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J I Rotter

Publications and source records attributed to J I Rotter.

At least 37 records · Page 2Linked to original sources
PubMed1999

A genome scan for familial combined hyperlipidemia reveals evidence of linkage with a locus on chromosome 11.

Familial combined hyperlipidemia (FCHL) is a common familial lipid disorder characterized by a variable pattern of elevated levels of plasma cholesterol and/or triglycerides. It is present in 10%-20% of patients with premature coronary heart disease. The genetic etiology of the disease, including the number of genes involved and the magnitude of their effects, is unknown. Using a subset of 35 Dutch families ascertained for FCHL, we screened the genome, with a panel of 399 genetic markers, for chromosomal regions linked to genes contributing to FCHL. The results were analyzed by use of parametric-linkage methods in a two-stage study design. Four loci, on chromosomes 2p, 11p, 16q, and 19q, exhibited suggestive evidence for linkage with FCHL (LOD scores of 1.3-2.6). Markers within each of these regions were then examined in the original sample and in additional Dutch families with FCHL. The locus on chromosome 2 failed to show evidence for linkage, and the loci on chromosome 16q and 19q yielded only equivocal or suggestive evidence for linkage. However, one locus, near marker D11S1324 on the short arm of human chromosome 11, continued to show evidence for linkage with FCHL, in the second stage of this design. This region does not contain any strong candidate genes. These results provide evidence for a candidate chromosomal region for FCHL and support the concept that FCHL is complex and heterogeneous.

Adult↗
PubMed1999

Novel genes for familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is a complex genetic disorder of unknown etiology. Recently, 'modifier' genes of the FCHL phenotype, such as the apolipoprotein AI-CIII-AIV gene cluster and LPL, have been identified in several populations. A 'major' gene for FCHL has been identified in a Finnish isolate which maps to a region syntenic to murine chromosome 3 where a locus for combined hyperlipidemia has been identified. We review these and other recent studies which indicate that FCHL is genetically heterogeneous.

Age Factors↗
PubMed1999

A genome-wide search identifies potential new susceptibility loci for Crohn's disease.

Chronic inflammatory bowel disease (IBD) presents as two major clinical forms, Crohn's disease (CD) and ulcerative colitis (UC). Genetic epidemiological studies and animal models suggest that inherited factors play significant roles in the susceptibility to both forms of IBD. From four genome-wide scans, putative susceptibility loci on chromosome 16 (IBD1 for CD), and on chromosomes 1, 3, 4, 6, 7, 10, and 12 for IBD, have been identified. Several other groups, including ours, have confirmed linkage to the loci on chromosomes 12 and 16. The aim of this study is to identify other potential susceptibility loci for CD with a genome-wide search approach. In our sample of 222 individuals from 46 families (20 Jewish and 26 non-Jewish), with a total of 65 sibpairs diagnosed with CD, we observed a novel locus with suggestive linkage [multipoint logarithm of the odds score (Mlod) > 2] at chromosome 14q11.2 (Mlod = 2.8, p = 0.0002). In addition, suggestive linkage was observed in our Jewish families at chromosome 17q21-q23 (Mlod = 2.1, p = 0.01) and chromosome 5q33-q35 (Mlod = 2.2, p = 0.0003). The syntenic regions of the latter locus are mapped within two putative loci on mouse chromosomes 11 and 18, which were identified in a mouse IBD model induced by dextran sulfate sodium (29). Our preliminary results provide potential evidence for several susceptibility loci contributing to the risk of CD. The observation of man-mouse synteny may accelerate the identification of CD susceptibility gene(s) on human chromosome 5.

Chromosome Mapping↗
PubMed1999

Linkage of Crohn's disease to the major histocompatibility complex region is detected by multiple non-parametric analyses.

