The class II and especially the DQB1 locus of MHC genes, as well as C4 deficiency alleles appear to be associated with genetic risk for developing aPL. The extensive linkage disequilibrium among some of these risk factors makes it difficult to assign a causal role for any of these alleles by means of previous population studies of patients with APS; studies a patients with primary APS, in particular, have involved relatively few patients. Although there appear to be some overall similarities between the known MHC associations of primary APS and those of secondary APS, only a modest relative risk of APS is associated with MHC alleles, as discussed above, and other unknown risk factors must also be important. Whether these unknown risk factors for primary APS are different from those in secondary APS is an area for further investigation. In addition, new genes continue to be identified in the MHC class II and III regions that appear to have important roles in antigen processing and recognition. Interethnic studies of these and other alleles in large cohorts would be informative since ethnic groups of African, Japanese or Caucasian backgrounds often exhibit differing allelic linkage disequilibria within the MHC. Studies of linkage relationships in various MHC haplotypes have, for example, helped to clarify the role of MHC class II oligo alleles in rheumatoid arthritis. Further clarification of the roles of these MHC alleles will also depend on functional studies in experimental models and in vitro, to assess the roles of these risk factors in aPL production. The roles of non-MHC risk factors and of environmental agents that are operative within families also warrant further studies.