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PubMed1997

Is there a genetic basis to endometriosis?

It is likely that endometriosis is a common multifactorial disease, like diabetes and asthma, caused by an interaction between multiple gene loci and the environment. Such conditions do not have a clear Mendelian pattern of inheritance. This chapter reviews the existing evidence, in human and non-human primates, that suggests there is a genetic basis to endometriosis. The environmental agents that have been implicated in the development of endometriosis are also reviewed. The identification of genetic loci conferring susceptibility to endometriosis using linkage analysis may lead to a better understanding of disease aetiology and, in time, improved therapeutic strategies and diagnostic methods.

Animals↗

PubMed2002

Genetic approaches to the molecular understanding of type 2 diabetes.

The appreciation that individual susceptibility to type 2 diabetes (T2D) and related components of the dysmetabolic syndrome has a strong inherited component provides a coherent framework within which to develop a molecular understanding of the pathogenesis of T2D. This review focuses on the main approaches currently adopted by researchers seeking to identify the inherited basis of T2D and the present state of our knowledge. One central theme that emerges is that progress in defining the genetic basis of the common, multifactorial forms of T2D is hindered by etiological heterogeneity: T2D is likely to represent the final common pathway of diverse interacting primary disturbances. Such heterogeneity equally compromises efforts to understand the basis for T2D by use of other approaches, such as cellular biochemistry and classical physiology. Analyses that seek to ally sophisticated physiological characterization with measures of genomic variation are likely to provide powerful tools for redressing the loss of power associated with such heterogeneity.

Diabetes Mellitus, Type 2↗

PubMed1986

Evidence that autoimmunity in man is a Mendelian dominant trait.

Family studies of autoimmune diseases are consistent with multifactorial etiology. However, familial occurrence of the autoimmune trait as defined by the presence of autoimmune disease and/or high titer autoantibody supports the hypothesis that autoimmunity is inherited as an autosomal dominant trait. Based on genetic analysis of 18 autoimmune kindreds, the population frequency of this primary autoimmune gene is approximately .10 with penetrance estimates of 92% in females and 49% in males. The estimated high penetrance of the autoimmune gene in females suggests that the interacting genetic and/or environmental factors must be numerous or ubiquitous. Sex, age, and specific major histocompatibility complex (MHC) antigens are among the genetic and physiological factors known to influence autoimmunity. A genetic model is proposed that takes these factors into account. Inherent in the hypothesis of a primary autoimmune gene is that it is epistatic to other, secondary, genes that influence the autoimmune phenotype. The genetic model further postulates that the secondary genes, including those of the MHC, confer specificity to the phenotype. The effects of the secondary genes can be modulated by gonadal steroids and, over time, may be abrogated by environmental challenges, such as viral infections.

Autoimmune Diseases↗

PubMed1998

Thrombophilia as a multigenic disorder.

Substantial progress has been made in the study of inherited abnormalities that predispose to venous thrombosis. With new discoveries, the focus has shifted from rare deficiencies associated with high probability for events to relatively common aberrations that produce high risk only in combination. Interactions between inherited and acquired disorders are also attracting much attention. The challenge for the future is how to best discover new risk factors and understand their contributions to multifactorial events.

Activated Protein C Resistance↗

PubMed1996

Prolactinomas in a large kindred with multiple endocrine neoplasia type 1: clinical features and inheritance pattern.

