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PubMed2002

Genetic predispositions for the presence of cryoglobulinemia and serum autoantibodies in Chinese patients with chronic hepatitis C.

Chronic hepatitis C virus (HCV) infection may induce immunological disorders in the host such as the presence of cryoglobulinemia or serum autoantibodies. The pathogenesis of these phenomena remains unclear but may reflect the host's genetic predispositions. The aim of this study was to evaluate the association between these immunological manifestations and human leukocyte antigen (HLA) expression in Chinese patients with chronic hepatitis C. The presence of serum cryoglobulin and autoantibodies (antinuclear antibody, antismooth muscle antibody, antimitochondrial antibody, antiliver-kidney-microsomal antibody) was determined in 122 Chinese patients with chronic hepatitis C. HLA class I and class II antigens were measured by microlymphocytotoxicity assay or by DNA typing in 122 chronic hepatitis C patients and 228 healthy controls. Of the 122 patients with chronic hepatitis C, 52 (43%) had cryoglobulinemia and 48 (39%) had serum autoantibodies. A significant difference in HLA frequency was noted for DR3, which was found in 36.5% of patients with cryoglobulinemia compared with 8.6% of patients without cryoglobulinemia and 11.3% of healthy controls. A significant difference in HLA frequency was also noted for DR4, which was found in 45.8% of patients with serum autoantibodies compared with 17.6% of patients without serum autoantibodies and 19% of healthy controls. Our results suggest the existence of HLA-linked susceptibility genes (DR3 or DR4) for the development of cryoglobulinemia or serum autoantibodies in Chinese patients with chronic hepatitis C.

Adult↗
PubMed1996

Ethical aspects of genetic predisposition to environmentally-related disease.

Some individuals are highly susceptible to disease caused by chemical exposures and this hypersusceptibility can be genetically determined. Because biomarker technology for the determination of genetic predisposition is at the disposal of researchers, the capability therefore exists to include genetic screening in epidemiologic studies. The application of this technological advance in population-based research is, however, fraught with ethical tensions heretofore unknown. Moral duties alone are of limited use in resolving these problems. Scientific documentation is almost always insufficient to clarify the exact nature of the ethical implications, and ways to deal with uncertainties arising as a result of information generated from genetic screening studies must be considered. The most important tensions relate to autonomy and the right to privacy, fairness and equality, while balancing potential public interest in paternalistic measures. Because no moral framework has been accepted for dealing with this technological advance, an ethical discourse in an open forum is required with all affected parties. Scientists alone, or any other group in isolation, should not expect to resolve these questions, but they should participate in and facilitate the process.

Disease Susceptibility↗
PubMed1986

Genetic predisposition to diabetes mellitus is associated with impaired humoral immunity to coxsackievirus B4.

Experiments were performed to determine whether genetic predisposition to diabetes mellitus (DM) or clinical DM or both exert an influence on the production of neutralization antibodies to coxsackievirus B4 (CB4). The homozygous diabetic mutant mouse db+/db+, on the inbred C57BL/KsJ genetic background, develops a diabetes-like disease when maintained on ad libitum diet but restriction of excess food intake prevents overt disease. The doubly heterozygote db+/+m or the homozygote +m/+m misty coat color mutant, on the C57BL/KsJ genetic background, do not develop DM and served as controls. Animals infected with one-half a previously determined LD50 of CB4 were bled prior to infection and at 3, 5, 7, 14, 21 days and at 1, 2, 3, 4 and 5 months after infection. Serum neutralization antibody (NA) levels were determined from the percent CB4 plaque reduction. Until 2 months following infection, NA levels were not significant in either of the homozygous diabetic mutant groups, db+/db+. In the diabetic mutant group db+/db+, without overt disease, neutralization of CB4 when observed, was low, short-lived, and apparently not specific. However, in the homozygous diabetic mutants with spontaneous diabetes, CB4 NA became evident at 2 months after infection. By 3 months post-infection, serum NA levels were sufficient to cause 90% virus plaque reduction. These observations demonstrate that hereditary DM as characterized by the mutation diabetes, db, in the C57BL/KsJ mouse, is associated with a marked impaired humoral immune response to a diabetogenic human CB4. Specifically, there is an inability to develop an adequate level of anti-CB4 antibodies. The type and degree of immunological impairment are apparently different prior to and after onset of diabetes mellitus.

