The receptor for advanced glycation end products (RAGE)

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. A genome screen for allele sharing was performed, using 379 microsatellite markers. A nonparametric analysis using SIBPAL confirmed linkage of the HLA locus to RA (P < .00005), with lambdaHLA = 1.79. However, the analysis also revealed a number of non-HLA loci on chromosomes 1 (D1S235), 4 (D4S1647), 12 (D12S373), 16 (D16S403), and 17 (D17S1301), with evidence for linkage at a significance level of P<.005. Analysis of X-linked markers using the MLOD method from ASPEX also suggests linkage to the telomeric marker DXS6807. Stratifying the families into white or seropositive subgroups revealed some additional markers that showed improvement in significance over the full data set. Several of the regions that showed evidence for nominal significance (P < .05) in our data set had previously been implicated in RA (D16S516 and D17S1301) or in other diseases of an autoimmune nature, including systemic lupus erythematosus (D1S235), inflammatory bowel disease (D4S1647, D5S1462, and D16S516), multiple sclerosis (D12S1052), and ankylosing spondylitis (D16S516). Therefore, genes in the HLA complex play a major role in RA susceptibility, but several other regions also contribute significantly to overall genetic risk.

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.Methods. We performed a second genome-wide screen of 256 new multicase RA families recruited from across the United States by the North American Rheumatoid Arthritis Consortium. Affected sibling pair analysis on the new data set was performed using SIBPAL. We subsequently combined our first and second data sets in an attempt to enhance the evidence for linkages in a larger sample size. We also evaluated the impact of covariates on the support for linkage, using LODPAL.Results. Evidence of linkage at 1p13 (D1S1631), 6p21.3 (the HLA complex), and 18q21 (D18S858) (P < 0.05) was replicated in this independent data set. In addition, there was new evidence for linkage at 9p22 (D9S1121 [P ‫؍‬ 0.001]) and 10q21 (D10S1221 [P ‫؍‬ 0.0002] and D10S1225 [P ‫؍‬ 0.0038]) in the current data set. The combined analysis of both data sets (512 families) showed evidence for linkage at the level of P < 0.005 at 1p13 (D1S1631), 1q43 (D1S235), 6q21 (D6S2410), 10q21 (D10S1221), 12q12 (D12S398), 17p13 (D17S1298), and 18q21 (D18S858). Linkage at HLA was also confirmed (P < 5 ؋ 10 ؊12 ). Inclusion of DRB1‫40ء‬ as a covariate significantly increased the probability of linkage on chromosome 6. In addition, some linkages on chromosome 1 showed improved significance when modeling DRB1‫40ء‬ or rheumatoid factor positivity as covariates.

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.

To gain insight into the timing of twinning, we have examined a closely related event, X-chromosome inactivation, in female MZ twin pairs. X-inactivation patterns in peripheral blood and buccal mucosa were compared between monochorionic MZ (MC-MZ) and dichorionic MZ (DC-MZ) twins. Overall, the MC-MZ twins displayed highly similar X-inactivation patterns, whereas DC-MZ twins frequently differed in their X-inactivation patterns, when both tissues were tested. Previous experimental data suggest that commitment to X inactivation occurs when there are 10-20 cells in the embryo. Simulation of embryo splitting after commitment to X inactivation suggests that MC-MZ twinning occurs three or four rounds of replication after X inactivation, whereas a DC-MZ twinning event occurs earlier, before or around the time of X inactivation. Finally, the overall degree of skewing in the MZ twins was not significantly different from that observed in singletons. This indicates that X inactivation does not play a direct role in the twinning process, and it further suggests that extreme unequal splitting is not a common mechanism of twin formation.

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Oligoclonality of circulating CD8+ T cells is a characteristic feature of the human immune system; both host genetic factors and environment shape the pattern of oligoclonality in this T cell subset. The high frequency of this phenomenon in normal subjects provides a background with which to evaluate CD8+ T cell oligoclonality in the setting of infection or autoimmune disease. Further phenotypic and functional characterization of these clonally expanded T cells should provide insight into normal immune homeostasis.

CM, Langston JW (1998a) Absence of mutations in the coding region of the alpha-synuclein gene in pathologically proven Parkinson's disease. Neurology 50:1136-1137 Chan P, Tanner CM, Jiang X, Langston JW (1998b) Failure to find the alpha-synuclein gene missense mutation (G209A) in 100 patients with younger onset Parkinson's disease. Neurology 50:513-514 Letters to the Editor