Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population.
Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever with serositis or synovitis. The FMF gene (MEFV) was cloned recently, and four missense mutations were identified. Here we present data from non-Ashkenazi Jewish and Arab patients in whom we had not originally found mutations and from a new, more ethnically diverse panel. Among 90 symptomatic mutation-positive individuals, 11 mutations accounted for 79% of carrier chromosomes. Of the two mutations that are novel, one alters the same residue (680) as a previously known mutation, and the other (P369S) is located in exon 3. Consistent with another recent report, the E148Q mutation was observed in patients of several ethnicities and on multiple microsatellite haplotypes, but haplotype data indicate an ancestral relationships between non-Jewish Italian and Ashkenazi Jewish patients with FMF and other affected populations. Among approximately 200 anonymous Ashkenazi Jewish DNA samples, the MEFV carrier frequency was 21%, with E148Q the most common mutation. Several lines of evidence indicate reduced penetrance among Ashkenazi Jews, especially for E148Q, P369S, and K695R. Nevertheless, E148Q helps account for recessive inheritance in an Ashkenazi family previously reported as an unusual case of dominantly inherited FMF. The presence of three frequent MEFV mutations in multiple Mediterranean populations strongly suggests a heterozygote advantage in this geographic region. (+info)
Ethnicity, nationality and health care accessibility in Kuwait: a study of hospital emergency room users.
In mid-1994, non-Kuwaiti expatriates constituted 61.7% of the total population of Kuwait (1.75 million). Despite this numerical majority, non-Kuwaitis exist as a social minority. Non-Kuwaitis may be grouped into three broad categories along ethnic/nationality lines into Bidoon (without nationality), Arabs, and Asians. The objective of this paper was to compare the relative accessibility of the various groups to health care services in Kuwait. The study is based on data collected as part of a survey of 2184 Emergency Room (ER) users in January-February 1993. All patients attending the hospital ERs between 7:30 am and 9:00 pm were interviewed about their reasons for coming to the ER instead of going to the primary health care (PHC) centres, as required. The major reason given was low accessibility of the PHCs. Compared to Kuwaiti nationals, 92% of whom were registered at the PHC centres, only 62% of the Arabs and 39% of the Asians were registered. Multiple logistic regression of the factors in registration indicated that nationality was the most important reason for lack of registration, with Asians only about one-quarter as likely to be registered as Kuwaitis. Also, people who had been in Kuwait for shorter durations (< 5 years) were less likely to be registered than the Kuwaiti nationals or expatriates who had been here for 10 years or longer. In the absence of registration at the PHC centre, the civil identification card (ID) may be used as a valid means to enter the health system. Among the Arabs and Asians, 22% and 29% did not have a civil ID card. Thus, for many expatriates, the hospital ER, which does not provide the necessary follow-up care is often the only source of health care available. (+info)
The human platelet alphaIIb gene is not closely linked to its integrin partner beta3.
alphaIIbb3 integrin is a heterodimeric receptor facilitating platelet aggregation. Both genes are on chromosome 17q21.32. Intergenic distance between them has been reported to be 125 to 260 kilobasepairs (kb) by pulsed-field gel electrophoresis (PFGE) genomic analysis, suggesting that they may be regulated coordinately during megakaryopoiesis. In contrast, other studies suggest these genes are greater than 2.0 megabasepairs (mb) apart. Because of the potential biological implications of having these two megakaryocytic-specific genes contiguous, we attempted to resolve this discrepancy. Taking advantage of large kindreds with mutations in either alphaIIb or beta3, we have developed a genetic linkage map between the thyroid receptor hormone-1 gene (THRA1) and beta3 as follows: cen-THRA1-BRCA1-D17S579/alphaIIb-beta3-qte r, with a distance of 1.3 centiMorgans (cM) between alphaIIb and beta3 and the two genes being oriented in the same direction. PFGE genomic and YAC clone analysis showed that the beta3 gene is distal and >/=365 kb upstream of alphaIIb. Additional restriction mapping shows alphaIIb is linked to the erythrocyte band 3 (EPB3) gene, and beta3 to the homeobox HOX2b gene. Analysis of alphaIIb(+)-BAC and P1 clones confirm that the EPB3 gene is approximately 110 kb downstream of the alphaIIb gene. Sequencing the region surrounding the human alphaIIb locus showed the Granulin gene approximately 18 kb downstream to alphaIIb, and the KIAA0553 gene approximately 5.7 kb upstream. This organization is conserved in the murine sequence. These studies show that alphaIIb and beta3 are not closely linked, with alphaIIb flanked by nonmegakaryocytic genes, and imply that they are unlikely to share common regulatory domains during megakaryopoiesis. (+info)
Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group.
