Comments for:
Abstract
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.
Authors
Betty P. Tsao, Rita M. Cantor, Jennifer M. Grossman, Nan Shen, Nickolay T. Teophilov, Daniel J. Wallace, Frank C. Arnett, Klaus Hartung, Rose Goldstein, Kenneth C. Kalunian, Bevra H. Hahn, Jerome I. Rotter
Re: HRES-1 also a candidate gene?
Submitter: Betty P. Tsao | btsao@mednet.ucla.edu
UCLA School of Medicine
Published July 11, 1999
We thank Dr. Perl and his colleagues for their interesting comments concerning our recent publication implicating poly(ADP-ribose) polymerase (PARP or ADPRT) as an SLE susceptibility gene (1). In reference to their suggestion, we acknowledge that HRES-1 may also be a positional candidate gene within the 1q41-q42 chromosomal region that shows linkage to SLE (2-4). In choosing which positional candidates to pursue for the manuscript, we decided to assess only genes exhibiting strong supporting evidence in peer-reviewed articles.
In reference to our placement of ADPRT in relation to other linked markers, we found that the position of this gene is in dispute. In the Unigene database (http://www.ncbi.nlm.nih.gov/genemap98 ), GB4 physical mapping results are in conflict. M29786 places the gene at 719 cR, while T96642 places it at 634 cR. In Figure 1 of our manuscript (1), we placed PARP at the average of these two locations. Subsequently, we have mapped this gene in very close proximity to 719 cR, which is within the 5 cM peak in the linked region.
While all three candidates we studied are within the 1q41-q42 linked region, as is HRES-1, application of the Transmission Disequilibrium Test to PARP provides evidence for association with SLE and implicates PARP in SLE susceptibility, regardless of its exact position.
Betty P. Tsao1 and Rita M. Cantor2
1Departments of Medicine, 2Pediatrics and Human Genetics, UCLA School of Medicine, Los Angeles, California 90095, USA
1. Tsao, B.P., et al. 1999. PARP alleles with the linked chromosomal region are associated with systemic lupus erythematosus. J. Clin. Invest. 103:1135-1140.
2. Tsao, B.P., et al. 1997. Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus. J. Clin. Invest. 99:725-731.
3. Gaffney, P.M., et al. 1998. A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc. Natl. Acad. Sci. USA. 95:14875-14879.
4. Moser, K.L., et al. 1998. Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc. Natl. Acad. Sci. USA. 95:14869-14874.
HRES-1 also a candidate gene?
Submitter: Andras Perl | perla@mailbox.hscsyr.edu
SUNY HSC (Syracuse)
Published July 11, 1999
Screening studies with polymorphic microsatellite markers suggested that the q42 region of human chromosome 1 may correspond to a susceptibility locus for systemic lupus erythematosus (SLE) (1-3). A recent paper by Tsao et al. identified three candidate genes in the 1q42 chromosomal region: (a) poly(ADP-ribose) polymerase (PARP) or ADP-ribosyltransferase (ADPRT), involved in DNA repair and apoptosis (b) transforming growth factor B2 (TGFB2), and (c) the HLX1 homeobox gene, possibly involved in T-cell development and shown an association between polymorphic ADPRT alleles and SLE (4). These candidate genes were selected from the Genome Database (http://gdbwww.gdb.org). The Genome Database also reveals the presence of the HRES-1 human endogenous retrovirus at the 1q42 locus (5). Listing of genes at 1q42 in the Genome Database (http://gdbwww.gdb.org) shows a close proximity between ADPRT and HRES-1. Interestingly, the HRES-1 locus encodes a 28 kD nuclear autoantigen recognized by antibodies in up to half of the patients with SLE and overlap syndromes (6-9). Thus, mapping of HRES-1/p28 lupus autoantigen to 1q42 previously marked this chromosomal location as a potential lupus susceptibility site (10). Furthermore, polymorphic alleles have been identified in the long terminal repeat promoter of the HRES-1 element (11) and a differential segregation of these alleles were noted in patients with SLE (10). More recently, a diminished frequency of genotype I alleles was associated with production of antibodies to HRES-1/p28 in patients with SLE (12, 13).
