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PubMed2003

Multiple and high-titer single autoantibodies in schoolchildren reflecting the genetic predisposition for type 1 diabetes.

The study aimed to compare the HLA specificities of AAb-positive healthy schoolchildren with those of patients with type 1 diabetes (T1D). HLA-DRB1 and DQB1 alleles were determined in 178 AAb-positive and 339 AAb-negative schoolchildren aged 6-17 years without first-degree relatives with T1D and in 274 patients with T1D. AAbs against glutamic acid decarboxylase (GADA), protein tyrosine phosphatase (IA-2A), and insulin (IAA) were determined by (125)I-antigen binding, and islet cell cytoplasmic antibodies (ICAs) immunohistochemically. Here, 82.6% (147/178) of AAb-positive schoolchildren had single AAbs and 17.4% (31/178) had multiple AAbs. In both groups, GADA occurred with highest and IAA with lowest frequency. In children with single AAbs at levels between the 99th and 99.9th percentile, frequencies of the diabetes-associated DRB1 (*03, *04) and DQB1 (*02, *0302) alleles and the protective DRB1 (*15) and DQB1 (*0602) alleles did not differ from those of controls. In patients, the positive associations were confirmed for DRB1*04 (OR = 5.39) and DQB1*0302 (OR = 9.05), whereas DRB1*15 (OR = 0.05) and DQB1*0602 (OR = 0.06) were negative-associated (p < 0.001). The same association was found in schoolchildren with multiple AAbs for DRB1*04 (OR = 3.84), DQB1*0302 (OR = 4.95), and DRB1*15 (OR = 0.1; p < 0.001-0.014), and with high-titer single AAbs (>/=99.9th percentile), but none of them had DQB1*0602. The highest risk genotype DQB1*02/*0302 occurred in 36.5% of patients (OR = 21.07) and in 19.3% of children with multiple AAbs (OR = 8.8; p<0.001). It is concluded that probands with multiple and high-titer single AAbs in the general population have the same genetic predisposition for T1D as patients and are therefore at highest risk for the disease.

Adolescent↗

PubMed2001

The Malmö International Brother Study (MIBS): further support for genetic predisposition to inhibitor development in hemophilia patients.

The issue of factors predisposing for inhibitor development in haemophilia patients is still largely unresolved. In an attempt to address this problem, we initiated a registry in 1996 of siblings with haemophilia and with or without a history of inhibitors. Four hundred and sixty families have accrued, of whom 388 suffer from haemophilia A and 72 haemophilia B. Twenty-five of the brother pairs are twins. The inhibitor incidence in all families with severe haemophilia A was 31.7%. The corresponding figure in the caucasian patients was 27.4%, whereas a higher incidence of inhibitors was reported in the black subjects (55.6%). Twins were reported in six of the 100 inhibitor families, for whom monozygocity was confirmed in three cases. In 32 families (32%), at least two brothers had a history of inhibitors. In 22 (69%) of these families, the inhibitor was also of the same type, i.e. either high- or low-responding. The overall concordance within the severe haemophilia A families was found to be 78.3% (195/249) compared to an expected figure of 68.0% and 58.0% using an inhibitor incidence of 20 and 30%, respectively (P < 0.0001). The corresponding figure for the twins was 88.2% (15/17). Moreover, the risk for inhibitor development in families with a previous inhibitor history was found to be 48% (95% confidence interval [CI] 35-62%), whereas the risk in families with no previous known inhibitor was only 15% (95% CI 11-21%) corresponding to a relative risk of 3.2 (95% CI 2.1-4.9). Immune-tolerance induction was reported in 24 families, of whom 13 siblings were successfully treated. Our data clearly support the concept that a genetic predisposition for inhibitor development exists. However, the markers of this predisposition remain to be elucidated and we believe that the MIBS registry will be useful for this purpose.

Chi-Square Distribution↗

PubMed1999

Impaired airway function and wheezing in infancy: the influence of maternal smoking and a genetic predisposition to asthma.