BACKGROUND: There is evidence for genetic susceptibility to Crohn's disease, and a tentative association with tumour necrosis factor (TNF) and HLA class II alleles. AIMS: To examine the potential of genetic linkage between Crohn's disease and the MHC region on chromosome 6p. METHODS: TNF microsatellite markers and, for some families, additional HLA antigens were typed for 323 individuals from 49 Crohn's disease multiplex families to generate informative haplotypes. Non-parametric linkage analysis methods, including sib pair and affected relative pair methods, were used. RESULTS: Increased sharing of haplotypes was observed in affected sib pairs: 92% (48/52) shared one or two haplotypes versus an expected 75% if linkage did not exist (p=0.004). After other affected relative pairs were included, the significance level reached 0.001. The mean proportion of haplotype sharing was increased for both concordant affected (pi=0.60, p=0.002) and unaffected sib pairs (pi=0.58, p=0. 031) compared with the expected value (pi=0.5). In contrast, sharing in discordant sib pairs was significantly decreased (pi=0.42, p=0. 007). Linear regression analysis using all three types of sib pairs yielded a slope of -0.38 at p=0.00003. It seemed that the HLA effect was stronger in non-Jewish families than in Jewish families. CONCLUSIONS: All available analytical methods support linkage of Crohn's disease to the MHC region in these Crohn's disease families. This region is estimated to contribute approximately 10-33% of the total genetic risk to Crohn's disease.

Alleles↗
PubMed1999

Linkage of a candidate gene locus to familial combined hyperlipidemia: lecithin:cholesterol acyltransferase on 16q.

Familial combined hyperlipidemia (FCHL) is a common lipid disorder characterized by elevated levels of plasma cholesterol and triglycerides that is present in 10% to 20% of patients with premature coronary artery disease. To study the pathophysiological basis and genetics of FCHL, we previously reported recruitment of 18 large families. We now report linkage studies of 14 candidate genes selected for their potential involvement in the aspects of lipid and lipoprotein metabolism that are altered in FCHL. We used highly polymorphic markers linked to the candidate genes, and these markers were analyzed using several complementary, nonparametric statistical allele-sharing linkage methodologies. This current sample has been extended over the one in which we identified an association with the apolipoprotein (apo) AI-CIII-AIV gene cluster. We observed evidence for linkage of this region and FCHL (P<0.001), providing additional support for its involvement in FCHL. We also identified a new locus showing significant evidence of linkage to the disorder: the lecithin:cholesterol acyltransferase (LCAT) locus (P<0.0006) on chromosome 16. In addition, analysis of the manganese superoxide dismutase locus on chromosome 6 revealed a suggestive linkage result in this sample (P<0.006). Quantitative traits related to FCHL also provided some evidence of linkage to these regions. No evidence of linkage to the lipoprotein lipase gene, the microsomal triglyceride transfer protein gene, or several other genes involved in lipid metabolism was observed. The data suggest that the lecithin:cholesterol acyltransferase and apolipoprotein AI-CIII-AIV loci may act as modifying genes contributing to the expression of FCHL.

Adult↗
PubMed1999

PARP alleles within the linked chromosomal region are associated with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by various autoantibodies that recognize autoantigens displayed on the surface of cells undergoing apoptosis. The genetic contribution to SLE susceptibility has been widely recognized. We previously reported evidence for linkage to SLE of the human chromosome 1q41-q42 region and have now narrowed it from 15 to 5 cM in an extended sample using multipoint linkage analysis. Candidate genes within this region include (a) PARP, poly(ADP-ribose) polymerase, encoding a zinc-finger DNA-binding protein that is involved in DNA repair and apoptosis; (b) TGFB2, encoding a transforming growth factor that regulates cellular interactions and responses; and (c) HLX1, encoding a homeobox protein that may regulate T-cell development. Using a multiallelic, transmission-disequilibrium test (TDT), we found overall skewing of transmission of PARP alleles to affected offspring in 124 families (P = 0.00008), preferential transmission of a PARP allele to affected offspring (P = 0.0003), and lack of transmission to unaffected offspring (P = 0.004). Similar TDT analyses of TGFB2 and HLX1 polymorphisms yielded no evidence for association with SLE. These results suggest that PARP may be (or is close to) the susceptibility gene within the chromosome 1q41-q42 region linked to SLE.

Alleles↗
PubMed1999

Association of plasma lipids and apolipoproteins with the insulin response element in the apoC-III promoter region in familial combined hyperlipidemia.