Primary hyperoxaluria type 1 is an autosomal recessive inherited metabolic disease in which excessive oxalates are formed by the liver and excreted by the kidneys, causing a wide spectrum of phenotypes ranging from renal failure in infancy to mere renal stones in late adulthood. Mutations in the AGXT gene, encoding the liver-specific enzyme alanine:glyoxylate aminotransferase, are responsible for the disease. Seven mutations were detected in eight families in Israel. Four of these mutations are novel and three occur in children living in single-clan villages. The mutations are scattered along various exons (1, 4, 5, 7, 9, 10), and on different alleles comprising at least five different haplotypes. All but one of the mutations are in a homozygous pattern, reflecting the high rate of consanguinity in our patient population. Two affected brothers are homozygous for two different mutations expressed on the same allele. The patients comprise a distinct ethnic group (Israeli Arabs) residing in a confined geographic area. These results, which are supported by previous data, suggest for the first time that the phenomenon of multiple mutations in a relatively closed isolate is common and almost exclusive to the Israeli-Arab population. Potential mechanisms including selective advantage to heterozygotes, digenic inheritance, and the recent emergence of multiple mutations are discussed. (+info)
Giardia lamblia carriage in Israeli Bedouin infants: risk factors and consequences.
Giardiasis is a common protozoan infection, with varying clinical manifestations. We investigated the associations between Giardia lamblia carriage and environmental, family, illness, and growth characteristics. Bedouin infants (n=234) were followed from birth to age 18-23 months. At monthly home visits, stool samples were obtained, history of illness was determined, and an environmental assessment was done. The comparisons presented are between 4 groups defined by length of carriage of G. lamblia. Study children had a mean+/-SD of 4.1+/-2.9 diarrhea episodes. No illness, environmental, or family characteristics were associated with length of carriage. Significant differences were found in weight-for-age and weight-for-height z scores between the never-positive-for-G. lamblia group and all other carriage groups combined. Faltering growth was shown to be subsequent to G. lamblia infection rather than preceding it. Our findings confirm that G. lamblia carriage is not associated with diarrhea. However, the effect on growth deserves further investigation. (+info)
Acute otitis media caused by antibiotic-resistant Streptococcus pneumoniae in southern Israel: implication for immunizing with conjugate vaccines.
The potential coverage of antibiotic-resistant pneumococci causing acute otitis media (AOM) by 7-, 9-, and 11-valent conjugate pneumococcal vaccines was studied in southern Israel. A total of 876 cases of pneumococcal AOM were studied in the context of various clinical conditions. Of the isolates, 68% were resistant to >/=1 drug, 61% were resistant to penicillin, and 13% were resistant to >/=3 antibiotic classes. Antibiotic resistance and coverage by the various candidates were age and population dependent and were higher among those with a complicated clinical course, as indicated by recent antibiotic use and recurrence of AOM. The results suggest that, if efficacious, the conjugate pneumococcal vaccines can substantially reduce the occurrence of pneumococcal AOM in general and complicated pneumococcal AOM in particular. (+info)
Candidate locus for a nuclear modifier gene for maternally inherited deafness.
Maternally inherited deafness associated with the A1555G mutation in the mitochondrial 12S ribosomal RNA (rRNA) gene appears to require additional environmental or genetic changes for phenotypic expression. Aminoglycosides have been identified as one such environmental factor. In one large Arab-Israeli pedigree with congenital hearing loss in some of the family members with the A1555G mutation and with no exposure to aminoglycosides, biochemical evidence has suggested the role of nuclear modifier gene(s), but a genomewide search has indicated the absence of a single major locus having such an effect. Thus it has been concluded that the penetrance of the mitochondrial mutation appears to depend on additive effects of several nuclear genes. We have now investigated 10 multiplex Spanish and Italian families with 35 members with the A1555G mutation and sensorineural deafness. Parametric analysis of a genomewide screen again failed to identify significant evidence for linkage to a single autosomal locus. However, nonparametric analysis supported the role of the chromosomal region around marker D8S277. The combined maximized allele-sharing LOD score of 3.1 in Arab-Israeli/Spanish/Italian families represents a highly suggestive linkage result. We suggest that this region should be considered a candidate for containing the first human nuclear modifier gene for a mitochondrial DNA disorder. The locus operates in Arab-Israeli, Spanish, and Italian families, resulting in the deafness phenotype on a background of the mitochondrial A1555G mutation. No obvious candidate genes are located in this region. (+info)
The impact of new immigrants from the former Soviet Union on the severity of coronary angiographic findings in a public hospital in Israel.
BACKGROUND: The arrival of 610,000 new immigrants to Israel from the former Soviet republics accounted for 58% of the population growth in the early 1990's. OBJECTIVE: To compare the coronary angiographic findings and risk factors between the new immigrants and local Jewish and Arab patients in this era of cost containment. METHODS AND RESULTS: A total of 550 consecutive patients--314 Jews, 95 new immigrants and 141 Arabs--were catheterized and analyzed during a 5 month period in 1995. Of this group 403 were males (73%). The mean age was 63.6 +/- 10.2 years among new immigrants, 62.4 +/- 9.4 among Jews, and 55.1 +/- 10.9 among Arabs (P < 0.05). Immigrants, including those under age 60, had the highest prevalence of multivessel disease (88.7%). Arabs had a high prevalence of single vessel disease (34.6%) and a low prevalence of multivessel (65.4%) and left main coronary disease (5.6%). Age, gender, risk factors and ethnic origin in descending order were determinants of the extent of coronary angiographic disease as revealed by multiple regression analysis. CONCLUSION: New immigrants had the most extensive angiographic coronary involvement, while Arab patients were younger and had less severe coronary artery disease. More intensive risk factor modification may have a major impact on disease progression particularly in the new immigrant subgroup. (+info)