Multiple endocrine neoplasia type 1 (MEN 1) is associated with neoplasia and hyperfunction of the parathyroid and pituitary glands, pancreatic islet cells, and neuroendocrine cells of the gut. The inheritance pattern is autosomal dominant, and the underlying genetic defect is situated at chromosome 11q13. The MEN 1 gene behaves as a defective copy of a normally constitutive tumor suppressor gene. Development of the MEN 1 phenotype, however, is a multistep and multifactorial process. The Tasman 1 genealogy is the largest MEN 1 pedigree detected to date. Thus far, 90 related members with MEN 1 have been screened for evidence of prolactinoma. Prolactinomas were found in 18 patients (20%). Prolactinomas were not evenly distributed in the genealogy; in 2 branches of the overall genealogy prolactinomas were present in 50% or more of MEN 1-affected members. The familial distribution of prolactinomas in these branches was consistent with an autosomal dominant mode of inheritance. In the remainder of the pedigree, prolactinomas were uncommon and did not display this inheritance pattern. This pedigree represents one of the largest published MEN 1 genealogies in which the risk of developing prolactinoma follows an autosomal dominant pattern of transmission. It is the first to demonstrate an inheritance pattern for prolactinomas acting in addition to, yet distinct from, the inheritance of the underlying MEN 1 gene defect. These findings are consistent with the existence of an undefined second genetic defect involved in the pathogenesis of prolactinoma in MEN 1.

Adult↗

PubMed2000

Evidence of pleiotropic loci for fasting insulin, total fat mass, and abdominal visceral fat in a sedentary population: the HERITAGE family study.

OBJECTIVE: To examine whether there is a major gene effect on fasting insulin and pleiotropic loci for fasting insulin, total fat mass (FM), and abdominal visceral fat (AVF). RESEARCH METHODS AND PROCEDURES: A major gene hypothesis for fasting plasma insulin levels was assessed using segregation analyses of data on 495 members in 98 normolipidemic sedentary families of white descent who participated in the HERITAGE Family Study. RESULTS: Segregation analyses were performed on insulin adjusted for age, on insulin adjusted for age and FM, and on insulin adjusted for age and AVF. Before adjustment for AVF and FM, a major gene effect on fasting insulin levels was indicated. The putative locus accounted for 54% of the variance under a recessive inheritance pattern, affecting 11% of the sample (i.e., allele frequency = 0.33). However, after adjusting for the effects of AVF or FM, neither a major effect alone nor a multifactorial component alone could be rejected, and support for a major gene was equivocal, i.e., neither the hypothesis of Mendelian tau values or that of the equal tau(s) were rejected and the equal tau model fit the data better than the Mendelian tau model. This pattern (i.e., major gene evidence for insulin before but not after adjustment for AVF or FM) suggests that there is a putative locus with pleiotropic effects on both insulin and FM and another pleiotropic locus for both insulin and AVF. DISCUSSION: Although these data do not directly support an additional major gene for insulin independent of AVF and FM, such support cannot be ruled out because there is still a significant major effect on FM- or AVF-adjusted insulin (albeit the Mendelian nature of this effect is ambiguous).

Abdomen↗

PubMed2001

Molecular diagnostics in monogenic and multifactorial forms of type 2 diabetes.

Type 2 diabetes represents a major and increasing contributor to morbidity and mortality worldwide. Of the world's population, 10% either have Type 2 diabetes, or will develop it during their lifetime. Realization that inherited factors play a leading role in determining individual susceptibility to this condition provides a framework for improved molecular understanding of disease pathogenesis through susceptibility gene discovery. In particular, identification and characterization of these susceptibility variants should lead to improved targeting of available preventative and therapeutic measures and increasingly 'personalized' therapy. This article surveys present knowledge about the genetic basis of Type 2 diabetes and discusses the current and future role of genetic diagnostics, with an emphasis on lessons learned from study of monogenic forms of the disease.

Diabetes Mellitus, Type 2↗

PubMed2005

Interferon regulatory factor-6: a gene predisposing to isolated cleft lip with or without cleft palate in the Belgian population.

Cleft lip with or without cleft palate is the most frequent craniofacial malformation in humans ( approximately 1/700). Its etiology is multifactorial; some are a result of a genetic mutation, while others may be due to environmental factors, with genetic predisposition playing an important role. The prevalence varies widely between populations and the mode of inheritance remains controversial. The interferon regulatory factor-6 (IRF6) gene has been shown to harbor mutations in patients with van der Woude syndrome, a dominant form of clefts associated with small pits of the lower lip. Moreover IRF6 has been associated with nonsyndromic cleft of the palate (CL/P) in two separate studies. We investigated the role of IRF6 in a set of 195 trios from Belgium. Cleft occurred as an isolated feature. We studied association of the IRF6 locus using two variants: one in the IRF6 gene and the other 100 kpb 3' of the gene. Our independent study group confirms that the IRF6 locus is associated with nonsyndromic cleft lip with or without palate. This result, with previous studies performed in the United States and Italy, shows for the first time the implication of IRF6 in isolated CL/P in northern Europe. It is likely that association to this locus can be identified in various populations and that the IRF6 locus thus represents an important genetic modifier for this multifactorial malformation.

