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PubMed2003

Genetic basis of psoriasis vulgaris and its pharmacogenetic potential.

Psoriasis vulgaris is one of the most prevalent T cell-mediated inflammatory diseases in humans. It is multifactorial in origin and shows polygenic inheritance. Systemic immunosuppressive therapies play an important role in management of severe disease cases but are associated with variable response and toxicity. Within the last decade there have been significant advances in our understanding of the genetic basis of this complex disease and polymorphic candidate genes have been proposed. Susceptibility gene characterization together with an explosion in knowledge of its primary immune basis will further define disease pathways involved in psoriasis pathogenesis. This holds the promise of rational design of new therapeutic agents and pharmacogenetic testing to predict responders from non-responders and those at risk of toxicity.

Drug Design↗

PubMed2000

[Genetic predisposition for multiple sclerosis].

Although the clinical manifestations and neuropathological signs of multiple sclerosis (MS) have been known for a century, the cause of this disease has not yet been determined. The epidemiological studies indicate that MS is of multifactorial etiology, including both environmental and inherited (genetic predisposition) factors. The role of the HLA system in genetic predisposition to MS has been known since the 1970s. As a result of the progress made in human genetics, it is now possible to study genetic predisposition to MS.

Genetic Predisposition to Disease↗

PubMed2000

Twin studies of schizophrenia: from bow-and-arrow concordances to star wars Mx and functional genomics.

Twin studies have been vital for establishing an important genetic contribution to the etiology of schizophrenia. The five newest studies since 1995 from Europe and Japan have confirmed earlier findings. They yielded probandwise concordance rates of 41-65% in monozygotic (MZ) pairs and 0-28% in dizygotic (DZ) pairs, and heritability estimates of approximately 80-85%. Twin studies are also valuable for investigating the etiological relationships between schizophrenia and other disorders, and the genetic basis of clinical heterogeneity within schizophrenia. Studies of discordant MZ pairs provide further insights into non-inherited factors that contribute to the multifactorial etiology of this disorder. More recently, twin studies have begun to be used to directly investigate molecular genetic and epigenetic processes underlying schizophrenia.

Data Interpretation, Statistical↗

PubMed2001

[Classification of alcohol metabolizing enzymes and polymorphisms--specificity in Japanese].

Multiple forms and gene loci of human alcohol dehydrogenase (ADH EC: 1.2.1.3) and aldehyde dehydrogenase (ALDH, EC: 1.2.1.3) in the major pathway of alcohol metabolism have been found and characterized in the last two decades. With the coenzyme NAD, these enzymes catalyze the reversible conversion of organic alcohols to ketones or aldehydes, and aldehyde to acetic acid. The ADH genes are mapped to chromosome 4p21-25, but the ALDH genes are localized at different chromosomes. The cytochrome P450 2E1 (CYP2E1) gene, which is mapped to chromosome 10q24.3-qter contributes also the conversion of ethanol to acetaldehyde. Genetic polymorphisms have been reported in these alcohol metabolizing enzymes. The metabolisms of alcohol and acetaldehyde in liver and blood after drinking alcohol are thought to be influenced by the interactive action of these enzymes. Amongst the five major classes of the ADH subunits (alpha, beta, gamma, pi, chi, sigma), beta and gamma subunits show genetic polymorphisms. Recently a new nomenclature for ALDH genes has been recommend based on divergent evolution and chromosomal mapping. Two major isoforms designated as cytosolic ALDH1 and mitochondrial ALDH2 can be distinguished by their electrophoretic and kinetic properties as well as by their subcellular localization. Mitochondrial ALDH2 is a major enzyme in the oxidation of acetaldehyde derived from ethanol metabolism. The catalytic deficiency of ALDH2 isozyme is responsible for flushing and other vasomotor symptoms caused by higher acetaldehyde levels after alcohol intake. So far, frequencies of the two alleles of ALDH2 in Mongoloid have been reported in the different population groups. The catalytic deficiency of ALDH2 is caused by a structural point mutation at amino acid position 487, where a substitution of Glu to Lys resulting from a transition of G (C) to A (T) at 1510 nucleotide from the initiation codon has occurred. Individuals deficient in ALDH2 activity refrain from excessive drinking of alcohol due to the aversive reactions, leading to protection against alcoholism. Prevalence of the ALDH2*1 allele is associated with alcoholism, and subsequent studies have confirmed the allelic association with alcoholism in different ethnic groups. The effects of polymorphisms of ADH2 and CYP2E1 remained controversial, even in the same ethnic group. Investigation of mutations for the transacting cis-element in promoter region of the ALDH2 gene will provide important information with respect to regulation of this gene. Transfection assays using the first 600 bp of the upstream nucleotide sequences indicated that a region from -75 to -120 was necessary for the ALDH2 gene expression, and especially NF-Y/CP1 binding site from -92 to -96 (CCAAT box) is important in the expression of the gene. A novel polymorphism due to the nucleotide replacement at -357 G to A was found in all the population groups. Alcoholism is thought to be a multifactorial disease with complex mode of inheritance in addition to psychological and social factors, and many studies of family, adoption and twins concerning alcoholism have revealed that hereditary factor is an important determinant for developing alcoholism. Genetic association studies have contributed to the identification of a number of genetic risk factors for the chronic diseases influenced by genetic disorders and environmental factors.

