Gender and racial differences in rates of total hip replacement.
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Black or African American↗
Biomedical subjects
Michael F Seldin
Publications and source records attributed to Michael F Seldin.
Markers that discriminate between European and African ancestry show limited variation within Africa.
Markers informative for ancestry are necessary for admixture mapping and improving case-control association analyses. In particular, African Americans are an admixed population for which genetic studies require accurately evaluating admixture. This will require markers that can be used in African Americans to determine if a given genomic region is of European or African ancestry. This report shows that, despite studies indicating high intra-African sequence variation, markers with large inter-ethnic differences have only small variations in allele distribution among divergent African populations and should be valuable for evaluating admixture in complex disease genetic studies.
Africa↗
Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice.
Germline mutations of the LKB1 gene are associated with Peutz-Jeghers syndrome, which is characterized by mucocutaneous pigmentation and gastrointestinal hamartoma with an increased risk of cancer development. To investigate the role of LKB1 in vivo, we have recently constructed Lkb1 gene knockout mice. Because of Lkb1 gene haploinsufficiency, the heterozygous Lkb1 mice develop gastrointestinal polyps of which the histological characteristics resemble those of the Peutz-Jeghers syndrome hamartomas. Here we demonstrate that the Lkb1 (+/-) mice develop hepatocellular carcinomas (HCCs). In Lkb1 (+/-) mice >50 weeks of age, >70% of the male mice developed HCCs, whereas only 20% of the females had HCCs, showing a sex difference in the susceptibility. Histological examinations revealed various types of HCCs, such as "trabecular," "clear cell," "pseudoglandular," and "sarcomatous" types, which were strikingly similar to those found in human HCCs. Western blotting and PCR analyses showed loss of Lkb1 heterozygosity in all of the HCC tissues examined, indicating a tumor suppressor role of LKB1 in the mouse liver. These results suggest that lack of LKB1 is a novel mechanism for HCC development. Thus, the Lkb1 (+/-) knockout mutant should be an important and useful model for human HCC.
AMP-Activated Protein Kinases↗
Dissecting the genetic complexity of the association between human leukocyte antigens and rheumatoid arthritis.
Rheumatoid arthritis (RA) is an inflammatory disease with a complex genetic component. An association between RA and the human leukocyte antigen (HLA) complex has long been observed in many different populations, and most studies have focused on a direct role for the HLA-DRB1 "shared epitope" in disease susceptibility. We have performed an extensive haplotype analysis, using 54 markers distributed across the entire HLA complex, in a set of 469 multicase families with RA. The results show that, in addition to associations with the DRB1 alleles, at least two additional genetic effects are present within the major histocompatibility complex. One of these lies within a 497-kb region in the central portion of the HLA complex, an interval that excludes DRB1. This genetic risk factor is present on a segment of a highly conserved ancestral A1-B8-DRB1*03 (8.1) haplotype. Additional risk genes may also be present in the HLA class I region in a subset of DRB1*0404 haplotypes. These data emphasize the importance of defining haplotypes when trying to understand the HLA associations with disease, and they clearly demonstrate that such associations with RA are complex and cannot be completely explained by the DRB1 locus.
Alleles↗
Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice.
Peutz-Jeghers syndrome (PJS) is a hereditary disorder characterized by gastrointestinal hamartomatous polyposis associated with mucocutaneous pigmentation. Germ-line mutations of the gene encoding LKB1 (STK11), a serine/threonine kinase, are identified in most PJS patients. To investigate the role of LKB1 in the PJS phenotypes, we introduced a germ-line mutation in the mouse Lkb1 gene by homologous recombination in mouse embryonic stem cells. In most Lkb1 (+/-) mice >20 weeks of age, hamartomatous polyps developed in the glandular stomach, often in the pyloric region. Small intestinal hamartomas also developed in approximately one-third of the Lkb1 (+/-) mice >50 weeks of age. A genomic PCR and sequence analysis showed that all hamartomas retained both the wild-type and targeted Lkb1 alleles, indicating that allelic loss of the wild-type Lkb1 was not the cause of polyp formation. Moreover, the LKB1 protein level was not reduced in hamartomatous polyps compared with that in the Lkb1 (+/-) normal gastric mucosa. In addition, the remaining allele showed neither missense mutations in the coding sequence nor produced truncated LKB1 in the hamartoma. Taken together, these data suggest that the wild-type Lkb1 is expressed in the hamartoma at the haploid amount. Accordingly, the gastrointestinal hamartomas appear to develop because of the Lkb1 haploinsufficiency. Although additional genetic events may be critical in hamartoma and adenocarcinoma development, these data strongly suggest that the initiation of polyposis is not the result of loss of heterozygosity in Lkb1.
AMP-Activated Protein Kinases↗
Differentiation-specific effects of LHON mutations introduced into neuronal NT2 cells.
Inheritance of one of three primary mutations at positions 11778, 3460 or 14484 of the mitochondrial genome in subunits of Complex I causes Leber's Hereditary Optic Neuropathy (LHON), a specific degeneration of the optic nerve, resulting in bilateral blindness. It has been unclear why inheritance of a systemic mitochondrial mutation would result in a specific neurodegeneration. To address the neuron-specific degenerative phenotype of the LHON genotype, we have created cybrids using a neuronal precursor cell line, Ntera 2/D1 (NT2), containing mitochondria from patient lymphoblasts bearing the most common LHON mutation (11778) and the most severe LHON mutation (3460). The undifferentiated LHON-NT2 mutant cells were not significantly different from the parental cell control in terms of mtDNA/nDNA ratio, mitochondrial membrane potential, reactive oxygen species (ROS) production or the ability to reduce Alamar Blue. Differentiation of NT2s resulted in a neuronal morphology and neuron-specific pattern of gene expression, and a 3-fold reduction in mtDNA/nDNA ratio in both mutant and control cells; however, the differentiation protocol yielded significantly less LHON cells than controls, by 30%, indicating either a decreased proliferative potential or increased cell death of the LHON-NT2 cells. Differentiation of the cells to the neuronal form also resulted in significant increases in ROS production in the LHON-NT2 neurons versus controls, which is abolished by rotenone, a specific inhibitor of Complex I. We infer that the LHON genotype requires a differentiated neuronal environment in order to induce increased mitochondrial ROS, which may be the cause of the reduced NT2 yield; and suggest that the LHON degenerative phenotype may be the result of an increase in mitochondrial superoxide which is caused by the LHON mutations, possibly mediated through neuron-specific alterations in Complex I structure.