Belgium↗

PubMed2003

Genetic epidemiology of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a late onset, rapidly progressive and ultimately fatal neurological disorder, caused by the loss of motor neurons in the brain and spinal cord. Familial aggregation of ALS, with an age-dependent but high penetrance, is a major risk factor for ALS. Familial ALS (FALS) is clinically and genetically heterogeneous. Three genes and linkage to four additional gene loci have been identified so far and may either predominantly lead to ALS (ALSI-ALS6) or cause multisystem neurodegeneration with ALS as an occasional symptom (tauopathies, ALS-dementia complex). This review presents a tentative classification of the "major" ALS genes and ALS "susceptibility" genes, that may act as susceptibility factors for neurodegeneration in interaction with other genetic or environmental risk factors. Considering that mutations in ALS genes explain approximately 10% of familial as well as sporadic ALS, and most remaining cases of the discase are thought to result form the interaction of several genes and environmental factors, ALS is a paradigm for multifactorial discases.

Age Factors↗

PubMed2005

Animal models of hypertension: an overview.

Hypertension is a multifactorial disease involving complex interactions between genetic and environmental factors. Development of experimental models of hypertension allowed dissection and isolation of various factors associated with regulation of blood pressure, inheritance of hypertensive traits, and cellular responses to injury. The phenotype-driven approach is taking advantage of selective breeding of animals (primarily rats) that exhibit a desired phenotype, like the useful SHR. Genotype-driven models include transgenic techniques, in which mice are the most successful for selective deletion or overexpression of target genes. Notably, a combination of comparative genomics strategies and phenotypic correlates enhances the utility of hypertension models and their clinical relevance. Indeed, experimental models enabled development of targeted interventions aimed at decreasing not only blood pressure but also target organ injury. Continued utilization of experimental models simulating human hypertension, particularly those that combine other clinically relevant comorbidities like obesity or hypercholesterolemia, may afford development of effective strategies to address this common disease. Nevertheless, a cautious approach is mandatory when experimental findings in these models are extrapolated to human hypertension.

Animals↗

PubMed2004

[DNA diagnosis in the age of individual made-to-order medications].

