Biomedical subjects

Marek Kimmel

Publications and source records attributed to Marek Kimmel.

24 records · Page 2Linked to original sources

PubMed2003

Molecular mechanisms of autosomal recessive hypercholesterolemia.

PURPOSE OF REVIEW: Autosomal recessive hypercholesterolemia (ARH) is a rare Mendelian dyslipidemia characterized by markedly elevated plasma LDL levels, xanthomatosis, and premature coronary artery disease. LDL receptor function is normal, or only moderately impaired in fibroblasts from ARH patients, but their cultured lymphocytes show increased cell-surface LDL binding, and impaired LDL degradation, consistent with a defect in LDL receptor internalization. Recently, the disorder was shown to be caused by mutations in a phosphotyrosine binding domain protein, ARH, which is required for internalization of low density lipoproteins in the liver. This review summarizes the findings of new investigations into the pathophysiology and molecular genetics of ARH. RECENT FINDINGS: All mutations that have been characterized to date preclude the synthesis of a full-length protein. GST-pulldown experiments indicate that the phosphotyrosine binding domain of ARH interacts with the internalization sequence (NPVY) in the cytoplasmic tail of LDLR, and that conserved motifs in the C-terminal portion of the protein bind to clathrin and to the beta2-adaptin subunit of AP-2. SUMMARY: The available data suggest that ARH functions as an adaptor protein that couples LDLR to the endocytic machinery.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Genetic susceptibility for lung cancer: interactions with gender and smoking history and impact on early detection policies.

OBJECTIVES: To identify a subgroup of former, current and never smokers (males and females) at high risk for developing lung cancer, based on their genetic susceptibility profiles, to estimate their lifetime probabilities of the disease, and to assess the potential mortality reduction that could be achieved by screening the high-risk group. METHODS: Case-control data (764 cases and 677 matched controls), on two assays of DNA damage and repair (mutagen susceptibility and DNA repair capacity, DRC) in different smoking categories were used to obtain estimates of susceptibility using the formula of total probability. The estimates were inserted into a model of lung cancer natural history and detection by screening to assess mortality reduction due to screening of high-risk individuals. RESULTS: The high-risk group was defined as that 12.5% of the population who were above the third quartile for bleomycin sensitivity and below the median for DRC. High-risk male current, former, and never smokers had lifetime probabilities for developing lung cancer of 38, 21, and 5%, respectively. Females had lower probabilities to develop lung cancer: 15, 8, and 1.5% for high-risk current, former, and never smokers, respectively. Screening of high-risk smokers (12.5% of all smokers) reduced overall mortality by 7% compared to 30% reduction if all smokers were screened. Analogous results were obtained for former and never smokers. CONCLUSIONS: Genetic susceptibility constitutes an important factor in the selection of a high-risk group for early lung cancer detection.

Age of Onset↗

PubMed2002

Non-homogeneous infinite sites model under demographic change: mathematical description and asymptotic behavior of pairwise distributions.

We developed a mathematical model, which makes possible to predict joint distributions of numbers of mismatches in two or more linked regions of the genome, based on the Infinite Sites Models, under mutation-drift equilibrium as well as under various patterns of population growth. With mutation rates varying in the region, one of the predictions is different correlation between numbers of mismatches in the two regions, depending on the pattern of the past population growth (constant, slowly growing, or rapidly growing). Also, for slower growth patterns of population sizes, the coalescence tree is not necessarily 'starlike'. Thus, the joint distribution of mismatches, predicted by the model, provides additional insights into the demographic history of the populations. We also developed expectations and variances of sample statistics under different growth scenarios. As an application we used a sample of mitochondrial sequences from hypervariable regions 1 and 2 (HV1 and HV2), representing major world populations (Europeans, Asians and Africans). The patterns of joint distributions of numbers of mismatches differ markedly from one population to another. In addition, there is a considerable variability in the proportion of numbers of mismatches between HV1 and HV2 sequences. The patterns of bivariate distributions from the HV1 and HV2 data in these data are consistent with those generated by the model involving a stepwise change in population size.