Alcohol Dehydrogenase↗

PubMed2004

The genetics of psoriasis.

There is considerable epidemiologic evidence that genetic component plays a key role in the pathogenesis of psoriasis. The disease is multifactorial in origin and shows polygeneic inheritance. In the last decade, there have been significant advances in our understanding of the genetic basis of this common disease. Susceptibility gene characterization and knowledge of the immune basis of psoriasis have better defined the disease pathways involved in the pathogenesis of psoriasis. A number of genetic loci have been identified by genome wide-linkage scans. In particular, the importance of PSORS 1 linkage characterization is emphasized, as this information will help develop more specific diagnostic and prognostic tools.

Genetic Linkage↗

PubMedDate not supplied

[Genetic role in hernia of the esophageal hiatus. Description of the disease in 2 brothers].

Two brothers born 15 years apart from normal healthy parents were affected by esophageal hiatus hernia diagnosed at 4 and 8 months respectively. We found 37 other families with more than one member affected by EHH reported in the literature. Since the anomaly often runs asymptomatic, familiarity is probably more frequent than generally thought. The type of inheritance is still uncertain, but a multifactorial etiology is the most likely explanation.

Age Factors↗

PubMed1986

Mendelian inheritance of isolated nonsyndromic cleft palate.

Isolated, apparently nonsyndromic cleft palate (CP) is thought to be etiologically heterogeneous. The multifactorial threshold explanation for CP is postulated in most cases. Mendelian inheritance has been documented in 3 families. We report on three unrelated white families with 17 relatives in several generations affected with CP, including submucous CP and bifid/absent uvula. We could find no evidence of a cleft syndrome. In one family, the pattern is consistent with autosomal dominant inheritance. In 2 families, the pattern is consistent with X-linked recessive inheritance. The specific findings and their implications for family evaluation and genetic counseling are discussed.

Adolescent↗

PubMed1976

[Genetics of diabetes mellitus (author's transl)].

Since Pincus and White's claim in 1933 that diabetes mellitus is an inherited disease, the precise mode of inheritance remains a matter of dispute. The reason for the controversy is that the geneticist is confronted with a number of impediments to genetic analysis. As pointed by Neel, "diabetes mellitus is in many respects a geneticists nightmare". The obstacles are : 1) a precise definition of diabetes is difficult to establish, 2) the frequency of the disease which is sex and age dependent is not well known, 3) the probability of genetic heterogeneity is great but whether early onset and late onset diabetes are different genetic diseases or the same one remains controversial, 4) the basic defect (s) is unknown, 5) environmental factors (e.g. nutritional status) influence the frequency of the disease. Despite these problems many studies have been devoted to the mode of inheritance of diabetes mellitus. Many authors favour an autosomal recessive mechanism. However, low penetrance (25 %) is necessary to support this mode of inheritance. Simple autosomal dominant mode of inheritance has also been suggested, but this pattern fits only few families. The majority of geneticists think, at the present time, that diabetes has a multifactorial mode of inhritance. The heritability which express the extent to which the phenotypes exhibited by parents are transmitted to their offspring is in the neighbourhood of 50%. Many arguments favour this mode of inheritance: 1) low penetrance is necessary to aistinct genetic diseases, and especially in chronic glaucoma, which also have a multifactorial mode of inheritance; in particular, one must note the association between glucose intolerance and ocular hypertension induced by dexamethasone, 3) the association between diabetes and antigen A of the ABO system and antigens HL-A8 and W 15 of the HL-A system.