Human diseases develop by complex mutual relationships of genetic and environmental factors. In inherited diseases, DNA diagnosis of the disease-causing genes provides a confirmation of the disease. On the other hand, DNA diagnosis of the disease-sensitive genes in multifactorial diseases, such as the lifestyle-related diseases (common diseases), provides the risk of developing the disease. Two new technologies are being used for DNA diagnosis in the clinic. The first is called Invader Technology and is a non-PCR method and is useful for detecting well-known genetic variations in large samples efficiently. We have developed a method to quantify the heteroplasmy of mitochondrial DNA mutations by this technique. The second technique, called WAVE, uses denaturing high-performance liquid chromatography to screen for mutations in a large number of samples automatically and efficiently. Clinical DNA diagnoses are divided into those for single genetic diseases and those for multifactorial diseases. The purposes for DNA diagnosis in single genetic diseases are: 1) to propose a new clinical classification of the disease, such as TGFB1-related corneal dystrophy or retinitis pigmentosa, based on the genotypes; 2) to confirm a clinical diagnosis, such as Leber's hereditary optic neuropathy (LHON); and 3) to provide an early diagnosis before the development of the disease and thus provide an opportunity to start early treatment. For example, a family history of glaucoma is one of the risk factors for developing glaucoma. The frequency of mutations in the glaucoma genes, myocilin and optineurin, were found to be about 3% and 0.25%, respectively, in Japanese. The significance of DNA diagnosis in multifactorial diseases is that it provides a risk diagnosis for an individual. Single nucleotide polymorphisms (SNPs) of disease-sensitive genes are associated with only a 2- to 3-fold risk of developing the disease. A case-control association study was performed using many SNP markers to identify glaucoma-sensitive genes. A total of 671 Japanese individuals, 201 POAG patients, 234 NTG patients, and 236 normal controls were examined. Fifty-two SNPs in the 38 genes were examined to identify the glaucoma-sensitive genes as candidate genes, and SNPs in AT 1, AT 2, PON 1, GSTT 1, NOS 3, and EDN 1 were associated with glaucoma statistically. Mitochondrial (mt) DNA mutations associated with LHON might be risk factors for open-angle glaucoma, because abnormal optic disc excavations are also found in LHON patients. A total of 651 blood samples were screened for 6 LHON-associated mutations with the Invader assay. Seven patients had one of the five mutations, but none had developed LHON. The 5 mutations were not identified in 236 normal controls. MtDNA mutations may make the optic disc more susceptible to damage in glaucoma patients. The clinical variability in LHON patients suggests that the disease most likely results from multi factorial mechanisms. To determine whether genetic polymorphisms for oxidative stress and apoptosis cause clinical variability in patients with LHON, 12 polymorphisms in 10 genes were analyzed in 87 patients with the 11778 mutation in relation to the age at onset and final visual acuity. LHON patients carrying homozygous His 113 in the EPHX1 gene or homozygous Arg 72 in the TP53 gene developed the disease earlier than those without this genotype. Thus, nuclear genetic polymorphisms related to oxidative stress or apoptosis may modify the age of LHON onset. A clinical trial of 38 healthy volunteers without systemic diseases or eye diseases was performed using an angiotensin II receptor blocker (candesartan cilexetil) as an alternative drug for lowering intraocular pressure (IOP). After a single oral dose of candesartan cilexetil, the IOP fell significantly for 24 hr. There was no association between the effects of oral candesartan cilexetil and the three SNPs in the AT 1 gene. In the 21th century, DNA diagnosis for multifactorial diseases will be required to determine the treatment plan for individuals or to prevent diseases. We have developed a panel of tests by Invader assay for clinical use to detect mutations in the myocilin gene or in LHON. In the future, we will develop a panel to detect SNPs in the glaucoma-sensitive genes to diagnose individuals at risk for developing glaucoma. Such information is expected to help develop new medications.

DNA, Mitochondrial↗

PubMed1980

[Genetic markers of atypical phasic psychoses].

The 93 patients of the present study resemble each other in their psychosis by phasic course and complete recovery. Frequently the attacks showed an anxious and paranoid syndrome in monopolar repetition or in bipolar change with ecstatic symptoms. Rarely an incoherent state of agitation or stupor could be observed. Considering the distribution of simple inherited serum groups, there is a significant increase of Gc 1-1 and Hp 2-2 in the patient collective. Evidently these serum groups are risk components in a multifactorial hereditary system possessing with Gc 1-1 a marker of the schizophrenic disposition and with Hp 2-2 a determinating trait for affective psychoses. A selective interaction is discussed for both serum groups regarding the vitamin D transport of the Gc fraction with their relation to enuronal function and the possible role of Hp 2-2 in a transport or regulatory system.

Adult↗

PubMed1996

The ulcer disease: an updated classification system.

The study included 736 probands with ulcer disease and 110 healthy subjects as well as all their relatives up to a third-degree of relation (n = 21889). All subjects underwent a thorough genealogical analysis, blood group, PTC and dermatoglyphic studies were performed on the whole contingent. Using extensive genealogical, genetico-mathematical and multifactorial analysis we studied the manifestations of anticipation, the influence of hereditary predisposition on gastric secretion and acidity under conditions of maximum pentagastrin stimulation as well as the disease inheritance pattern. The results of our comprehensive studies suggest that type I gastric ulcer according to H. Johnson, unlike type II and type III, is not genetically determined. On the other hand, type II and type III gastric ulcer do not differ substantially from duodenal ulcer and should therefore be categorised as belonging to this form of the disease. On this basis we propose a new classification system which accepts the existence of two ulcer diseases: gastric ulcer disease, and ulcer disease of the pyloroduodenal region.

