Screening the genome for rheumatoid arthritis susceptibility genes: a replication study and combined analysis of 512 multicase families.

Objective: A number of non-HLA loci that have shown evidence (P < 0.05) for linkage with rheumatoid arthritis (RA) have been previously identified. The present study attempts to confirm these findings.

Examination of sequence homology between human chromosome 20 and the mouse genome: intense conservation of many genomic elements.

The conservation of genomic organization of mammalian species has been of interest for its usefulness in characterizing the genetics of traits and diseases and as one tool for examining evolution. The recent rough draft sequencing of the mouse and human genomes provides the opportunity for more detailed analyses. The current study examines the extent of homology between human chromosome 20 and the mouse genome by comparing putative coding and non-coding sequence to provide insight into organizational and sequence similarities between the species.

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.

Association of angiotensin-converting enzyme polymorphisms with systemic lupus erythematosus and nephritis: analysis of 644 SLE families.

Angiotensin II is a strong candidate for the perpetuation of autoimmunity, nephritis and visceral damage in systemic lupus erythematosus (SLE). Our goal was to determine whether angiotensin-converting enzyme (ACE) gene polymorphisms are associated with SLE and/or lupus nephritis (LN). We genotyped 644 SLE patients and 1130 family members for three ACE gene polymorphisms: Alu insertion/deletion (I/D), 23949 (CT)(2/3) and 10698 (G)(3/4).

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.

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.

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.

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).

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.

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.

Primary biliary cirrhosis and autoimmunity: evaluating the genetic risk.

The genetic basis of autoimmunity is receiving increased attention. Organ-specific diseases, such as primary biliary cirrhosis, may be considered model diseases to use for development of databases and extrapolation to other autoimmune diseases. PBC is an enigmatic autoimmune disease that predominantly affects females and leads to destruction of intrahepatic bile ducts.

The Fcgamma receptor IIIA-158F allele is a major risk factor for the development of lupus nephritis among Caucasians but not non-Caucasians.

Objective: To determine whether inheritance of Fcgamma receptor (FcgammaR) alleles conferring lower affinity for IgG binding increases the risk of developing lupus nephritis.

Methods: We compared the frequency of low-affinity alleles of two FcgammaR polymorphisms (FcgammaRIIA and FcgammaRIIIA) among 235 patients with systemic lupus erythematosus (SLE) and proven nephritis (nephritis patients) and among 352 SLE patients with no evidence of renal disease (non-nephritis control subjects). The ethnic distribution of patients in the study was 49% Caucasian, 20% Hispanic, 17% Asian/Pacific Islander, 12% African American, and 2% from other ethnic groups.

A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases.

Rheumatoid arthritis (RA) is an autoimmune/inflammatory disorder with a complex genetic component. We report the first major genomewide screen of multiplex families with RA gathered in the United States. The North American Rheumatoid Arthritis Consortium, using well-defined clinical criteria, has collected 257 families containing 301 affected sibling pairs with RA.

Genetic analysis of multiplex rheumatoid arthritis families.

To examine the genetic contribution of HLA and non-HLA genes in the etiopathogenesis of rheumatoid arthritis (RA), 60 Caucasian multiplex families were identified and DNA analyzed for over 52 markers including DRB1, DQA1 and DQB1 alleles. Many of the markers were chosen because of close proximity to candidate genes suggested by previous studies or models of pathogenesis. Sibling pair analysis (SIBPAL), relative pair analysis (RELPAL) and linkage studies using two different models of inheritance suggested linkage for the MHC and two additional chromosomal regions: chromosome 2 (D2S443 near CD8 and IGk; 2p13-2p11.

25-hydroxyvitamin D 1alpha-hydroxylase: structure of the mouse gene, chromosomal assignment, and developmental expression.

The murine homologue of the 25-hydroxyvitamin D [25(OH)D] 1alpha-hydroxylase gene [1alpha(OH)ase; Cyp27bl], which is mutated in humans with vitamin D-dependent rickets type I (VDDR-I; also known as pseudovitamin D-deficiency rickets [PDDR]) was cloned and characterized. Like the human, the mouse gene has nine exons, and the exon-intron organization is well conserved. By interspecific backcross analysis, the Cyp27bl gene was mapped to 70.

Mouse Wnt receptor gene Fzd5 is essential for yolk sac and placental angiogenesis.

Wnts are secreted signaling molecules implicated in various developmental processes and frizzled proteins are the receptors for these Wnt ligands. To investigate the physiological roles of frizzled proteins, we isolated and characterized a novel mouse frizzled gene Fzd5. Fzd5 mRNA was expressed in the yolk sac, eye and lung bud at 9.

Fas-mediated apoptosis of proliferating, transiently growth-arrested, and senescent normal human fibroblasts.

Previous studies suggest that apoptotic signaling may require proteins that are critical to cellular proliferation and cell cycle regulation. To further examine this question, proliferating, transiently growth-arrested, and senescent normal human fibroblasts were induced to undergo apoptosis in response to two distinct mediators of apoptosis-Fas (APO-1/CD95) death receptor and staurosporine. Ligation of the Fas receptor in the presence of cycloheximide or actinomycin D resulted in apoptosis of proliferating cells, cells transiently growth arrested by gamma-irradiation or serum starvation (i.

Chromosomal mapping of Adam9, Adam15 and Adam21.

Adam9, Adam15 and Adam21, genes encoding members of the ADAM or MDC family of metalloproteases, have been mapped to mouse chromosomes 8, 1, and 12, respectively, using an interspecific cross. The mapping of these mouse loci and the extrapolated loci for their human orthologs may facilitate the mapping of diseases involving these genes.

A simple and accurate method for determination of microsatellite total allele content differences between DNA pools.

DNA pooling is a potential tool for the efficient analysis of the large numbers of samples and DNA markers that are necessary for genome-wide association studies. A simple accurate method for measuring total allele differences in comparisons between two pools containing large numbers of DNA samples is presented. This method compares relative peak height differences between electrophoretograms for each allele of a microsatellite.

Gene structure and chromosome mapping of mouse transcription elongation factor S-II (Tcea1).

We report the organization and chromosome localization of the mouse transcription elongation factor S-II gene (Tcea1). This gene was found to be a single copy gene consisting of 10 exons spanning approximately 30kb. Its organization was the same as those of the mouse testis-specific S-II gene (Tcea2) and Xenopus general S-II gene (xTFIIS.