Asian People↗

PubMed2002

Complex SNP-based haplotypes in three human helicases: implications for cancer association studies.

We have initiated a candidate gene approach to study variation and predisposition to cancer in the four major ethnic groups that constitute the U.S. population (African Americans, Caucasians, Hispanics, and Asians). We resequenced portions of three helicase genes (BLM, WRN, and RECQL) identifying a total of 37 noncoding single nucleotide polymorphisms (SNPs). Haplotype inference predicted 50 haplotypes in BLM, 56 in WRN, and 47 in RECQL in a sample of 600 chromosomes. Approximately 10% of the predicted haplotypes were shared among all ethnic groups. Linkage disequilibrium and recombination effects showed that each locus has taken a diverse evolutionary path. Primate DNA analysis of the same loci revealed one human haplotype per gene shared with the great apes, indicating that the observed diversity occurred since the divergence of humans from the last common ancestor. In BLM, we confirmed the presence of a founder haplotype among Ashkenazi Jews homozygous for the blm(Ash) mutation. The cosegregating haplotype was seen in all (6/6) samples of Ashkenazi descent, whereas in the general population it has a low frequency (0.02) and was not found in African Americans. In WRN, ethnic samples were studied for their haplotype content and the presence or absence of six previously described coding SNPs (cSNPs). Hispanic individuals carrying two of these cSNPs showed a 60% increase in the frequency of a common haplotype (haplotype No. 28). In the pooled sample, no association was found. Because (1) the majority of the haplotypes are population specific and (2) the patterns of linkage disequilibrium, recombination, and haplotype diversity are markedly different between gene regions, these data show the importance of either ethnically matched controls or within-family-based disease-gene association studies.

Alleles↗

PubMed2002

Haplotype and linkage disequilibrium architecture for human cancer-associated genes.

To facilitate association-based linkage studies we have studied the linkage disequilibrium (LD) and haplotype architecture around five genes of interest for cancer risk: ATM, BRCA1, BRCA2, RAD51, and TP53. Single nucleotide polymorphisms (SNPs) were identified and used to construct haplotypes that span 93-200 kb per locus with an average SNP density of 12 kb. These markers were genotyped in four ethnically defined populations that contained 48 each of African Americans, Asian Americans, Hispanic Americans, and European Americans. Haplotypes were inferred using an expectation maximization (EM) algorithm, and the data were analyzed using D', R(2), Fisher's exact P-values, and the four-gamete test for recombination. LD levels varied widely between loci from continuously high LD across 200 kb to a virtual absence of LD across a similar length of genome. LD structure also varied at each gene and between populations studied. This variation indicates that the success of linkage-based studies will require a precise description of LD at each locus and in each population to be studied. One striking consistency between genes was that at each locus a modest number of haplotypes present in each population accounted for a high fraction of the total number of chromosomes. We conclude that each locus has its own genomic profile with regard to LD, and despite this there is the widespread trend of relatively low haplotype diversity. As a result, a low marker density should be adequate to identify haplotypes that represent the common variation at a locus, thereby decreasing costs and increasing efficacy of association studies.

Alleles↗

PubMedDate not supplied

CT screening for lung cancer: the first ten years.

This article reviews the current state of knowledge regarding computed tomography (CT) screening for lung cancer. The initial 3 studies have demonstrated the superiority of CT-based screening for lung cancer over traditional radiography. Furthermore, false-positive tests common on baseline screening were manageable without notable excess of biopsies or thoracotomies. Differences and similarities of various screening regimens are discussed in relation to reported study results. When comparing the various studies, the focus should be placed on the diagnostic distribution achieved under annual repeat screening, as it is this distribution which is obtained year after year of repeat screening and this distribution and the curability of these repeat screen-diagnosed lung cancer which determine the usefulness of the screening regimen. To date, these studies demonstrate a consistent shift to over 80% of the cancer being diagnosed in Stage IA. This marked shift suggest that the curability of screen-detected lung cancers will be markedly improved.

Follow-Up Studies↗