This prospective community-based study of infants born in inner London was undertaken to examine the association between premorbid airway function and subsequent wheezing in the first year of life and to explore the influence on this association of a family history of asthma and maternal smoking during pregnancy. Healthy Caucasian term infants were recruited shortly after birth, and physician-diagnosed wheezing episodes were identified retrospectively from medical records. Specific airway conductance was determined from plethysmographic measurements of lung volume and airway resistance, before 13 wk and prior to any respiratory illness, in 101 infants, 28 of whom experienced at least one episode of wheezing during the first year. Mean (SD) specific airway conductance was significantly diminished in infants who subsequently wheezed: 2.02 (1.07) s-1. kPa-1 and 2.60 (0.93) s-1. kPa-1, respectively (p < 0.05), and in those with a first-degree relative with asthma: 1.98 (0.83) s-1. kPa-1 and 2.60 (1.0) s-1. kPa-1, respectively (p < 0.05), but not in those whose mothers smoked during pregnancy, in whom airway resistance was, however, significantly elevated (p < 0.05). The odds ratio (95% confidence interval [CI]) for wheezing was 2.1 (1.1 to 3.8) for every unit (s-1. kPa-1) decline in specific airway conductance (p = 0.02). After adjustment for premorbid airway function, the odds of wheezing were significantly increased in those with a family history of asthma (4. 3; 95% CI, 1.3 to 13.8; p = 0.016) and those exposed to maternal smoking during pregnancy (4.9; 95% CI, 1.6 to 15.0; p = 0.005). Our findings confirm previous reports that impaired premorbid airway function precedes and predicts wheezing in the first year. Among those with a genetic predisposition to asthma, alterations in airway geometry or tone may increase susceptibility to wheezing. Maternal smoking has important and potentially preventable adverse effects on somatic growth and respiratory morbidity in early life.

Airway Resistance↗

PubMed1996

Prophylactic mastectomy for genetic predisposition to breast cancer: the proband's story.

The identification of the BRCA1 gene may prove a mixed blessing in the short term. First, the demand for testing might outstrip available resources, the ethics of testing are complex and the advice to give someone who tests positive is as yet unclear. Furthermore, the psychological dynamics within such families have not yet been considered seriously. As these families might be widespread, there will inevitably be problems involving clinical genetic centres in different parts of the country, or for that matter, in different areas of the world. In this paper we provide a case report, which might be considered an adumbration of things to come. The proband in this story (a co-author) was known to have inherited a genetic predisposition to cancer. This was because her identical twin had already developed the disease and she came from a kindred with a very high probability for carrying a dominant breast cancer gene in the germ line. We describe the personal reactions of an individual woman faced with these difficult decisions, the impact on her family and the impact on the clinical genetic services in different parts of the country. Our experience could help to provide a template for the development of regional services once genetic testing for predisposition to breast cancer becomes widely available.

Adult↗

PubMed1994

Altered levels of erythrocyte calcium-binding proteins in essential hypertensives with genetic predisposition: correlation with ambulatory blood pressure.