Diabetes Mellitus↗

PubMed1983

Familial Hirschsprung's disease and type D brachydactyly: a report of four affected males in two generations.

Hirschsprung's disease usually occurs as an isolated malformation as a result of multifactorial causation. A family in which four males (two brothers and two maternal uncles) had Hirschsprung's disease and absence or hypoplasia of the nails and distal phalanges of the great toe and thumb (type D brachydactyly) is described. Hand abnormalities were not present in any other family members, and the obligate heterozygous females were without gastrointestinal problems. The pattern of inheritance was consistent with X-linked recessive inheritance; however, autosomal dominant inheritance with incomplete penetrance in females or multifactorial causation could not be completely excluded.

Adolescent↗

PubMed2006

Complex gene-gene interactions in multiple sclerosis: a multifactorial approach reveals associations with inflammatory genes.

The complex inheritance involved in multiple sclerosis (MS) risk has been extensively investigated, but our understanding of MS genetics remains rudimentary. In this study, we explore 51 single nucleotide polymorphisms (SNPs) in 36 candidate genes from the inflammatory pathway and test for gene-gene interactions using complementary case-control, discordant sibling pair, and trio family study designs. We used a sample of 421 carefully diagnosed MS cases and 96 unrelated, healthy controls; discordant sibling pairs from 146 multiplex families; and 275 trio families. We used multifactor dimensionality reduction to explore gene-gene interactions. Based on our analyses, we have identified several statistically significant models including both main effect models and two-locus, three-locus, and four-locus epistasis models that predict MS disease risk with between approximately 61% and 85% accuracy. These results suggest that significant epistasis, or gene-gene interactions, may exist even in the absence of statistically significant individual main effects.

Case-Control Studies↗

PubMed2004

Progress in defining the molecular basis of type 2 diabetes mellitus through susceptibility-gene identification.

The rapid increase in the prevalence of type 2 diabetes (T2D) represents a major challenge for health care delivery worldwide. Identification of genes influencing individual susceptibility to disease offers a route to better understanding of the molecular mechanisms underlying pathogenesis, a necessary prerequisite for the rational development of improved preventative and therapeutic methods. The past decade has seen substantial success in identifying genes responsible for monogenic forms of diabetes (notably, maturity-onset diabetes of the young), and, in patients presenting with early-onset diabetes, a precise molecular diagnosis is an increasingly important element of optimal clinical care. Progress in gene identification for more common, multifactorial forms of type 2 diabetes has been slower, but there is now compelling evidence that common variants in the PPARG, KCNJ11 and CAPN10 genes influence T2D-susceptibility, and positional cloning efforts within replicated regions of linkage promise to deliver additional components of inherited susceptibility. The challenge in the years to come will be to understand how T2D risk is influenced by the interaction of these variants with each other and with pertinent environmental factors encountered during gestation, childhood and adulthood; and to establish how best to apply this understanding to provide individuals with clinically-useful diagnostic, prognostic and therapeutic information.

Diabetes Mellitus, Type 2↗

PubMed2007

Complex segregation analysis accounting for GxE of bone mineral density in European pedigrees selected through a male proband with low BMD.