Animals↗
PubMed2005

C1858T functional variant of PTPN22 gene is not associated with celiac disease genetic predisposition.

Recent findings have demonstrated that the single nucleotide polymorphism 1858C-->T located at the P1 motif of the PTPN22 (protein tyrosine phosphatase nonreceptor 22) gene has functional relevance and is associated with a variety of autoimmune diseases. The aim of this study was to assess the role of the PTPN22 1858C-->T polymorphism in the genetic predisposition to celiac disease (CD). We analyzed a case-control cohort composed by 534 patients with CD and 653 healthy controls and additionally a panel of 271 celiac families. The PTPN22 1858C-->T genotyping was performed by TaqMan 5' allelic discrimination assay. We did not observed any statistically significant deviation after comparing allele and genotypic frequencies of PTPN22 1858C-->T between patients with CD and controls. Accordingly, the familial analysis did not reach statistically significant deviation in the transmission of PTPN22 1858C-->T alleles to the affected offspring. Therefore, our data suggest that the PTPN22 1858 single nucleotide polymorphism has no, or only a negligible, effect on CD susceptibility in this Spanish population.

Autoimmune Diseases↗
PubMed2003

[New hereditary immunodeficiencies and genetic predisposition to infective diseases in children].

Since 10 years severe pediatric infections which were idiopathic have now molecular explanation, because new primary immunodeficiencies responsible of these severe infections were identified. These children presented a new kind of hereditary immunodeficiency with severe and/or recurrent infections caused by only one microorganisms family, in opposition to other patients with "classic" primary immunodeficiency. Standard immunologic explorations for example white blood counts, lymphocyte counts, vaccine serology, immunoglobulin levels and complement were normal. However, these children presented a vulnerability, sometimes lethal, caused by one type of microorganism. The aim of this review is to describe 3 new syndromes with a genetic predisposition of infectious diseases: IL-12-IFN gamma axis deficiency (Mendelian susceptibility to mycobacterial disease), STAT1 deficiency (predisposition to viral disease) and NEMO and IRAK-4 deficiencies (predisposition to infections caused by pyogenic bacteria).

Child↗
PubMed2000

Microsatellite instability in colorectal-cancer patients with suspected genetic predisposition.

Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited syndrome linked to DNA-mismatch-repair (MMR) gene defects, which also account for microsatellite instability (MSI) in tumour tissues. Diagnosis is based mainly on family history, according to widely accepted criteria (Amsterdam Criteria: AC). Aim of this work was to assess MSI in colorectal-cancer patients with suspected genetic predisposition, and to verify whether MSI represents a tool to manage MMR gene (hMSH2 and hMLH1) mutation analysis. We investigated 13 microsatellites (including the 5 NCI/ICG-HNPCC markers) in 45 patients with suspected hereditary predisposition (including 16 subjects from HNPCC families fulfilling the AC). We found MSI-H (high frequency of instability, i.e., in > or =30% of the markers) in 85% of the HNPCC patients and in 16% of the non-HNPCC subjects. The 5 NCI/ICG-HNPCC microsatellites proved to be the most effective in detecting MSI, being mononucleotide repeats the most unstable markers. We investigated the association between hMSH2- and hMLH1 gene mutations and MSI. Our results indicate that AC are highly predictive both of tumour instability and of MMR-gene mutations. Therefore, as the most likely mutation carriers, HNPCC subjects might be directly analyzed for gene mutations, while to test for MSI in selected non-HNPCC patients and to further investigate MMR genes in MSI-H cases, appears to be a cost-effective way to identify subjects, other than those from kindred fulfilling AC, who might benefit from genetic testing.