OBJECTIVE: To examine whether changes in calcium-binding proteins, one of the components of the calcium ion handling mechanism, occur in humans with essential hypertension. DESIGN: We measured the levels of cytosolic calcium-binding proteins purified from human erythrocytes using a felodipine fluorescence assay, and examined the correlation between this parameter and the ambulatory blood pressure (ABP). We divided 127 subjects into four age-matched groups according to their mean ABP levels and whether they had a family history of both hypertension and stroke [group A hypertensives with a positive family history (n = 30), group B hypertensives with no family history (n = 31), group C normotensives with a family history (n = 31) and group D normotensives with no family history (n = 35) of hypertension and stroke]. RESULTS: The erythrocyte cytosolic level of calcium-binding proteins in group A was significantly lower than that in group B, as was that in group C compared with group D. There was no significant correlation between the erythrocyte level of calcium-binding proteins and casual blood pressure values in any group. However, in group A significant negative correlations between the erythrocyte level of calcium-binding proteins and systolic and mean ABP were observed (r = -0.34, P < 0.05 and r = -0.39, P < 0.05, respectively). No significant correlations between the ABP and erythrocyte levels of calcium-binding proteins were observed in the other groups. When each group was subdivided according to sex, there were significant negative correlations between the erythrocyte level of calcium-binding proteins and the systolic and mean ABP in the males of groups A and C, but no correlations were found in any of the female subgroups or the males of groups B and D. Reducing the blood pressure by antihypertensive drug therapy did not affect the erythrocyte calcium-binding proteins level in 13 patients from groups A and B. Analysis using anion-exchange fast-performance liquid chromatography on a Mono-Q column and sodium dodecyl sulphate-polyacrylamide gel electrophoresis revealed that the calcium-binding proteins in human erythrocytes, the levels of which were low in group A, formed a single protein band with a molecular weight of 17,000, which was assumed to be a calmodulin. CONCLUSIONS: These results suggest that there are subgroups of hypertensive patients with low erythrocyte cytosolic levels of calcium-binding proteins, which are genetically determined. Furthermore, our data suggest that the erythrocyte level of calcium-binding proteins and ABP in male subjects with hypertension and normotensives with a genetic predisposition are correlated strongly, whereas no such correlation was observed in any female subgroup. This indicates that the regulatory mechanism or mechanisms involved in the control of blood pressure in men and women may be different.

Aging↗

PubMed2002

Chromosomal radiosensitivity in young cancer patients: possible evidence of genetic predisposition.

PURPOSE: To investigate the G2 chromosomal radiosensitivity of patients with cancers diagnosed when the patients are less than 20 years of age. Earlier studies demonstrated an enhanced sensitivity in substantial proportions of patients with breast or colorectal cancer, and in early onset head and neck cancer cases. Heritability of chromosomal radiosensitivity in families of breast cancer patients was also demonstrated. It is suggested that elevated sensitivity in this assay could be a marker of genetic predisposition to cancer, mediated through inherited genetic determinants of low penetrance. MATERIALS AND METHODS: Stimulated lymphocytes were exposed to 0.5 Gy X-rays in the G2-phase of the cell cycle and chromatid aberrations were scored in metaphase cells. RESULTS: The assay was performed on 32 patients with early onset cancers (aged 0.5-19 years) of various types and their sensitivity was compared with that of 41 young normal controls (0.25-19 years) and 32 adult normals (20-60 years). The proportion of cases showing enhanced sensitivity in the three groups was 44, 15 and 10%, respectively. The difference between the young patients and normals was highly significant (p = 0.004). CONCLUSIONS: The results suggest the possibility that a substantial proportion of early onset cancers are associated with the inheritance of predisposing genes of low penetrance. However, support for this hypothesis requires that the heritability of chromosomal radiosensitivity be demonstrated in family members. In addition, a larger study is now required to investigate the chromosomal radiosensitivity of specific early onset cancers.

Adolescent↗

PubMed1993

Novel association approach for determining the genetic predisposition to schizophrenia: case-control resource and testing of a candidate gene.

We have developed a two-tiered approach to elucidating the genetic predisposition to schizophrenia. The approach first involves the examination of candidate genes in a subset of schizophrenic individuals to identify DNA sequence variations of likely functional significance, i.e., that produce either structural alterations in the protein or affect the level of gene expression. Once identified, the prevalence of the aberrant allele is examined in a large group of unrelated schizophrenic cases and controls to assess whether a true disease association exists. Herein, we describe the establishment of a DNA bank on nearly 200 unrelated schizophrenic cases defined by DSM-III-R criteria and on over 300 unrelated, ethnically similar controls. Characteristics of the study sample are described. The study approach then is illustrated by testing known mutations in the phenylalanine hydroxylase gene, responsible for the autosomal recessive disease of phenylketonuria, in the case-control sample to determine if carriership of a mutant allele is associated with an increased risk of schizophrenia. Using PCR amplification of specific alleles (PASA), we screened 190 schizophrenic cases and 336 controls for two common point mutations in the phenylalanine hydroxylase gene. Two carriers were found among the controls, while none of the cases was shown to carry a mutant allele. Thus, carriership of either of two common mutations in the phenylalanine hydroxylase gene does not appear to be associated with an increased risk of schizophrenia. As additional candidate genes are tested in this case-control resource, adjustment for multiple comparisons will become crucial in order to reduce the chance of false positive findings.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2004

