Israel Medical Association Journal

Background: Cardiovascular disease is now well established as a multifactorial disease. In a given individual, the level of cardiovascular risk is due to the interaction between genetic and environmental components. The BIP cohort comprised 3000 patients with cardiovascular disease who were tested for the benefits of bezafibrate treatment. This cohort has the data for the lipid profile of each individual, fibrinogen, Insulin, as well as clinical, demographic and lifestyle parameters

Objectives: To genotype up to 64 variable sites in 36 genes in the BIP cohort. The genes tested in this assay are involved in pathways implicated in the development and progression of atherosclerotic plaques, lipid and homocystein metabolism, blood pressure regulation, thrombosis, rennin-angiotensin system, platelet aggregation, and leukocyte adhesion.

Methods:  DNA was extracted from 1000 Israeli patients from the BIP cohort. A multilocus assay, developed by the Roche Molecular System, was used for genotyping. Allele frequencies for some of the markers were compared to the published frequencies in a healthy population (the French Stanislas cohort, n=1480).

Results: Among the 26 comparable alleles checked in the two cohorts, 16 allele frequencies were significantly different from the healthy French population: ApoE (E3, E2, E4), ApoB (71ile), ApoC (3482T, 455C, 1100T, 3175G, 3206G), CETP (405val), ACE (Del), AGT (235thr), ELAM (128arg); p<0001 and LPL (93G, 291Ser, 447ter); p < 005.

Conclusions: Although a comparable healthy Israeli population study is needed for more precise interpretation of these results, frequency differences in these polymorphic alleles, associated with lipid metabolism, renin-angiotensin system and leukocyte adhesion mechanism, between CVD patients and healthy individuals nevertheless implicate these candidate genes as predisposing for CVD.lic safety.
 

Tumor necrosis factor-associated fever syndrome is an autosomal dominant disorder caused by mutations of the TNFRSF 1A gene encoding the 55 kD TNF receptor (p55 TNF-RI).

At the WHO meeting on primary immunodeficiency held in Orvetto, Italy in 1994, mutations in the genes involved in the classical PID disorders, such as X-linked agammaglobulinemia (Bruton).

Background: Since 1984, several waves of Ethiopian immigrants have settled in Israel. On arrival they were found to be highly infected with intestinal parasites and to have increased serum immunoglobulin E and eosinophilia. 

Objectives: To study serum IgE [1] levels in Ethiopian children growing up in the environment of Israel . 

Methods: We assessed four groups of children of Ethiopian origin: a) adolescents examined on their arrival to Israel (group 1, n=11); b) adolescents born in Ethiopia and living in Israel for more than 7 years (group 2, n=10); c) children of Ethiopian origin born in Israel, without a history of allergy or asthma (group 3, n=15); and d) asthmatic children of Ethiopian origin born in Israel (group 4, n=8). A thorough clinical interview and examination as well as serum IgE levels, stool parasites and absolute eosinophil count were performed. 

Results: Group 1 (11 newly arrived Ethiopian adolescents) had a mean eosinophil count of 688 cells/ml (0–1739) and a mean serum IgE of 1043 IU/ml (253–2932), P < 0.0009 as compared to group 2. Helminthic parasites were observed in 8/11 individuals; after 1 year of follow-up and anti-parasitic treatment, serum IgE levels did not change significantly. Group 2 (10 Ethiopian born adolescents living in Israel for on average 10 years, 7–15 years) had a normal leukocyte count, MEC [2] 192 cells/ml (range 54–289), serum IgE 142 IU/ml (range 14–399 IU/ml) and no parasites in stool. Group 3 (15 Ethiopian children born in Israel) had a normal leukocyte count, MEC 128 cells/ml (0–324), serum IgE 55 IU/ml (7–189 IU/ml), similar to age-matched Israeli controls. In group 4 (8 Israeli born children of Ethiopian descent diagnosed with asthma), serum IgE showed significant elevation compared to Israeli age-matched asthmatic children (P < 0.005).  

Conclusions: High levels of IgE found in Ethiopian children on arrival to Israel declined to Israeli control levels after several years of living in the new environment. Ethiopian children born in Israel had normal levels of IgE, suggesting that environment is the main factor affecting IgE levels in this population. Israeli born Ethiopian children with asthma had significantly increased serum IgE levels compared to asthmatics of Israeli origin. These findings suggest that both environmental and genetic factors determine the level of serum IgE in these children. 