Adult↗
PubMed1976

Genetic predisposition and stress-induced hypertension.

When chronically exposed to an approach-avoidance conflict, rats with a genetic susceptibility to hypertension showed persisten elevations in systolic blood pressure, but rats with a genetic resistance to hypertension did not. Hence, psychic stress is selectively efficacious in producing hypertensive effects depending on genetic predisposition of the animal.

Animals↗
PubMed2006

Genetic predisposition to colorectal cancer: new pieces in the pediatric puzzle.

Colorectal cancer is rare in childhood. The 2 best characterized familial syndromes, hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) and familial adenomatous polyposis (FAP), are autosomal dominant inherited disorders. HNPCC is relevant to pediatric gastroenterology practice because children and adolescents with underlying colorectal cancer can have germ-line mutations of mismatch repair genes. Recent attention has focused on characterizing genetic predisposition to attenuated FAP in individuals who do not have germ-line mutations in the APC gene. The identification of a second mechanistic explanation called MYH-associated polyposis (MAP), which is an autosomal-recessive condition, has important implications for both screening and management strategies. Hereditary colorectal cancer including HNPCC, FAP, attenuated FAP and MYH-associated polyposis in children are the subject of this review.

Adenomatous Polyposis Coli↗
PubMed1994

Genetic predisposition to hypertension (as detected by Na+/Li+ countertransport) and risk of diabetic nephropathy in childhood diabetes.

In order to evaluate whether insulin-dependent diabetes mellitus patients with incipient nephropathy have an overactivity of erythrocyte sodium-lithium countertransport (Na+/Li+ CT), 82 diabetic children and 38 healthy age-matched control subjects and their parents and grandparents were studied. The children were divided into two groups according to the presence of persistent microalbuminuria (MA). Diabetic children with MA had Na+/Li+ CT activity higher than normoalbuminuric diabetics and healthy controls. The parents and grandparents of microalbuminuric patients showed higher Na+/Li+ CT than parents and grandparents of normoalbuminuric diabetics and of the controls. This study demonstrates that predisposition to hypertension, as indicated by increased Na+/Li+ CT activity in erythrocytes, is more frequently detectable in patients with persistent microalbuminuria than in diabetics without persistent microalbuminuria or in healthy controls. Overactivity of Na+/Li+ CT is present also in parents and grandparents of diabetic children with MA. This study suggests that genetic predisposition to hypertension is more frequent in patients at risk of developing diabetic nephropathy, as well as in their parents and grandparents.

Adolescent↗
PubMed2001

Differences in genetic predisposition to high anxiety in two inbred rat strains: role of substance P, diazepam binding inhibitor fragment and neuropeptide Y.

RATIONALE: Regulatory neuropeptide systems appear to modulate anxiety and emotionality, since anxiety in rats can be increased by intracerebroventricular (ICV) administration of diazepam-binding-inhibitor fragment (DBI) and decreased by ICV administration of neuropeptide Y (NPY) or substance P (SP). OBJECTIVE: Involvement of these three neuropeptides in genetic predisposition to anxiety was studied in two inbred rat strains. METHODS: Levels of anxiety to novel environments were first measured in Fischer-344 (F-344/N) and Wistar Albino Glaxo (WAG/G) rats using open-field conflict, hole-board, black and white box, elevated-plus maze and Vogel lick suppression procedures. Levels of SP, DBI and NPY in the hippocampus, midbrain and hypothalamus of F-344/N and WAG/G rats were then measured without stress (basal levels) or after stress induced by shuttle-box, shock-avoidance testing. Finally, effects of ICV injection of SP or NPY rats were measured in F-344/N and WAG/G rats using the hole-board test. RESULTS: F-344/N rats had elevated level of anxiety compare to WAG/G rats with all five procedures. Levels of SP in the hippocampus, midbrain and hypothalamus of F-344/N rats were significantly lower than in WAG/G rats and levels of SP decreased in WAG/G, but not F-344/N, rats after stress. Levels of DBI in the hippocampus and midbrain of F-344/N rats were also lower than in WAG/G rats, but they increased in F-344/N rats after stress. In contrast, levels of NPY were higher in the midbrain of F-344/N rats than in WAG/G rats, especially after stress. ICV injection of SP or NPY decreased anxiety in the black and white box in both F-344/N and WAG/G rats, but F-344/N rats were more sensitive. CONCLUSIONS: These findings support the hypothesis that decreased levels of SP in certain brain regions may contribute to high levels of anxiety in rats. Decreased levels of DBI and increased levels of NPY in high-anxiety animals may act as compensatory mechanisms.