Duodenal Ulcer↗

PubMed2001

Genetics of male osteoporosis.

In the past years, several epidemiological and clinical observations have underlined the importance of genetics in the pathogenesis of both female and male osteoporosis. It has been estimated that from 50 to 80% of the inter-individual variability in bone mass is genetically determined. In rare instances, osteoporosis in men could be inherited in a simple Mendelian pattern. Examples of this include familial osteoporotic syndromes due to mutations in the aromatase and ER alpha genes. Families have also been described in which high bone mass is inherited as an autosomal dominant trait, consistent with the effect of a single gene located on chromosome 11. However, except for these rare conditions, osteoporosis has to be considered a multifactorial disease in which genetic determinants are modulated by hormonal, environmental, and nutritional factors. The genetic effect on bone may also be gender- and site-specific, with different genes regulating bone density at different skeletal sites in males and females. To date, most of the work on the genetics of osteoporosis has focused on women. In some studies, polymorphisms at the IGF-I, VDR, COLI-alpha1, ER alpha, and aromatase gene have been recently shown to predict BMD variation and osteoporotic risk in males. These observations remain to be confirmed by other independent studies. Other candidate genes, are still awaiting mapping and identification.

Bone Density↗

PubMed2000

Achievements in Understanding and Treatment of Myelodysplastic Syndromes.

The myelodysplastic syndromes (MDS) constitute a challenge for the biologist as well as for the treating physician. In Section I, Dr. Willman reviews the current classifications and disease mechanisms involved in this heterogeneous clonal hematopoietic stem cell disorder. A stepwise genetic progression model is proposed in which inherited or acquired genetic lesions promote the acquisition of "secondary" genetic events mainly characterized by gains and losses of specific chromosome regions. The genetic risk to develop MDS is likely multifactorial and dependent on various constellations of risk-producing and -protecting alleles. In Section II Dr. Barrett with Dr. Saunthararajah addresses the immunologic factors that may act as important secondary events in the development of severe pancytopenia. T cells from patients with MDS may suppress autologous erythroid and granulocytic growth in vitro, and T cell suppression by antithymocyte globulin or cyclosporine may significantly improve cytopenia, especially in refractory anemia. Recent studies have also demonstrated an increased vessel density in MDS bone marrow, and a phase II trial of thalidomide showed responses in a subgroup of MDS patients especially in those with low blast counts. In Section III Dr. Hellström-Lindberg presents results of allogeneic and autologous stem cell transplantation (SCT), intensive and low-dose chemotherapy. The results of allogeneic SCT in MDS are slowly improving but are still poor for patients with unfavorable cytogenetics and/or a high score according to the International Prognostic Scoring System. A recently published study of patients between 55-65 years old showed a disease-free survival (DFS) at 3 years of 39%. Consolidation treatment with autologous SCT after intensive chemotherapy may result in long-term DFS in a proportion of patients with high-risk MDS. Low-dose treatment with 5-azacytidine has been shown to significantly prolong the time to leukemic transformation or death in patients with high-risk MSA. Erythropoietin and granulocyte colony-stimulating factor may synergistically improve hemoglobin levels, particularly in sideroblastic anemia. Recent therapeutic advances have made it clear that new biological information may lead to new treatment modalities and, in combination with statistically developed predictive models, help select patients for different therapeutic options.

Journal Article↗

PubMed2002

[Icelandic genealogical registry sheds light on the significance of heredity in osteoarthritis].

