Addition To The Hla Drb 1 Locus example essay topic

Rheumatoid arthritis is an inflammatory disease, primarily of the joints, with autoimmune features and a complex genetic component. INHERITANCE Occasional families show a considerable number of cases of this common disorder. A simple Mendelian mechanism could not be proved, however. Indeed, some (Burch et al., 1964) could not demonstrate significant familial aggregation. Lynn et al. (1995) conducted family studies and segregation analyses of RA based on consecutive patients with RA ascertained without regard to family history or known risk factors.

Included in the analyses were first-degree relatives from 135 simplex and 30 multiplex families. A highly penetrate recessive major gene, with a mutant allele frequency of 0.005, was identified as the most parsimonious genetic risk factor. Significant evidence for heterogeneity in risk for RA was observed for prob and gender but not for prob and age at onset. Kaplan-Meier risk analysis demonstrated significant evidence for differences in the distribution of risk among first-degree relatives. Although both prob and gender and age at onset were identified as important risk factors, prob and gender appeared to be the more important determinant of risk, with relatives of male pro bands having the greatest cumulative risk for RA.

For future genetic analyses, Lynn et al. (1995) suggested that families with an excess of affected males having a young age at onset might be most informative in identifying the putative recessive gene and its modifies. Hasstedt et al. (1994) studied 28 pedigrees ascertained through pairs of first-degree relatives with RA. RA was confirmed in 77 pedigree members, including pro bands; the absence of disease was verified in an additional 261 pedigree members. Members of the pedigrees were typed serologically for HLA.

Analyses supported the existence of an HLA-linked RA susceptibility locus, estimated the susceptibility allele frequency as 0.0216, and estimated the lifetime penetrance as 41% in male homozygote's and 48% in female homozygote's. Inheritance was recessive in males and was nearly recessive in females. In addition, the analysis attributed 78% of the variants with HLA genotypes to genetic or environmental effects shared by sibs. The genetic model inferred in this analysis was considered consistent with previous association, linkage, and familial aggregation studies of RA.

The inferred HLA-linked RA susceptibility locus accounted for approximately one-half of familial RA, although it accounted for only approximately one-fifth of the RA in the population. PATHOGENESIS In a T-cell receptor transgenic mouse model, an inflammatory arthritis that resembles human RA is initiated by T cells but is sustained by antibodies to GPI (172400). Using ELISA analysis, Schaller et al. (2001) detected high levels of antibody to GPI, independent of the presence of rheumatoid factor, in serum and synovial fluid of most RA patients; antibodies to GPI were rare in controls or in patients with Lyme arthritis or Sjogren syndrome.

In addition, the authors found high levels of GPI in sera and synovial fluid and the presence of GPI-containing immune complexes in RA synovial fluid. Immunohistochemical analysis and confocal microscopy demonstrated intense expression of GPI on the surface of endothelial cells of synovial arterioles and some capillaries, but not venules or in other tissues. Intense patchy expression was observed on the surface lining of hypertrophic, particularly where the hypertrophic villous formed; this expression pattern resembled that for vascular permeability factor (VEGF / VP; 192240). Schaller et al. (2001) suggested that GPI may be presented to the immune system either on endothelial cell surfaces or as a soluble protein in synovial fluid of inflamed RA joints, leading to antibody binding or to immune complex formation with complement activation, respectively.

In either case, they concluded that there is a role for auto antibody in the pathology of RA and that there may be scope for antibody treatments for the disease. MAPPING Cornelis et al. (1998) performed a genome scan with 114 European Caucasian rheumatoid arthritis sib pairs from 97 nuclear families. Linkage was significant only for HLA and nominal for 19 markers in 14 other regions. Four of the loci implicated in IDDM potentially overlap with these regions: IDDM 6 (601941), IDDM 9, IDDM 13 (601318), and DXS 998. The first 2 of these candidate regions, defined in the rheumatoid arthritis genome scan on 18 q 22-q 23 and 3 q 13, were studied in 194 additional RA sib pairs from 164 nuclear families.

Support for linkage to chromosome 3 only was extended significantly (P = 0.002). The analysis of all 261 families provided a linkage evidence of P = 0.001 and suggested an interaction between this putative RA locus and HLA. This locus could account for 16% of the genetic component of RA; HLA had previously been estimated to account for one-third of the genetic component. The candidate genes in this area included those coding for CD 80 (112203) and CD 86 (601020), molecules involved in antigen-specific T-cell recognition.

The HLA-DRB 1 (142857) locus has been shown to be linked to and associated with RA susceptibility. In addition to the HLA-DRB 1 locus, it was considered likely that genes with weaker effects are also involved. Cox et al. (1999) used a combined sib-TDT (transmission / disequilibrium test) and TDT, in addition to parametric and nonparametric linkage methods, to investigate candidate genes of the interleukin-1 (IL 1) gene cluster (see IL 1 A; 147760) on 2 q 13, since IL 1 is an important cytosine in the control of the inflammatory response central to RA pathology. Several tightly linked IL 1 cluster markers yielded suggestive evidence for linkage in those families in which affected sibs did not share 2 HLA-DRB 1 alleles identical by descent. The evidence was significant in those with severe disease, as assessed by the presence of bone erosion's.

Jawaheer et al. (2001) reported a genome wide screen of multiplex families with RA gathered in the U.S. by a consortium of investigators. Using 379 micro satellite markers, they screened for allele sharing in 257 families containing 301 affected sib pairs. The results suggested that genes in the HLA complex play a major role in RA susceptibility, but that several other regions also contribute significantly to overall genetic risk. Some of these regions had previously been implicated in other diseases of an autoimmune nature, including systemic lupus erythematous (152700), inflammatory bowel disease (266600), multiple sclerosis (126200), and ankylosing spondylitis (106300).

Using 54 markers distributed across the entire HLA complex, Jawaheer et al. (2002) performed an extensive analysis in a set of 469 multiplex families with RA. The results showed that, in addition to associations with the DRB 1 alleles, at least 2 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 DRB 1. This genetic risk factor is present on a segment of a highly conserved ancestral Al-B 8-DRB 1 03 (8.1).

Additional risk genes may also be present in the HLA class I region in a subset of DRB 1 0404. The data emphasized the importance of defining when trying to understand HLA associations with disease, and clearly demonstrated that such associations with RA are complex and cannot be completely explained by the DRB 1 locus. In a set of Japanese patients with RA and a control group, Ota et al. (2001) identified a second HLA-DRB 1-independent RA susceptibility locus at the end of the HLA class region, almost 1 Mb away from HLA-DRB 1. Z anelli et al. (2001) and Jawaheer et al.

(2002) likewise reported findings indicating the existence of a second RA susceptibility locus at the end of the HLA region. Using micro satellites, Ota et al. (2001) narrowed the second RA susceptibility region to 70 kb of the TNF A gene (191160). John et al. (2004) compared the utility of single-nucleotide polymorphisms (SNPs) with that of micro satellites for linkage analysis in a whole-genome screen of 157 families with multiple cases of RA. The SNP analysis detected HLA DRB 1, the major RA susceptibility locus (P = 0.00004), with a linkage interval of 31 cM, compared with a 50-cM linkage interval detected by the micro satellite scan.

In addition, 4 loci were detected at a nominal significance level (P less than 0.05) in the SNP linkage analysis; these were not observed in the micro satellite scan. Thus, they demonstrated the utility of a dense SNP map for performing linkage analysis in a late-age-at-onset disease, where DNA from parents is not always available. The high SNP density allowed loci to be defined more precisely.