The apoAI-CIII-AIV gene cluster, located on chromosome 11, contributes to the phenotype of familial combined hyperlipidemia (FCH), but this contribution is genetically complex. Combinations of haplotypes, based on three restriction enzyme polymorphisms: XmnI and MspI sites, 5' of the start site of the apoA-I gene and SstI polymorphism in the 3' untranslated region of exon 4 of the apoC-III gene, were analyzed to characterize their effect on the expression of severe hyperlipidemia. An epistatic interaction was demonstrated: the S2 allele on one haplotype was synergistic in its hyperlipidemic effect to the X2M2 allele on the other haplotype (Dallinga-Thie, G. M. et al. J. Clin. Invest. 1997. 99: 953-961). In the present study two additional polymorphic sites in the insulin response element (IRE) of the apoC-III gene promoter, T-455C: FokI restriction site, C-482T: MspI restriction site, were studied in 34 FCH pedigrees including 34 probands, 220 hyperlipidemic relatives, 300 normolipidemic relatives, and 236 spouses. In contrast to the earlier data for the other polymorphisms in this gene cluster (XmnI, MspI/AI, and SstI), there were no differences in frequency distributions of the T-455C and the C-482T variants between probands, hyperlipidemic and normolipidemic relatives and spouses. No significant associations between plasma lipid traits and DNA variants in the IRE were observed. Analysis of combinations of haplotypes based on the five polymorphisms in the gene cluster provided further evidence for a dominant role of the SstI polymorphism as a major susceptibility locus in FCH. The inclusion of the IRE markers did not improve genetic informativeness, nor our understanding of the observed synergistic relationship associated with the high risk combination of haplotypes in FCH families.

Adult↗
PubMed1998

Evidence for complex nuclear inheritance in a pedigree with nonsyndromic deafness due to a homoplasmic mitochondrial mutation.

The relationship between mitochondrial genotype and clinical phenotype is complicated in most instances by the heteroplasmic nature of pathogenic mitochondrial mutations. We have previously shown that maternally inherited hearing loss in a large Arab-Israeli kindred is due to the homoplasmic A1555G mutation in the mitochondrial 12S ribosomal RNA gene [Prezant et al., 1993: Nat Genet 4:289-294]. Family members with this mutation have phenotypes ranging from profound hearing loss to completely normal hearing, and we have shown that there is genetic and biochemical evidence for nuclear gene involvement in this family [Bu et al., 1993: Genet Epidemiol 9:27-44; Guan et al., 1996: Hum Mol Genet 5:963-971]. To identify such a nuclear locus, two candidate genes were excluded through linkage analysis and sequencing, and a genome-wide linkage search in family members who all have the identical homoplasmic mitochondrial mutation, but differ in their hearing status, was performed. In two stages a total of 560 polymorphic genetic markers was genotyped, and the data were analyzed under model-dependent and model-free assumptions. No chromosomal region was identified as a major contributor to the phenotypic expression of the mitochondrial mutation. Thus, in this simplified paradigm of a homoplasmic mitochondrial mutation in a single kindred who all live in the similar environment of a small village, the penetrance of the mitochondrial mutation appears to depend on the interaction of multiple nuclear genes.

Chromosome Mapping↗
PubMed1998

Amyloidosis in familial mediterranean fever is associated with a specific ancestral haplotype in the MEFV locus.

Familial Mediterranean fever (FMF) is a recessive disease characterized by recurrent attacks of inflammation of serosal membranes, and the gene responsible, MEFV, has been recently identified. Amyloidosis is considered to be the most severe complication. Since colchicine is effective in preventing FMF amyloidosis and since this process can develop even prior to the FMF symptoms, lifelong colchicine treatment is recommended for all FMF patients. Identification of the factor which determines amyloidosis will allow treatment to be directed only to those at risk. In order to investigate the association between amyloidosis and MEFV haplotypes, we studied 56 families from three ethnic groups. We compared the haplotypes of FMF patients with and without amyloidosis in each ethnic group separately and identified 14 different MEFV core haplotypes. A significant association (P < 0.004) was found between amyloidosis and a specific core haplotype, 153bp:104bp at markers D16S3370 and D16S2617, respectively. Amyloidosis was present in 20 out of 70 homozygotes for this haplotype and in 6 out of 35 compound heterozygotes for this and other core haplotypes. None of the patients who did not carry this allele had amyloidosis. There was no association between the various haplotypes and severity of the FMF symptoms, age of onset, or age at commencement of colchicine. Further investigation of the MEFV haplotypes in additional patients is recommended as such an association may save many mildly affected or asymptomatic patients with non-amyloidotic genotypes from receiving unnecessary lifelong colchicine treatment.