Osteoarthritis is a heterogeneous and multifactorial disease with many pathogenic mechanisms implicated in its development and progression. Although osteoarthritis is a manifestation of certain metabolic, mechanical or inflammatory events, several distinct forms of osteoarthritis are inherited as dominantly acquired Mendelian traits. Gathering evidence is showing that inheritance and possible mutations in genes associated with osteoarthritis can play a major role in the common form of osteoarthritis in many joints. By the introduction of new biological methods for finding gene defects the search for possible gene defects have taken mainly three forms: (1) Parametric linkage analysis of rare families in which osteoarthritis segregates as a Mendelian trait; (2) model free linkage analysis of affected sibling pairs, and (3) association analysis of known candidate genes. Mutations today known to be associated with osteoarthritis all occur in relatively rare syndromes or diseases, which have osteoarthritis as a major component. In recent years many loci have been found associated with the "common osteoarthritis phenotype". Chromosomes 2, 4, 6, 11 and 16 were identified in multiple genome scans and are therefore the most likely to encode susceptibility. Ongoing studies will lead to classifications of the "common osteoarthritis" based on the exact causative gene defects, rather than on their variable clinical and radiographic phenotype. Hopefully, these studies will lead to future new therapy of osteoarthritis.

Databases, Factual↗

PubMed2005

[Two promising candidate genes in the ethiopathogenesis of DM2 - PPARgamma2 and KCNJ11].

Type 2 DM represents a multifactorial disease--both genetic and environmental factors are implicated in the etiology. In spite of an enormous effort, unraveling the genetics of type 2 DM has proved problematic. A polygenic inheritance is proposed for most cases. More than 250 candidate genes have been studied and increasing attention is being directed at two of them: the PPARgamma2 gene (peroxisome proliferator-activated receptor gama2) and KCNJ11 (potassium channel inwardly rectifying). The PPARgamma2 is a member of the nuclear hormone receptor subfamily of transcription factors. It plays a key role in regulation of adipocyte differentiation and energy balance. The KCNJ11 gene codes for a pore-forming subunit of the inwardly rectifying ATP sensitive K+ channel, which is involved in the direct regulation of insulin secretion. Here, recent knowledge regarding involvement of these two genes in complex metabolic pathways is summarized. In the whole review, we focus on the glucose homeostasis.

Diabetes Mellitus, Type 2↗

PubMed1996

Candidate gene approach of familial morbid obesity: linkage analysis of the glucocorticoid receptor gene.

BACKGROUND: Morbid obesity is a multifactorial disease, with a strong but almost unknown genetic component. Familial linkage studies using the candidate gene approach have been shown to be powerful tools for identifying susceptibility genes for inherited diseases. AIM OF THE STUDY: We have investigated the role of the Glucocorticoid Receptor gene (GRL) in morbid obesity. SUBJECTS: Eighty obese families were recruited through a multimedia campaign (42 families, sample 1) or from the department of nutrition of the Hotel Dieu hospital in Paris (38 families, sample 2). METHODS: A multipoint linkage analysis with markers on chromosome 5q placed the GRL gene between D5S658 and D5S436 at genetic distances of 3.5 and 5 centimorgans, respectively. Using this map, we have chosen seven polymorphic microsatellite markers located in the vicinity of the GRL gene locus for sib pair linkage analysis. In addition to the obesity status, different quantitative phenotypes associated with obesity and insulin resistance were used for analysis. RESULTS: In sample 1, the results show a tendency towards linkage between three markers (one bc/1 intragenic RFLP and two microsatellite markers) in the GRL region and obesity characterised by a BMI > 27. However, using this phenotype, we failed to replicate the results in the second set of families. When using a more precise phenotype (the individual coefficient of variation of the BMI compared to a sex and age matched French reference population (pop) defined as the Zscore (indBMI-popBMI/SD of popBMI), a tendency for linkage was found for one marker in sample 2 as well as in the whole sample. No linkage was found when using quantitative traits associated with obesity. CONCLUSION: The GRL locus does not appear to be a major locus for obesity, but we cannot exclude that this gene or gene located nearby may have some minor effects on the obese phenotype or may be involved in some subtypes of obesity. Larger cohorts of families are probably necessary to improve the power of such linkage analysis in this heterogeneous disease.

Adult↗