Israel Medical Association Journal

Behavioral genetics is the identification of behavioral traits that are genetically determined, the identification of the genes that are involved, and the discovery of modes of intervention to alter the expected course of the disease. Unlike the classical Mendelian traits, many specific aspects of behavior are, in part, determined by several genes. The corresponding abnormalities of behavior or deficiencies are therefore polygenic. New genetic techniques are leading to the discovery of these genes, and the techniques and knowledge developed in the Human Genome Project make it possible to screen the genome of any individual for the presence of known polymorphisms. This raises great hopes for diagnosis and the individualization of therapy. However, the genetic prediction of unacceptable behavior can further lead to social and occupational discrimination and enforced therapy. This raises serious concerns about how this information will be collected and who will have access to it.

Background: Various studies support the concept of an inherited vulnerability to drug dependency, while emphasizing the importance of social and environmental influences and their interactions

Objectives: To compare the characteristics of heroin-dependent Jewish men in Israel with those of the general population, focusing on the nature of family history of substance abuse.

Method: This case-control study compares 64 heroin-dependent Jewish male residents of Jerusalem with a community sample of 131 randomly selected Jerusalem residents with no drug use disorder. Univariate and mulbvariate moderns were employed to appraise the independent associations between heroin dependence and exposure variables such as family history of substance misuse and exposure to legal psychoactive substances.

Results: The case group is characterized by heavy tobacco and' alcohol involvement. Nearly 70% of the cases report an alcohol and/or drug problem in at least one first-degree relative compared with 10% of controls (odds ratio 14.5, adjusted for sociodemographic and other potential confounders). Cases with a positive family history have, on average, higher alcohol consumption levels and higher heroin-use severity scores, as compared with cases with no such history.

Conclusions: Familial aggregation of drug and alcohol problems, along with smoking at a young age, is the strongest predictor of heroin dependence in this population. Better understanding of the components underlying this familial aggregation can lead to improved prevention and treatment strategies.
 

The etiology of inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, is uncertain. Studies of specific environmental factors and immune dysfunction have provided limited insight into disease pathogenesis. There is ample evidence that these diseases are in part the result of genetic predisposition. The early search for candidate genes focused on genes involved in the regulation of immune function.

Recent genome wide searches reported several susceptibility loci for Crohn’s disease and ulcerative colitis. The recent identification of the IBD1 gene (NOD2) with mutations that are associated with susceptibility to Crohn’s disease will have a major impact on the understanding of the genetics of this disease.
 

The complex genetic nature of many common diseases makes the identification of the genes that predispose to these ailments a difficult task. In this review we discuss the elements that contribute to the complexity of polygenic diseases and describe an experimental strategy for disease-related gene discovery that attempts to overcome these factors. This strategy involves a population-based case-control paradigm and makes use of a highly informative, homogeneous founder population, many of whose members presently reside in Israel. The properties of single nucleotide polymorphisms, which are presently the markers of choice, are discussed, and the technologies that are currently available for SNP[1] genotyping are briefly presented.

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[1] SNP = single nucleotide polymorphism

This review summarizes the clinical, metabolic and genetic characteristics of early-onset type 2 diabetes in Mexico. Early-onset type 2 diabetes is both a clinical challenge and a public health problem. It is calculated that almost 300,000 Mexican diabetics are diagnosed between the ages of 20 and 40. The large Mexican family structure and the high prevalence of the disease provide a unique opportunity to identify the genes and the metabolic abnormalities involved in this form of the disease. In a hospital-based population, our group found that insulin deficiency was the main defect in this form of diabetes. Mutations in the HNF-1α or HNF-4α genes or autoimmunity to the beta cell were found in a small proportion of cases, leaving unexplained the majority of cases. Also discussed are the epidemiologic and therapeutic implications of early-onset type 2 diabetes, and the possible role of genetic testing for prevention.

Background: The Bloom syndrome gene, BLM, was mapped to 15q26.1 and its product was found to encode a RecQ DNA helicase. The Fanconi anemia complementation group C gene was mapped to chromosome 9q22.3, but its product function is not sufficiently clear. Both are recessive disorders associated with an elevated predisposition to cancer due to genomic instability. A single predominant mutation of each disorder was reported in Ashkenazi Jews: 2281delATCTGAinsTAGATTC for Bloom syndrome (BLM-ASH) and IVS4+4A®T for Fanconi anemia complementation group C.

Objectives: To provide additional verification of the mutation rate of BLM and FACC[1] in unselected Ashkenazi and non-Ashkenazi populations analyzed at the Sheba Medical Center, and to trace the origin of each mutation.

Methods: We used polymerase chain reaction to identify mutations of the relevant genomic fragments, restriction analysis and gel electrophoresis. We then applied the Pronto^TM kit to verify the results in 244 samples and there was an excellent match.

Results: A heterozygote frequency of 1:111 for BLM-ASH and 1:92 for FACC was detected in more than 4,000 participants, none of whom reported a family history of the disorders. The Pronto^TM kit confirmed all heterozygotes. Neither of the mutations was detected in 950 anonymous non-Ashkenazi Jews. The distribution pattern of parental origin differed significantly between the two carrier groups, as well as between each one and the general population.

Conclusions: These findings as well as the absence of the mutations in non-Ashkenazi Jews suggest that: a) the mutations originated in the Israelite population that was exiled from Palestine by the Roman Empire in 70 AD and settled in Europe (Ashkenazi), in contrast to those who remained; and b) the difference in origin distribution of the BS[2] and FACC mutations can be explained by either a secondary migration of a subgroup with a subsequent genetic drift, or a separate geographic region of introduction for each mutation.

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[1] FACC = Fanconi anemia complementation group C

Background: Familial Mediterranean fever is a genetic disease in which some characteristic gene mutation have been found.

Objective: To analyze the phenotype-genotype correlations in North African Jews and Armedians with FMF.

Methods: We studied MEFV gene mutations and phenotype-genotype correlations in North African Jews and Armedians with Familial Mediterranean Fever living in France.

Results: M694V mutation was the most common mutation in Jews and in Armenians. Patients with M6801 homozygosity or M6801/M694V compound heterozygosity had a phenotype as severe as patients with M694V homozygosity.

Conclusions: This study characterizes the phenotype-genotype in specific ethnic groups of patients with FMF.