Adolescent↗
PubMed1998

Families with familial combined hyperlipidemia and families enriched for coronary artery disease share genetic determinants for the atherogenic lipoprotein phenotype.

Small, dense LDL particles consistently have been associated with hypertriglyceridemia, premature coronary artery disease (CAD), and familial combined hyperlipidemia (FCH). Previously, we have observed linkage of LDL particle size with four separate candidate-gene loci in a study of families enriched for CAD. These loci contain the genes for manganese superoxide dismutase (MnSOD), on chromosome 6q; for apolipoprotein AI-CIII-AIV, on chromosome 11q; for cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT), on chromosome 16q; and for the LDL receptor (LDLR), on chromosome 19p. We have now tested whether these loci also contribute to LDL particle size in families ascertained for FCH. The members of 18 families (481 individuals) were typed for genetic markers at the four loci, and linkage to LDL particle size was assessed by nonparametric sib-pair linkage analysis. The presence of small, dense LDL (pattern B) was much more frequent in the FCH probands (39%) than in the spouse controls (4%). Evidence for linkage was observed at the MnSOD (P=.02), CETP/LCAT (P=.03), and apolipoprotein AI-CIII-AIV loci (P=.005) but not at the LDLR locus. We conclude that there is a genetically based association between FCH and small, dense LDL and that the genetic determinants for LDL particle size are shared, at least in part, among FCH families and the more general population at risk for CAD.

Adult↗
PubMed1997

Association between serum amyloid A proteins and coronary artery disease: evidence from two distinct arteriosclerotic processes.

BACKGROUND: Serum amyloid A (SAA) proteins are a family of inflammatory apolipoproteins that may modify high-density lipoprotein structure and function. Elevations of SAA have been reported in unstable coronary syndromes, but the levels and types of SAA protein in humans with spontaneous or transplant-associated coronary artery disease are not known. METHODS AND RESULTS: SAA levels were analyzed using an ELISA in 76 sera from 36 patients after cardiac transplantation and in 346 other individuals, 85 patients with atherosclerotic coronary disease plus 261 of their relatives. The mean SAA level was 5-fold higher in transplant patients (203+/-181 microg/mL [23 to 934 microg/mL]) compared with normal subjects without coronary disease (36+/-16 microg/mL [2.8 to 193 microg/mL], P<.005). The mean SAA level was significantly elevated in patients with transplant coronary disease (206+/-160 microg/mL, n=23) compared with those without (140+/-104 microg/mL, n=12, P=.02). Elevated SAA levels were associated with increased mortality after transplantation. On multiple regression analysis, SAA levels were predicted by corticosteroid dose, pretransplant diagnosis of atherosclerotic coronary artery disease, and the presence of transplant coronary disease. SAA levels were elevated in patients with spontaneous atherosclerotic coronary disease (49+/-31 microg/mL) compared with unaffected relatives (39+/-36 microg/mL, mean+/-SD, P=.02). There was no evidence for a genetic contribution to SAA levels. All inducible human SAA protein types were documented by immunoblotting in both spontaneous and transplant coronary disease. CONCLUSIONS: Environmentally determined elevations in SAA levels in patients with both spontaneous and transplant coronary artery disease provide further evidence for a potential pathophysiological link between inflammation, lipoprotein metabolism, and the development of atherosclerosis.

Adult↗
PubMed1997

A high-resolution genetic map of the familial Mediterranean fever candidate region allows identification of haplotype-sharing among ethnic groups.