Role of alpha-adducin DNA polymorphisms in the genetic predisposition to diabetic nephropathy.

BACKGROUND: There is substantial evidence for genetic susceptibility to diabetic nephropathy. In particular, genes that predispose to hypertension in the general population may confer susceptibility to nephropathy in patients with diabetes. A Gly460Trp variant in the alpha-adducin gene has been associated with essential hypertension. Our aim was to screen the alpha-adducin gene for polymorphisms and to determine if any variants predisposed patients with diabetes to nephropathy. A secondary objective was to assess for association between the Gly460Trp variant and hypertension. METHODS: The exons of the alpha-adducin gene were resequenced in 30 individuals. Selected variants were then genotyped in 155 patients with type 1 diabetes and nephropathy (cases) and 216 persons with type 1 diabetes but no evidence of nephropathy (controls) from Northern Ireland and in 95 cases and 118 controls from the Irish Republic. RESULTS: Eleven polymorphisms were detected, of which six were novel and three caused amino-acid substitutions. The Gly460Trp and a novel Ser617Cys polymorphism were in strong linkage disequilibrium (D' = 0.98). Neither the genotype nor allele frequencies for the Gly460Trp polymorphism (P = 0.89 and 0.93 respectively) or the Ser617Cys polymorphism (P = 0.46 and 0.76) were significantly different between cases and controls when the Northern Ireland and Irish Republic sample groups were combined. Carriage of the 460Trp allele was not significantly associated with systolic or diastolic blood pressure in either the cases (P = 0.48 and 0.06, respectively) or in the controls (P = 0.50 and 0.94, respectively). CONCLUSIONS: Variation in the alpha-adducin gene does not play a major role in the development of nephropathy in persons with type 1 diabetes in the Irish population. Furthermore, the Gly460Trp variant was not associated with hypertension in this population.

Adult↗

PubMed1980

Bone sarcoma as a second malignant neoplasm in children: influence of radiation and genetic predisposition for the Late Effects Study Group.

Osteosarcoma or chondrosarcoma developed as a second malignant neoplasm (SMN) in 40 of 188 individuals with SMN whose first neoplasm occurred in childhood. A genetic susceptibility to cancer was found in 23; the SMN developed in an irradiated field in 32; both factors wer present in 16; neither in one. When a genetic predisposition was present, radiation shortened the interval to SMN. The intervals between tumors and the age at which the bone sarcomas developed in relation to genetic disease and therapy were analyzed by a two-mutation hypothesis. Studies of SMN in childhood permit us to make observation about the role of genetic factors and environmental mutagens in cancer etiology.

Adolescent↗

PubMed2004

Genetic predisposition to neurological symptoms in lacunar infarction.