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 [1] Ig = immunoglobulin

 [2] MEC = mean eosinophil count
 

Melanoma is the leading cause of death from skin tumors worldwide, with an annual increase in incidence over the past decade. The molecular mechanisms involved in melanoma pathogenesis are beginning to be unraveled. While a family history of melanoma and exposure to ultraviolet irradiation have been known for years as risk factors in melanoma development, the precise genes involved in inherited predisposition were defined only in the past decade. Germline mutations in two genes that play a pivotal role in controlling cell cycle and division – CDKN2A and cyclin-dependent kinase 4 (CDK4) – have been detected in autosomal, dominant, high penetrance familial melanoma cases. In addition to these two highly penetrant genes, germline mutations and polymorphisms in a few low penetrance genes have been reported in familial melanoma cases: melanocortin-1 receptor, epidermal growth factor, glutathione s-transferase M1, cytochrome p450 debrisoquine hydroxylase locus (CYP2D6) and vitamin D receptor.

While some claim that germ-line engineering is a definite possibility, the law in Israel and in most countries states that it should be avoided. This paper suggests that using GLE[1] in order to ‘self-evolve’ (when it becomes safe) is not only inevitable but also morally justified. This paper argues that,  

• The great achievements of healthcare during the last century, enabling longer life, have made almost everyone prey to late-onset diseases.


• The conundrum of healthcare allocation is worsening, partly due to late-onset dysfunctional genes that have escaped the barriers of natural selection.


• Trying to free future generations from late-onset diseases (such as Alzheimer’s for instance) may be considered as ‘eugenics’ but, if pursued freely and justly, is a noble goal.


• We will be affecting future generations whether or not we use GLE.


• By definition, GLE might be reversible; it follows therefore that GLE may not necessarily represent the dramatic change inserted in the germ line forever – as is usually suggested.


• Reproductive freedom and justice are paramount in this scenario. These values are not necessarily incompatible if the right policies are in place.

Background: Primary pulmonary hypertension is a rare disorder, characterized by progressive pulmonary hypertension and right heart failure. It may be familial or sporadic. Mutations in bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor-beta receptor superfamily of receptors, underlie many cases of the disorder.

Objectives: To perform molecular analysis of a patient with familial PPH[1] and provide her and her family with suitable genetic counseling.

Methods: DNA was extracted from 10 ml whole blood, and the BMPR2 gene was screened for mutations. Individual exons were amplified by polymerase chain reaction and sequenced. Mutation confirmation and molecular characterization of additional family members was performed using restriction enzyme analysis followed by appropriate genetic counseling.

Results: We identified a novel T to C missense mutation expected to result in substitution of arginine for a conserved cysteine in the ligand-binding domain of BMPR2. Screening of family members demonstrated the presence of the mutation in the father and a younger asymptomatic sister of the index patient.

Conclusions: Molecular diagnosis in PPH allows for identification of at-risk family members and raises the option of earlier diagnosis and possibly instituting earlier treatment in affected individuals. However, molecular screening of asymptomatic family members raises difficult ethical questions that can only be resolved by conducting large multicenter prospective studies in BMPR2 carriers.

Background: Genetic hemochromatosis leads to iron overload in many tissues and may lead to liver cirrhosis and hepatocellular carcinoma. Early diagnosis and therapy are crucial. Since 80–100% of hemochromatosis patients of European origin are homozygous for a cysteine to tyrosine exchange in the HFE gene at codon 282, genetic screening might be useful. Representative population studies are needed to evaluate the phenotype of people heterozygous and homozygous for the C282Y mutation.

Objective: To determine the correlation between parameters of iron metabolism and the hemochromatosis genotype in a large population-based study.

Methods: A representative population-based survey, the Diabetomobil study, analyzed 5,083 German probands. Serum transferrin saturation and ferritin levels were determined, and the C282Y mutation of the HFE gene was analyzed by restriction fragment length polymorphism- polymerase chain reaction analysis.

Results: Nine of 373 probands with a transferrin saturation > 55% (2.4%) and none of 264 randomly selected probands with a transferrin saturation £ 55% (0%) were homozygous for the C282Y mutation. Three of the nine homozygous probands had ferritin values less than 250 µg/L. The frequency of the heterozygous genotype was 8.8%, and the percentage of heterozygous probands increased with increasing levels of transferrin saturation.

