Genes and Genetics

The risk for development of LE in a sibling in families with a member with LE is 20 times more than in the general population. The relatively high concordance rates for SLE in monozygotic twins (25%-57%) compared with dizygotic twins (2%-9%) supports the importance of the genetic background. It is currently believed that multiple genes confer susceptibility to SLE expression, several of which have been identified to associate with lupus. Most of these associations have been identified while investigating pathogenic mechanisms in the disease. For example, the conjecture that certain

MHC antigens should present autoantigens better than others led to unveiling of associations between the disease or individual manifestations and MHC antigens. On the other hand, the expectation that apoptosis-related genes should be associated with the expression of lupus was not fulfilled.

More recently, genome-wide searches in families with multiple affected members disclosed areas in the genome associated with lupus. Obviously, no single gene is sufficient or necessary for disease expression, and lupus diathesis is conferred by an as-yet-unidentified number of genes that differ in individual patients. Still, the fact that almost all of the rare patients with C1r/C1s and complete C4 deficiency develop lupus suggests that the number of the contributing genes may be limited in some patients. The complexity of deciphering genes involved in the expression of lupus is confounded by the number of additional environmental, hormonal, and immunoregula-tory factors in a given individual or population. Finally, genetic epistasis, the interaction of different genes to produce a disease phenotype, as has been shown in animal models, may occur in patients with LE.

The long arm of human chromosome 1, which was identified in almost all of the genome-wide searches as harboring loci associated with SLE, maps several of the potential lupus loci found in these genome-wide screens as well as others implicated in lupus, such as those encoding for FcyRIIA, FcyRIIIA, TCRZ, FasL, IL-10, complement receptor 1, complement receptor 2, and C1q proteins. These molecules have been implicated in SLE by either small-scale genetic or nongenetic studies.

The impact of genetic factors is also underscored by differences in the incidence and prevalence of the disease in various races. SLE has a higher incidence and prevalence in African Americans, Afro-Caribbeans, and East Asians, and the disease may also have a more severe course and prognosis. Certain clinical (e. g., discoid skin lesions and nephritis) and serologic (e. g., anti-Sm autoantibodies) manifestations are found more frequently in the African American LE population, and the high prevalence of severe nephritis encountered therein is responsible for the severe prognosis. Detailed genetic analysis may reveal the molecular basis for such interracial differences.

In summary, multiple genetic loci or genes contribute to susceptibility for the development of SLE. Genetic analyses may increase our understanding of the disease heterogeneity and provide a molecular basis for the racial differences in disease prevalence, manifestations, severity, and prognosis. The pathogenic contribution and complex interaction of lupus-susceptibility genes needs to be clarified by additional studies, and the precise role and contribution of each of the lupus-related genes should be addressed (Gregersen 1997).

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