OBJECTIVE: Lacunar infarction is a unique stroke entity with characteristic symptoms. However, it is often silent clinically. The possible genetic predisposition to symptoms of lacunar infarction was investigated. METHODS: One-hundred and fifty-one patients with lacunar stroke were consecutively recruited. Lacunar stroke was diagnosed based on both neurological symptoms and lacunar lesion(s), demonstrated by MRI, that were responsible for the symptoms. One-hundred and fifty control subjects with MRI-proven lacunar lesions without neurological symptoms served as controls. There was no significant difference in age, sex and prevalence of known risk factors between cases and controls. Insertion and deletion polymorphisms of the angiotensin-converting enzyme gene (ACE), M235T substitution of the angiotensinogen gene (AGT), and A1133C substitution of type 1 receptor of the angiotensin II gene were determined. RESULTS: The frequency of ACE D allele was significantly higher in symptomatic patients compared with asymptomatic subjects (0.44 vs. 0.36, p < 0.05). The genotype distribution of AGT was significantly different between symptomatic and asymptomatic patients (chi(2) = 6.6, p = 0.037). Multiple logistic regression analysis revealed that ACE gene and AGT genotypes were independently associated with the neurological manifestation of lacunar infarction. In subjects with 1 lacuna, the odds ratio of the ACE DD genotype for symptomatic manifestation was 4.98 (95% CI 1.25-19.9). In subjects with 4 or more lacunae, the odds ratio of the ACE II genotype for symptomatic manifestation was 0.24 (95% CI 0.10-0.56). Furthermore, the ACE gene polymorphism was significantly different between symptomatic patients with a single lacuna and asymptomatic subjects with 4 or more multiple lacunar infarctions (chi(2) = 10.6, p = 0.005). CONCLUSION: These findings suggest that 2 subtypes of lacunar infarction, single symptomatic lacuna and multiple asymptomatic lacunae, may possess different genetic backgrounds. Subjects with the ACE DD genotype could be more predisposed to be symptomatic in first-ever lacunar stroke, while the ACE II genotype may convey resistance to symptoms even after multiple lacunar strokes. Polymorphism of genes of the renin-angiotensin system could be involved in the manifestation of neurological symptoms of lacunar infarction.

Age Factors↗

PubMed1985

HLA and genetic predisposition to lupus erythematosus and other dermatologic disorders.

Human leukocyte antigen (HLA) associations with different clinical and serologic subsets of lupus erythematosus are providing important clues to genetic predisposition and pathogenesis. The evolving complexity of the HLA-D region is described, and currently recognized HLA-region associations with systemic lupus erythematosus, subacute cutaneous lupus erythematosus, homozygous C2-deficient lupus, Sjögren's syndrome, and the neonatal lupus syndrome are reviewed. The striking relationship between the Ro/SSA-La/SSB antibody responses and HLA-DR2 and DR3 are emphasized. Other dermatologic conditions associated with HLA are also noted.

Adult↗

PubMed1996

Parental cancer and genetic predisposition in malignant pleural mesothelioma: a case-control study.

Familial clustering of pleural mesothelioma (PM) has been previously reported suggesting that genetic factors (predisposition) may be involved in PM. We studied parental cancer history in a cohort of 39 cases of PM and 259 age matched controls to assess the possible influence of family history on PM risk. Cases consisted of 39 patients with PM treated at our institution between 1978 and 1993. An age frequency matched control group (by 5-year age groups) consisted of 259 subjects who were spouses or friends of patients undergoing resection of primary lung cancer. Data were obtained by interview of controls and interview of the patient or next of kin (usually spouse) for cases. The following data were obtained using a standard questionnaire and medical record review; age, sex, date of diagnosis, history of asbestos exposure, smoking history, method of diagnosis, histologic subtype, type of treatment, parental cancer history and tumor type. Cases and control frequency of parental cancer and site specific tumor frequency were compared using chi-square analysis. Twenty-eight (71%) cases reported a parental history of cancer versus 114 (44%) in the control group (P<0.01). Gastrointestinal malignancies were the predominant tumor type among parents of cases, i.e. 11 cases (40%) versus 25% of controls (P<0.01). No other tumor site showed an increased frequency among cases. These data suggest a possible role for family history in the development of PM. Genetic predisposition may be important in the etiology of this tumor.

Asbestos↗

PubMed1997

[Genetic predisposition and radiation sensitivity of normal tissue].