Animals↗
Ethnic-difference markers for use in mapping by admixture linkage disequilibrium.
Mapping by admixture linkage disequilibrium (MALD) is a potentially powerful technique for the mapping of complex genetic diseases. The practical requirements of this method include (a) a set of markers spanning the genome that have large allele-frequency differences between the parental ethnicities contributing to the admixed population and (b) an understanding of the extent of admixture in the study population. To this end, a DNA-pooling technique was used to screen microsatellite and diallelic insertion/deletion markers for allele-frequency differences between putative representatives of the parental populations of the admixed Mexican American (MA) and African American (AA) populations. Markers with promising pooled differences were then confirmed by individual genotyping in both the parental and admixed populations. For the MA population, screening of >600 markers identified 151 ethnic-difference markers (EDMs) with delta>0.30 (where delta is the absolute value of each allele-frequency difference between two populations, summed over all marker alleles and divided by two) that are likely to be useful for MALD analysis. For the AA population, analysis of >400 markers identified 97 EDMs. In addition, individual genotyping of these markers in Pima Amerindians, Yavapai Amerindians, European American (EA) individuals, Africans from Zimbabwe, MA individuals, and AA individuals, as well as comparison to the CEPH genotyping set, suggests that the differences between subpopulations of an ethnicity are small for many markers with large interethnic differences. Estimates of admixture that are based on individual genotyping of these markers are consistent with a 60% EA:40% Amerindian contribution to MA populations and with a 20% EA:80% African contribution to AA populations. Taken together, these data suggest that EDMs with large interpopulation and small intrapopulation differences can be readily identified for MALD studies in both AA and MA populations.
Black or African American↗
Punctin, a novel ADAMTS-like molecule, ADAMTSL-1, in extracellular matrix.
Punctin (ADAMTSL-1) is a secreted molecule resembling members of the ADAMTS family of proteases. Punctin lacks the pro-metalloprotease and the disintegrin-like domain typical of this family but contains other ADAMTS domains in precise order including four thrombospondin type I repeats. Punctin is the product of a distinct gene on human chromosome 9p21-22 and mouse chromosome 4 that is expressed in adult skeletal muscle. His-tagged punctin expressed in stably transfected High-Five(TM) insect cells was purified to apparent homogeneity by Ni-chromatography of conditioned medium. The NH(2) terminus is not blocked and has the sequence EEDRD and so forth as determined by Edman degradation, demonstrating signal peptidase processing. Recombinant epitope-tagged punctin has a calculated mass of 59,991 Da but exhibits major molecular species of 61970 +/- 6 Da and 62131 +/- 5 Da as measured by liquid chromatography electrospray mass spectrometry. Punctin is a glycoprotein based on carbohydrate staining and liquid chromatography electrospray mass spectrometry glycopeptide analysis. Glycosylation occurs at a single N-linked site as demonstrated by altered electrophoretic migration of punctin expressed in the presence of tunicamycin A. Punctin contains disulfide bonds based on antibody accessibility and electrophoretic migration under reducing versus nonreducing conditions. Rotary shadowing demonstrates that punctin is hatchet-shaped having a globular region attached to a short stem. In transfected COS-1 cells, punctin is deposited in the cell substratum in a punctate fashion and is excluded from focal contacts. Punctin is the first member of a novel family of ADAMTS-like proteins that may have important functions in the extracellular matrix.
ADAMTS Proteins↗
The Family Investigation of Nephropathy and Diabetes (FIND): design and methods.
BACKGROUND: The Family Investigation of Nephropathy and Diabetes (FIND) is a multicenter study designed to identify genetic determinants of diabetic nephropathy. It is conducted in eight U.S. clinical centers and a coordinating center, and with four ethnic groups (European Americans, African Americans, Mexican Americans, and American Indians). Two strategies are used to localize susceptibility genes: a family-based linkage study and a case-control study using mapping by admixture linkage disequilibrium (MALD). METHODS: In the family-based study, probands with diabetic nephropathy are recruited with their parents and selected siblings. Linkage analyses will be conducted to identify chromosomal regions containing genes that influence the development of diabetic nephropathy or related quantitative traits such as serum creatinine concentration, urinary albumin excretion, and plasma glucose concentrations. Regions showing evidence of linkage will be examined further with both genetic linkage and association studies to identify genes that influence diabetic nephropathy or related traits. Two types of MALD studies are being done. One is a case-control study of unrelated individuals of Mexican American heritage in which both cases and controls have diabetes, but only the case has nephropathy. The other is a case-control study of African American patients with nephropathy (cases) and their spouses (controls) unaffected by diabetes and nephropathy; offspring are genotyped when available to provide haplotype data. CONCLUSIONS: Identification of genes that influence susceptibility to diabetic nephropathy will lead to a better understanding of how nephropathy develops. This should eventually lead to improved treatment and prevention.
Case-Control Studies↗