Osteoporosis is a common multifactorial disorder characterized by low bone mass (BMD) and high susceptibility to low-trauma fractures. Family and twin studies have found a strong genetic component in the determination of BMD, but the mode of inheritance of this trait is not yet fully understood. BMD is a complex trait whose expression is confounded by environmental influences and polygenic inheritance. Detection of potential gene-environment interactions is of great interest in the determination of bone health status. Here we have conducted segregation analyses, using the regressive class D models, in a sample of 100 European pedigrees (NEMO) with 713 subjects (524 measured for phenotypes) identified via a male with low BMD values at either the Lumbar Spine or the Femoral Neck. Segregation analyses were conducted on the residuals of LS-BMD and FN-BMD adjusted for gender, age and BMI. We tested for gene-covariate (GxE) interactions, and investigated the impact of significant GxE interactions on segregation results. Without GxE a major effect was found to be marginally significant in LS-BMD and highly significant in FN-BMD. For both traits the Mendelian hypothesis was rejected. Significant Age x gene and BMI x gene interactions were revealed. Accounting for GxE increased statistical evidence for a major factor in LS-BMD, and improved the fit of the data to the Mendelian transmission model for both traits. The best fitting models suggested a codominant major gene accounting for 45% (LS-BMD) and 44% (FN-BMD) of the adjusted BMDs. However, substantial residual correlations were also found, and these remained highly significant after accounting for the major gene.

Adult↗

PubMed1996

Inherited disorders: a genetic primer.

Identification of inherited or genetic disorders has important implications for the prognosis and treatment of affected infants. This article addresses the three most common categories of genetic disorders--single-gene defects, chromosomal abnormalities, and multifactorial conditions. The principles of transmission, risk of inheritance, and clinical significance of each category are discussed, with examples of inherited disorders in each category.

Female↗

PubMed1999

Human leukocyte antigens as genetic markers in colorectal carcinoma.

PURPOSE: Similar to findings obtained for most carcinomas, the pathogenesis of colorectal cancer is considered to be multifactorial. There is strong evidence for an inherited, genetic predisposition to disease in patients with familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer. There is still debate, however, about the contribution of genetic factors to the pathogenesis of sporadic colorectal cancer. The present study was undertaken to search for human leukocyte antigen associations in a group of patients with colorectal cancer and to correlate the findings with both the histology of the disease and family history. SUBJECTS AND METHODS: The allele frequencies of serologically defined human leukocyte antigen class I and II antigens were studied in 101 patients with a recent, histologically confirmed diagnosis of colorectal cancer. All individuals in this study were unrelated to each other. After surgical treatment, all patients were grouped according to the stage (Dukes Stages A, B, C, and D), differentiation (Grades 1, 2, and 3), and the site of the tumor. Patients were also classified with regard to family history for colorectal cancer. The results obtained for human leukocyte antigen frequencies were compared with those of 105 healthy control subjects (control group). RESULTS: An increased frequency of human leukocyte antigen-B18 (27.72 vs. 14.28 percent; P < 0.025; odds ratio = 2.3) and of human leukocyte antigen-DQ5 (43.56 vs. 22.5 percent; P < 0.01; odds ratio = 2.65) was observed for patients with colorectal cancer vs. control subjects, respectively. In addition, human leukocyte antigen-B18 was present with increased frequency (30.76 percent; P < 0.05; odds ratio = 2.66; and 26.67 percent; P < 0.05; odds ratio = 2.18) among patients with rectal and colon carcinoma, respectively. A higher frequency of human leukocyte antigen-DQ5 (45.33 percent; P < 0.01; odds ratio = 2.84) was observed among patients with colon carcinoma. Remarkably, human leukocyte antigen-DQ5 (50 vs. 22.5 percent; P < 0.05; odds ratio = 3.43) and human leukocyte antigen-A1 (41.66 vs. 12.38 percent; P < 0.01; odds ratio = 5.05) were found to be strongly associated with a family history of colorectal cancer. CONCLUSION: The observation of specific human leukocyte antigen associations with particular subsets of colorectal cancer strongly suggests that genetic susceptibility for the development of colorectal cancer exists. Although the multifactorial pathogenesis of colorectal cancer must be considered, human leukocyte antigens may have useful predictive and diagnostic value.

Adolescent↗

PubMed1984

A family study of renal dysplasia.