BACKGROUND: After radiotherapy there are always some patients who develop strong acute and late reactions in normal tissues. In these patients frequently a genetic predisposition is observed. There are found DNA-repair deficiencies and changes in the regulation of the cell cycle which are responsible for the increased radiosensitivity with enhanced cell killing. METHODS: The micronucleus test and the comet assay appear to be appropriate tests in order to measure this increased radiosensitivity. Both tests are characterized by being relatively quick and simple and can be performed with small cell numbers. It is possible to study blood lymphocytes and fibroblasts with these tests. RESULTS: Both tests can predict the radiosensitivity of normal tissues especially if they are applied in combination. CONCLUSIONS: Epidemiological studies with patients after radiotherapy show evidence that the increased radiosensitivity also causes an enhanced induction of secondary tumors by ionizing radiation. This is supported by corresponding animal models.

Ataxia Telangiectasia↗

PubMed1997

Genetic predisposition of idiopathic pulmonary fibrosis.

The pulmonary parenchyma in interstitial fibrosis responds stereotypically to a variety of insults. The observation that only a small subset of persons exposed to known fibrogenic agents develop fibrosis and the induction of pulmonary fibrosis in genetically susceptible mice support a genetic predisposition. The description of familial idiopathic pulmonary fibrosis is the strongest evidence available supporting this hypothesis. Unfortunately, despite all the recent advances in molecular genetic techniques there have been few human studies to date. Given the poor prognosis and the lack of a cure for pulmonary fibrosis, future genetic studies will, it is hoped, clarify the pathogenesis of pulmonary fibrosis and lead to preventive measures and new therapeutic interventions. Idiopathic pulmonary fibrosis typically occurs in patients who are older than 50. The etiology is unknown.

Animals↗

PubMedDate not supplied

Genetic predisposition to cancer.

Over recent decades a number of genes causing predisposition to cancer have been identified. Some of these cause rare autosomal dominant monogenic cancer predisposition syndromes. In the majority of families, the increased incidence of cancers is due to a multifactorial aetiology with a number of lower penetrance cancer predisposition genes interacting with environmental factors. Identification of those at increased risk of cancer on account of their family history is important, as genetic testing, enhanced surveillance, prophylactic surgery and chemoprophylaxis may be indicated. In this article the issues surrounding genetic predisposition to cancer are considered by examining two common cancers: colorectal and breast cancer.

Adenomatous Polyposis Coli↗

PubMed1985

Assessment of genetic predisposition to alcoholism in male alcoholics.

Association between the history of alcoholism in different relatives with the development of alcoholism in male probands was analysed using the rate of development of alcoholism as a marker of genetic predisposition. It was found that a history of alcoholism in parents, grandparents and siblings of parents was associated with an accelerated rate in the development of alcoholism while a history of alcoholism in siblings and children of probands was not. The rate of development of alcoholism was positively associated with the number of generations of the proband's family in which alcoholism occurred.

Adult↗

PubMed1998

Genetic predisposition testing for cancer: effects on families' lives.

Genetic testing to identify a predisposition to the development of cancer affects not only the person undergoing DNA analysis but also his or her entire family. Multiple complex issues arise in conjunction with the clinical application of this new tool for assessing cancer risk. Counseling families regarding genetic risk is multifaceted and requires genetic knowledge that may go beyond the expertise of the health care provider. The article describes the psychosocial effects of cancer predisposition testing on families, ethical and social concerns of cancer risk testing, and implications for nurses in counseling individuals and families considering predisposition testing.

Adolescent↗

PubMed1975

The mechanism of genetic predisposition in congenital dislocation of the hip.

The important role of polygenic acetabular configuration and monogenic joint laxity has again been proved in the aetiology of congenital dislocation of the hip. According to the findings reported these two genetic predispositions seem to be unrelated. The time of diagnosis in accetabular dysplasia type and joint laxity type did not differ, thus the neonatal and late-diagnosed cases do not seem to be two clear-cut entities.

Acetabulum↗