Animals↗
PubMed2001

Genetic predisposition and pathogenetic mechanisms of interstitial lung diseases of unknown origin.

Understanding of the cellular and cytokine interactions associated with inflammation and fibrosis in interstitial lung diseases (ILDs) has increased substantially during the past few years. Presently, many agents are known to have the ability to induce ILDs, although only a small percentage of exposed individuals will develop the disease. In addition, the majority of ILDs are of unknown origin and many are labelled "idiopathic". Therefore, host susceptibility, genetic factors and, possibly, environmental cofactors may be important for the clinical expression of ILDs. The present review reports evidence of the genetic predisposition to develop ILDs of unknown origin, more specifically sarcoidosis, idiopathic pulmonary fibrosis (IPF), lymphangioleio-myomatosis and ILDs, in systemic sclerosis. For instance, for sarcoidosis and IPF several histocompatibility antigens have been associated with the development and/or the clinical presentation of the disease. Furthermore, there are also several types of ILD that are associated with inherited disorders, of which the tuberous sclerosis complex is only one example. This clearly indicates that pulmonary fibrosis can be influenced by genetic factors. Familial occurrence of sarcoidosis and IPF is also well known, although the exact modes of inheritance are debatable. Several studies have shown that extrinsic factors, such as single or multiple fibrosing agents, probably contribute to the development of clinical ILDs of unknown origin. It is probable that some of these studies deal with patients who do not have classical IPF, as recently defined by the American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus. Therefore, the true role of these extrinsic factors in the development of IPF, or even sarcoidosis, remains speculative. With the help of animal studies and, more specifically, by using knock-out mice, it may be possible in the near future to unravel at least some of the genes that are responsible for the increased susceptibility of the development of interstitial lung diseases.

Animals↗
PubMed2004

Genetic predisposition to testicular germ-cell tumours.

Testicular germ-cell tumours (TGCT) are the most common neoplasm in young men. Various studies have suggested the existence of an inherited predisposition to development of these tumours. Genome-wide screens subsequently provided evidence of a TGCT susceptibility gene on chromosome Xq27 (TGCT1) that might also predispose to cryptorchism. However, this putative gene has yet to be identified, and other TGCT susceptibility genes probably exist. Completion of the human gene map and advances in genetic research will facilitate further investigation of genetic predisposition to TGCT. Insight into inheritance of TGCT might lead to the identification of individuals at increased risk of developing the disorder, increase our understanding of the mutation pathways that lead to sporadic cases, and contribute to improvement in diagnosis and treatment. Clinicians should record the family history of cancer and urogenital differentiation defects in patients with TGCT.

Adult↗
PubMed1995

[Initial results of glutathione-S-transferase GSTM1 and GSTT1 genotypes and genetic predisposition for laryngeal carcinoma].