PCR amplification of nucleotides 1-1102 of the HRES-1 LTR from a radiation hybrid panel (Genebridge 4 panel, Research Genetics, Huntsville, Alabama, USA) mapped HRES-1 with a logarithm of odds (lod) score of 2.34 between markers WI-4922 (D1S2473; Genome Database number: 589200; 2.43 cR towards the telomere from HRES-1) and CHLC.GCT1E07 (Genome Database number 1220406; 5.02 cR towards the centromere from HRES-1). We localized HRES-1 within the radiation hybrid map of the human genome (14) using the Whitehead Institute Center for Genome Research Server (http://www-genome.wi.mit.edu). Thus, HRES-1 is found at 1q42 in a central position with respect to the polymorphic microsatellite markers associated with SLE (1-3). The consensus map from these databases is in apparent disagreement with the placement of PARP, TGFB2, and HLX1genes between markers D1S2860 and D1S213 by Tsao et al. (4). Orientation of intergenic markers physically mapped to contigs WC1.19 and WC1.20 (http://carbon.wi.mit.edu) placed all four candidate genes between D1S213 and D1S225, an interval towards the telomere of chromosome 1. The centromere to telomere order of the four candidate genes is: TGFB2, HLX1, ADPRT, and HRES-1. A more precise ordering and spacing of these genes will require complete sequencing of the locus. Nevertheless, among the candidate genes listed, HRES-1 appears to be closest to D1S3462 (3) and D1S235 (2), the markers which established the genome-wide significance of the 1q42 region in SLE.
Andras Perl,1 Paul Phillips,1 Roger Eddy,2and Thomas B. Shows2
1Department of Medicine, SUNY HSC, Syracuse, New York 13210, USA, and 2Department of Human Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA
1. Tsao, B.P., et al. 1997. Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus. J. Clin. Invest. 99:725-731.
2. Gaffney, P.M., et al. 1998. A genome-wide search for susceptibility genes in human systemic lupus erythematosus sib-pair families. Proc. Natl. Acad. Sci. USA. 95:14875-14879.
3. Moser, K.L., et al. 1998. Genome scan of human systemic lupus erythematosus: evidence for linkage on chromosome 1q in African-American pedigrees. Proc. Natl. Acad. Sci. USA. 95:14869-14874.
4. Tsao, B.P., et al. 1999. PARP alleles with the linked chromosomal region are associated with systemic lupus erythematosus. J. Clin. Invest. 103:1135-1140.
5. Perl, A., et al. 1991. The human T-cell leukemia virus-related endogenous sequence (HRES1) is located on chromosome 1 at q42. Genomics.11:1172-1173.
6. Banki, K., et al. 1992. Human T-cell lymphotropic virus (HTLV)-related endogenous sequence, HRES-1, encodes a 28-kDa protein: a possible autoantigen for HTLV-I gag-reactive autoantibodies. Proc. Natl. Acad. Sci. USA. 89:1939-1943.
7. Perl, A., et al. 1995. Antibody reactivity to the HRES-1 endogenous retroviral element identifies a subset of patients with systemic lupus erythematosus and overlap syndromes: correlation with antinuclear antibodies and HLA class II alleles. Arth. Rheum.38:1660-1671.
8. Brookes, S.M., et al. 1992. The immune response to and expression of cross-reactive retroviral gag sequences in autoimmune disease. Brit. J. Rheumatol.31:735-742.
9. Bengtsson, A., et al. 1996. Selective antibody reactivity with peptides from human endogenous retroviruses and nonviral poly(amino acids) in patients with systemic lupus erythematosus. Arth. Rheum. 39:1654-1663.
10. Magistrelli, C., K. Banki, P. Ferrante, and A. Perl. 1994. Mapping and cloning of polymorphic genotypes of the HRES-1 LTR. Arth. Rheum. 37:S316
11. Perl, A., et al. 1989. Detection and cloning of new HTLV-related endogenous sequences in man. Nucl. Acids Res. 17:6841-6854.
12. Magistrelli, C., et al. 1998. Polymorphic genotypes of the HRES-1 human endogenous retrovirus locus are associated with its autoantigenicity in SLE. Arth. Rheum.41:S282.
13. Magistrelli, C., et al. 1999. Polymorphic genotypes of the HRES-1 human endogenous retrovirus locus correlate with systemic lupus erythematosus and autoreactivity. Immunogenetics. In press.
14. Hudson, T.J., et al. 1995. An STS-based map of the human genome. Science. 270:1945-1954.
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