Familial Mediterranean fever (FMF) is a recessive disorder of inflammation caused by mutations in a gene (designated MEFV) on chromosome 16p13.3. We have recently constructed a 1-Mb cosmid contig that includes the FMF critical region. Here we show genotype data for 12 markers from our physical map, including 5 newly identified microsatellites, in FMF families. Intrafamilial recombinations placed MEFV in the approximately 285 kb between D16S468/D16S3070 and D16S3376. We observed significant linkage disequilibrium in the North African Jewish population, and historical recombinants in the founder haplotype placed MEFV between D16S3082 and D16S3373 (approximately 200 kb). In smaller panels of Iraqi Jewish, Arab, and Armenian families, there were significant allelic associations only for D16S3370 and D16S2617 among the Armenians. A sizable minority of Iraqi Jewish and Armenian carrier chromosomes appeared to be derived from the North African Jewish ancestral haplotype. We observed a unique FMF haplotype common to Iraqi Jews, Arabs, and Armenians and two other haplotypes restricted to either the Iraqi Jewish or the Armenian population. These data support the view that a few major mutations account for a large percentage of the cases of FMF and suggest that some of these mutations arose before the affected Middle Eastern populations diverged from one another.

Alleles↗
PubMed1997

Family history: a comprehensive genetic risk assessment method for the chronic conditions of adulthood.

Targeting individuals with increased risk for common, chronic disease can improve the efficiency and efficacy of preventive efforts by improving the predictability of screening tests and participant compliance. Individuals with the greatest risk for these disorders are those with a genetic susceptibility. The purpose of this study was to determine the feasibility of using a single, comprehensive family history as a method for stratifying risk for many preventable, common genetic disorders. Family histories obtained in a prenatal diagnostic clinic were reviewed regarding cardiovascular diseases, diabetes and several cancers; 42.5% of individuals reported a family history for at least one of the disorders under study. Familial coronary artery disease was most commonly reported (29% of participants), followed by noninsulin-dependent diabetes (14%). Qualitative characterization of disease susceptibility was also accomplished using family history data. For example, occurrence of different cancers within pedigrees was suggestive of familial cancer syndromes, and clustering of noninsulin-dependent diabetes and cardiovascular disease suggested an insulin resistance syndrome. Depending on the specific disease, 5 to 15% of at-risk individuals had a moderately increased risk (2 to 5 times the population risk), and approximately 1 to 10% had a high risk (absolute risks approaching 50%). Family history reports of common, chronic disease are prevalent among the population at large, and collection and interpretation of comprehensive family history data is a feasible, initial method for risk stratification for many preventable, chronic conditions. These findings may have important implications for disease prevention and management.

Adolescent↗
PubMed1997

Consanguinity and common adult diseases in Israeli Arab communities.

Consanguinity has a deleterious effect with regard to congenital malformation and rare autosomal recessive diseases; however, little information exists on its role in multifactorial common adult morbidity. We investigated the effects of consanguinity on the prevalence of common diseases in adulthood, including diabetes mellitus, myocardial infarction, bronchial asthma, and duodenal ulcer. As part of a larger study investigating the inbreeding coefficient in the Israeli-Arab community, we distributed questionnaires to parents of 4,100 second-grade students in 158 randomly chosen schools. Among the 3,772 responders (92%), 34.8% of the students' fathers and 31% of their mothers were found to be born to consanguineous matings. There was no difference in the prevalence (males, females) between the offspring of consanguineous versus non-consanguineous matings for diabetes mellitus (consanguinity: 4.3%, 1.5% vs. non-consanguinity: 2.9%, 1.6%) myocardial infarction (2.7%, 0.03% vs. 2.3%, 0.03%), bronchial asthma (2.4%, 2.0% vs. 3.7%, 2.3%), or duodenal ulcer (7.0%, 3.0% vs. 7.8%, 2.9%), respectively. The study suggests that even in a population with a high rate of consanguinity, there is no significant increase in the prevalence of these common adult diseases.

Adult↗
PubMed1997

Construction of a 1-Mb restriction-mapped cosmid contig containing the candidate region for the familial Mediterranean fever locus (MEFV) on chromosome 16p 13.3.

