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

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.

Figure 1

Multipoint linkage analysis of the chromosome 1q31–q42 region using the MAPMAKER/SIBS program. Positions of genetic markers relative to D1S510 are expressed in cM as the relative genetic distance shown on the x axis. All markers except HLX1 and TGFB2 were used in this analysis. The heuristic guideline of 1 lod below the peak value was used to identify a confidence interval of 5 cM (flanked by D1S2860 and D1S213) for the location of the putative SLE susceptibility gene.