplotype reconstruction revealed selection of seven genes: adenosine deaminase, RNA-specific (ADAR), caspase 5, apoptosis-related cysteine peptidase (CASP5), fibroblast growth factor 1 (FGF1), interferon consensus sequence binding protein 1 (ICSBP1), interferon-induced protein 44 (IFI44), transporter 2, ATP-binding cassette, subfamily B (TAP2) and transforming growth factor, beta receptor associated protein 1 (TGFBRAP1) for the responsiveness trait. Based on confirmed linkage disequilibrium block in the population, a minimal set of 26 SNPs in the seven selected genes was inferred. To predict treatment outcome, a multiple logistic regression model was constructed using susceptible genotypes of SNPs. The performance of the resultant model had a sensitivity of 68.2% and specificity of 60.7% on 317 CHC patients treated with IFN-combined therapy. In addition, a prediction model with both the host genetic and viral genotype information was also constructed which enhanced the performance with a sensitivity of 80.7% and specificity of 67.2%. CONCLUSIONS: A genetic model was constructed to predict outcomes of the combination therapy in CHC patients with high sensitivity and specificity. Results also provide a possible process of selecting targets for predicting treatment outcomes and the basis for developing pharmacogenetic tests.

Adult↗
PubMed1991

Investigation of the role of polymorphisms at the alcohol and aldehyde dehydrogenase loci in genetic predisposition to alcohol-related end-organ damage.

Little is known about factors determining individual susceptibility to the physical complications of alcohol abuse but genetically determined differences in ethanol metabolism may be important. The oxidative metabolism of alcohol is catalyzed by alcohol and aldehyde dehydrogenase. Polymorphisms have been observed at two of the five loci encoding alcohol dehydrogenase subunits: ADH2 (producing three beta subunits) and ADH3 (producing two tau subunits) and also at the locus encoding the metabolically important form of aldehyde dehydrogenase, ALDH2. We have compared ADH2, ADH3 and ALDH2 allele frequencies in patients with alcohol-related cirrhosis (n = 59) and chronic pancreatitis (n = 13) with 79 local healthy control subjects. The different alleles were detected with allele-specific oligonucleotide probes after amplification of leukocyte DNA by the polymerase chain reaction. All patients and all but one control subject were homozygous ADH2*1, encoding the beta 1 subunit. No ADH2*3 alleles were detected. All 34 patients and 39 control subjects tested were homozygous ALDH2*1 encoding the active enzyme. ADH3 allele frequencies were different in patients and control subjects. ADH3*1 frequency: control subjects, 55.1%; cirrhotic patients, 62.7%; chronic pancreatitis patients, 65.4%. The difference between the patient groups combined and the control subjects was significant (p less than 0.05; G-test of Sokal and Rohlf) if it was assumed that the allele frequency in our control population was a reasonable estimate of our local population allele frequency. These results suggest that genetically determined differences in alcohol metabolism may, in part, explain predisposition to alcohol-related end-organ damage.

Alcohol Dehydrogenase↗
PubMed1999

Hypocomplementemia discloses genetic predisposition to hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: role of factor H abnormalities. Italian Registry of Familial and Recurrent Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura.

Familial hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) carry a very poor outcome and have been reported in association with decreased serum levels of the third complement component (C3). Uncontrolled consumption in the microcirculation, possibly related to genetically determined deficiency in factor H--a modulator of the alternative pathway of complement activation--may account for decreased C3 serum levels even during disease remission and may predispose to intravascular thrombosis. In a case-control study by multivariate analysis, we correlated putative predisposing conditions, including low C3 serum levels, with history of disease in 15 cases reporting one or more episodes of familial HUS and TTP, in 25 age- and gender-matched healthy controls and in 63 case-relatives and 56 control-relatives, respectively. The relationship between history of disease, low C3, and factor H abnormalities was investigated in all affected families and in 17 controls. Seventy-three percent of cases compared with 16% of controls (P < 0.001), and 24% of case-relatives compared with 5% of control-relatives (P = 0.005) had decreased C3 serum levels. At multivariate analysis, C3 serum level was the only parameter associated with the disease within affected families (P = 0.02) and in the overall study population (P = 0.01). Thus, subjects with decreased C3 serum levels had a relative risk of HUS or TTP of 16.56 (95% confidence interval [CI], 1.66 to 162.39) within families and of 27.77 (95% CI, 2.44 to 314.19) in the overall population, compared to subjects with normal serum levels. Factor H abnormalities were found in four of the cases, compared with three of the healthy family members (P = 0.02) and none of the controls (P = 0.04) and, within families, factor H abnormalities were correlated with C3 reduction (P < 0.05). Reduced C3 clusters in familial HUS and TTP is likely related to a genetically determined deficiency in factor H and may predispose to the disease. Its demonstration may help identify subjects at risk in affected families.

Adolescent↗