A family study was undertaken to investigate genetic involvement in renal dysplasia, which is defined as abnormal metanephric differentiation. Probands were ascertained through the retrospective examination of necropsy records and the reevaluation of available material, which included microscopic examinations of the kidneys, gross descriptions of organs, and gross photographs. We obtained family histories and performed physical examinations and renal ultrasonography on parents and sibs of the 21 probands. In only one family a sibling with renal dysplasia was discovered; both the proband and the previous stillborn sib had renal dysplasia in association with posterior urethral values. Renal dysplasia could have resulted from urinary tract obstruction secondary to the urethral valves, with inheritance of the valves as the primary abnormality. However, we cannot exclude primary inheritance of the renal abnormality, perhaps with multifactorial determination with a threshold. The empiric recurrence risk of 2.1%, calculated from this family study, was statistically not significantly different from zero. We can assume, therefore, that the multicystic and aplastic types of renal dysplasia, which predominated in this study, are sporadic or rarely familial, but certain other types of renal dysplasia, identified in the literature as familial, probably carry a higher recurrence risk.

Abnormalities, Multiple↗

PubMed2001

CTLA-4 gene polymorphisms in Tunisian patients with Graves' disease.

Graves' disease (GD) is an organ-specific autoimmune disorder of multifactorial etiology with a polygenic mode of inheritance. A recent report has demonstrated that there is a linkage and an association between the genetic markers of the CTLA-4 gene on chromosome 2q33 and GD. In order to confirm this association in a Tunisian population, three polymorphisms of the CTLA-4 gene were analyzed: the first is at the -318 position from the ATG start codon consisting of a C/T change; the second is in position 49 of exon 1, which lies in the A/G transition; and the third is in the 3' untranslated region with variant lengths of the dinucleotide (AT)n repeat. The genomic DNA from 144 patients with GD and 205 healthy individuals was genotyped after specific polymerase chain reaction amplification. Comparative analysis using a chi(2) test showed a weak yet significant difference in allele frequencies of the A/G dimorphic marker between patients and controls (P < 0.05), and a significant increase of A/A homozygous individuals among patients (21.53 vs 12.7%, P = 0.02, odds ratio (OR) = 1.89) was found. Analyses of CTLA-4 A/G polymorphism with respect to sex showed a significant difference in A/A genotypes between female patients and controls (OR = 2.14; 95%, 1.13 < OR < 4.04, P < 0.05). The distribution of CTLA-4 (AT)n allele frequencies differed between patients and controls (chi(2) = 38.18, 20 degrees of freedom, P = 0.0084) and the highest OR was found with the CTLA-4 (AT)-224-bp allele (OR = 6.43, 1.7 < OR < 28.64; P = 0.001). In conclusion, these results show that the CTLA-4 gene, or one closely associated with it, confers susceptibility to GD in a Tunisian population.

Abatacept↗

PubMed1994

Two-locus linkage analysis in multiple sclerosis (MS).

One of the major challenges in genetic linkage analyses is the study of complex diseases. We demonstrate here the use of two-locus linkage analysis in multiple sclerosis (MS), a multifactorial disease with a complex mode of inheritance. In a set of Finnish multiplex families, we have previously found evidence for linkage between MS susceptibility and two independent loci, the myelin basic protein gene (MBP) on chromosome 18 and the HLA complex on chromosome 6. This set of families provides a unique opportunity to perform linkage analysis conditional on two loci contributing to the disease. In the two-trait-locus/two-marker-locus analysis, the presence of another disease locus is parametrized and the analysis more appropriately treats information from the unaffected family members than single-disease-locus analysis. As exemplified here in MS, the two-locus analysis can be a powerful method for investigating susceptibility loci in complex traits, best suited for analysis of specific candidate genes, or for situations in which preliminary evidence for linkage already exists or is suggested.

Alleles↗

PubMed1996

The genetics of idiopathic generalized epilepsy: implications for the understanding of its aetiology.

Epilepsy is one of the most common neurological disorders. Both inherited and acquired factors contribute to its multifactorial pathogenesis. A genetic predisposition plays a major role in the aetiology of the common idiopathic generalized epilepsies. Susceptibility genes for two syndromes of idiopathic generalized epilepsies, the benign familial neonatal convulsions and juvenile myoclonic epilepsy, have been assigned to the chromosomal regions 20q13 (EBN1), 8q24 (EBN2) and 6p21 (EJM1). Positional cloning of the mutations causing these traits will help to elucidate the molecular pathways of epileptogenesis and will imply a classification on a neurobiological basis. Insights into the underlying impairment of neuronal excitability should provide new concepts for the development of rational treatment strategies.

Animals↗