In this paper we describe the assembly and restriction map of a 1.05-Mb cosmid contig spanning the candidate region for familial Mediterranean fever (FMF), a recessively inherited disorder of inflammation localized to 16p13.3. Using a combination of cosmid walking and screening for P1, PAC, BAC, and YAC clones, we have generated a contig of genomic clones spanning approximately 1050 kb that contains the FMF critical region. The map consists of 179 cosmid, 15 P1, 10 PAC, 3 BAC, and 17 YAC clones, anchored by 27 STS markers. Eight additional STSs have been developed from the approximately 700 kb immediately centromeric to this genomic region. Five of the 35 STSs are microsatellites that have not been previously reported. NotI and EcoRI mapping of the overlapping cosmids, hybridization of restriction fragments from cosmids to one another, and STS analyses have been used to validate the assembly of the contig. Our contig totally subsumes the 250-kb interval recently reported, by founder haplotype analysis, to contain the FMF gene. Thus, our high-resolution clone map provides an ideal resource for transcriptional mapping toward the eventual identification of this disease gene.

Base Sequence↗
PubMed1997

Complex genetic contribution of the Apo AI-CIII-AIV gene cluster to familial combined hyperlipidemia. Identification of different susceptibility haplotypes.

Familial combined hyperlipidemia (FCH) is a common genetic lipid disorder in Western societies. In a recent report (Dallinga-Thie, G.M., X.D. Bu, M. van Linde-Sibenius Trip, J.I. Rotter, A.J. Lusis, and T.W.A. de Bruin. J. Lipid Res., 1996, 36:136-147) we have studied three restriction enzyme polymorphisms: XmnI, and MspI sites 5' of the apo AI gene and SstI site in the 3' untranslated region of exon 4 of the apo CIII gene in 18 FCH pedigrees, including 18 probands, 178 hyperlipidemic relatives, 210 normolipidemic relatives, and 176 spouses. DNA variations in the apo AI-CIII-AIV gene cluster had a modifying effect on plasma triglycerides, LDL cholesterol, and apolipoprotein CIII levels. In this study, combinations of haplotypes were analyzed to further characterize their interactions and effect on the expression of severe hyperlipidemia in FCH subjects. A specific combination of haplotypes with one chromosome carrying the X1M1S2 (1-1-2) haplotype and the other the X2M2S1 haplotype (2-2-1) was significantly more frequent in hyperlipidemic relatives (6%) than in normolipidemic relatives (3%) and spouses (0.5%). Associated with this combination of haplotypes were significantly elevated plasma cholesterol (P < 0.0001), triglycerides (P < 0.0001), and apo CIII (P < 0.001) levels when compared to the wild type combination of haplotypes 1-1-1/1-1-1. The only spouse with this specific combination of haplotypes showed a severe hyperlipidemic phenotype, similar to FCH. Furthermore, nonparametric sibpair linkage analysis revealed significant linkage between these markers in the gene cluster and the FCH phenotype (MspI P = 0.0088, SstI P = 0.044, and XMS haplotype P = 0.037). The present findings confirm that the apo AI-CIII-IV gene cluster contributes to the FCH phenotype, but this contribution is genetically complex. An epistatic interaction between different haplotypes of the gene cluster was demonstrated. The S2 allele on one haplotype was synergistic to the X2M2 allele on the other haplotype in its hyperlipidemic effect. Therefore, two different susceptibility loci exist in the gene cluster, demonstrating the paradigm of complex genetic contribution to FCH.

Adult↗
PubMed1997

Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus.

Genetic susceptibility confers significant risk for systemic lupus erythematosus (SLE). The MHC region and other polymorphic loci have been associated with SLE. Because more compelling evidence for an involvement of a genetic locus includes linkage, we tested a candidate region homologous to a murine SLE susceptibility region in 52 SLE-affected sibpairs from three ethnic groups. We analyzed seven microsatellite markers from the human chromosome 1q31-q42 region corresponding to the telomeric end of mouse chromosome 1, the region where specific manifestations of murine lupus, including glomerulonephritis and IgG antichromatin, have been mapped. Comparing the mean allele sharing in affected sibpairs of each of these seven markers to their expected values of 0.50, only the five markers located at 1q41-q42 showed evidence for linkage (P = 0.0005-0.08). Serum levels of IgG antichromatin also showed evidence for linkage to two of these five markers (P = 0.04), suggesting that this phenotype is conserved between mice and humans. Compared to the expected random distribution, the trend of increased sharing of haplotypes was observed in affected sibpairs from three ethnic groups (P < 0.01). We concluded that this candidate 1q41-q42 region probably contains a susceptibility gene(s) that confers risk for SLE in multiple ethnic groups.

Adolescent↗