Conclusion:We propose a population screening strategy with an initial transferrin saturation test, followed by genotyping for the C282Y mutation if the transferrin saturation is above 55%, regardless of the ferritin level. Heterozygous individuals with higher transferrin saturation values may be protected against iron loss but may also be more susceptible for certain liver diseases, depending on the simultaneous prevalence of other diseases.
 

Background: It has been argued that arginine replacement in locus16 (Arg16) of ß₂ adrenergic receptor with glycin (Gly16) increases asthma severity, while glutamin replacement in locus 27 (Gln27) with glutamic acid (Glu27) decreases it. In addition, ethnic dependency of these polymorphisms has been described, but few studies investigated its relation to asthma severity in a non-anglosaxic population.

Objectives: To investigate non-anglosaxic ethnic influences on ß₂AR[1] polymorphisms and its correlations to asthma severity.

Methods: Sixty-six Israeli Jewish and Arab asthmatics who had near-fatal asthma and/or severe nocturnal asthma and/or steroid-dependency were investigated for genetic polymorphisms of ß₂AR and compared to matched controls. The Jewish patients included both Ashkenazi (of East European origin) and non-Ashkenazi (originating from the Middle East or North Africa). The results were compared with those of ethnically matched 113 non-asthmatic Israelis, and of non-asthmatic Anglo-Saxons described in the literature.

Results: We found no significant genetic differences between the asthmatics and their controls or between the various ethnic groups of our population. However, the prevalence of Glu27 was significantly lower in non-asthmatic Israelis compared to non-asthmatic Anglo-Saxons.

Conclusions: The genetic distribution of ß₂AR polymorphisms in severe Israeli asthmatics is not different from that of non-asthmatic Israelis and therefore its clinical impact on asthma is probably minimal.

Background: The precise genes involved in conferring prostate cancer risk in sporadic and familial cases are not fully known.

Objectives: To evlauate the genetic profile within several candidate genes of unselected prostate cancer cases and to correlate this profile with disease parameters.

Methods: Jewish Israeli prostate cancer patients (n=224) were genotyped for polymorphisms within candidate genes: p53, ER, VDR, GSTT1, CYP1A1, GSTP1, GSTM1, EPHX and HPC2/ELAC2, followed by analysis of the genotype with relevant clinical and pathologic parameters.

Results: The EPHX gene His113 allele was detected in 21.4% (33/154) of patients in whom disease was diagnosed above 61 years, compared with 5.7% (4/70) in earlier onset disease (P < 0.001). Within the group of late-onset disease, the same allele was noted in 5.5% (2/36) with grade I tumors compared with 18% (34/188) with grade II and up (P = 0.004). All other tested polymorphisms were not associated with a distinct clinical or pathologic feature in a statistically significant manner.

Conclusions: In Israeli prostate cancer patients, the EPHX His113 allele is seemingly associated with a more advanced, late-onset disease. These preliminary data need to be confirmed by a larger and more ethnically diverse study.

Background: Infant mortality in Israel is twofold higher among non-Jews than Jews.

Objectives: To determine the impact of congenital malformations and Mendelian diseases on infant mortality.

Methods: We compared the causes of infant mortality in a 4 year period among Jewish and non-Jewish Israeli citizens. Classification was done by analyzing all the death reports according to whether or not the child had any known major malformation, Mendelian disease and/or a syndrome, irrespective of the immediate cause of death.

Results: The infant mortality among non-Jews was double that among Jews (9 versus 4.4 per 1,000 live births). The rate of children with malformations/genetic syndromes was 3.1 times higher among non-Jews than among Jews (2.94 vs. 1.25 per 1,000 live births). The most significant difference was in the rate of Mendelian diseases, which were 8.3 times more frequent in non-Jewish children (0.16 vs. 1.33 per 1,000 live births respectively). A Mendelian disease was diagnosed in almost 15% of the non-Jewish infants and in less than 5% of the Jewish infants.

Conclusions: The most striking difference between the Jewish and non-Jewish infants was the incidence of congenital malformations and Mendelian diseases parallel to the differences in the consanguinity rates between the two populations.