BACKGROUND: While cigarette smoking and alcohol consumption have been linked to laryngeal carcinoma, the role of genetic factors in determining individual susceptibility is unknown. We describe the role of allelism at glutathione-S-transferase GSTM1, GSTT1, and cytochrome P 450 CYP2D6 loci in determining individual susceptibility to laryngeal squamous cell carcinoma. METHODS: Enzyme genotypes were determined using the polymerase chain reaction in 169 patients suffering T1-T4 laryngeal carcinoma and in 145 controls. RESULTS: While the frequency of the heterozygote GSTM1 A/B genotype was statistically significantly lower in the cases than controls, the frequency of the GSTT1 null genotype was higher in cases than controls. CONCLUSION: These initial data suggest that allelism at GST loci mediates susceptibility to squamous cell carcinoma of the larynx. Thus, GSTM1 A/B appears to be associated with a reduced risk while GSTT1 null confers increased risk. The findings are compatible with the view that genetic predisposition is important in determining risk of this cancer.

Adult↗
PubMed1985

Analysis of DNA haplotypes suggests a genetic predisposition to trisomy 21 associated with DNA sequences on chromosome 21.

To test the hypothesis that there is a genetic predisposition to nondisjunction and trisomy 21 associated with DNA sequences on chromosome 21, we used DNA polymorphism haplotypes for chromosomes 21 to examine the distribution of different chromosomes 21 in Down syndrome and control families from the same ethnic group. The chromosomes 21 from 20 Greek families with a Down syndrome child and 27 control Greek families have been examined for DNA polymorphism haplotypes by using four common polymorphic sites adjacent to two closely linked single-copy DNA sequences (namely pW228C and pW236B), which map somewhere near the proximal long arm of chromosome 21. Three haplotypes, +, +---, and - with respective frequencies of 43/108, 24/108, and 23/108, account for the majority of chromosomes 21 in the control families. However, haplotype - was found to be much more commonly associated with chromosomes 21 that underwent nondisjunction in the Down syndrome families (frequency of 21/50; X2 for the two distributions is 9.550; P = 0.023; degrees of freedom, 3). The two populations (control and trisomic families) did not differ in the distribution of haplotypes for two DNA polymorphisms on chromosome 17. The data from this initial study suggest that the chromosome 21, which is marked in Greeks with haplotype - for the four above described polymorphic sites, is found more commonly in chromosomes that participate in nondisjunction than in controls. We propose an increased tendency for nondisjunction due to DNA sequences associated with a subset of chromosomes 21 bearing this haplotype.

Base Sequence↗
PubMed1999

[Genetic predisposition for multiple metabolic syndrome. Part 1. Diabetes mellitus type 2--incidence and prevalence].

Multiple metabolic syndrome (MMS) implies a frequent coincidence of four basic serious metabolic risk factors for subsequent manifestation of cardiovascular disease. The latter include: central type obesity, arterial hypertension, dyslipoproteinaemia and diabetes mellitus type II (non-insulin-dependent diabetes mellitus--NIDDM). MMS is also described as syndrome X, Reaven's syndrome, insulin resistance syndrome, metabolic syndrome or as the "deadly quartet". NIDDM in humans is conceived as a syndrome the pathogenesis of which is multifactorial and it is not an unequivocal nosological unit. It many epidemiological studies reliable evidence was provided that in the aetiology of NIDDM a marked genetic influence is involved. Its genetic predisposition is conditioned by the interaction of candidate genes and a complex of influences of the external environment. Evidence was provided that MMS phenotypes cumulate only in members of some families. The mode of genetic transmission of NIDDM remains obscure.

Adult↗
PubMed2000

Genetic predispositions to acute and chronic pancreatitis.

Advances in molecular genetics have provided the powerful tools necessary to identify the key molecules and mechanisms that underly the disease process. Continued work in this area promises to reveal new insights as new disease genes are discovered. This article focuses on the insights into the cause of acute and chronic pancreatitis gained by investigation of the HP genes, the diagnosis of the known mutations, the fascinating observation of nonpenetrance, and a look at future directions.

Acute Disease↗