EPIDEMIOLOGY OF RHEMATOID ARTHITIS--GENETIC DETERMINANTS

Despite recent advances, the etiology and pathogenesis of
rheumatoid arthritis (RA) remain unknown. The proposed research
seeks to improve our understanding of the genetic factors important
in the predisposition and expression of RA by applying the
techniques of genetic epidemiology and molecular genetics. A
cohort of multiplex and simplex families of RA will be identified
using a family history questionnaire and a defined sampling from
surveying 1000 consecutive outpatients with RA. From our pilot
data, we expect this survey to identify a minimum of 250 multiplex
families with RA. In a randomly selected subset of 100 multiplex
and 50 simplex families, the affection status of family members
will be verified using a detailed structured history and physical
examination, and serum rheumatoid factor testing. Affection status
will be categorized into those who are definitely unaffected,
possibly affected and definitely affected (i.e., having RA by 1987
ARA criteria). To avoid misclassification errors and address the
problem of disease heterogeneity, these categories will be further
subdivided into a total of seven subgroups based on clinical and
laboratory features. Cells and sera will be collected from
individuals in the randomly selected multiplex and simplex families
to identify genetic markers have been reported to be associated
with RA. These markers will be defined by specific allosera (i.e,
HLA-A, B, C,and DR specificities), and allele-specific
oligonucleotide c-DNA probes (e.g., DR beta I and DQ beta alleles).
The family history data and molecular genetic data will be analyzed
from several different perspectives. 1) Four specific genetic
models will be tested against the observed family data. The aim
is to determine whether the (a) environmental model (i.e., chance
aggregation), (b) multifactorial model (i.e., polygenes and
environment), (c) major gene model (i.e., dominant, recessive or
additive) or (d) mixed model (i.e., major gene and additional
polygenic factors) provides the best explanation of the observed
pattern of familial aggregation. 2) Utilizing the data from the
detailed clinical evaluation and serum rheumatoid factor testing,
a more specific model of the relationship of HLA to RA will be
tested. 3) The role of HLA genes will be examined utilizing the
HLA typing and molecular genetic data in combined segregation and
linkage analyses. 4) Based on demographic factors (i.e., age and
gender), serum rheumatoid factor measurement and the HLA marker
data, the risk of affection for any first-degree relative of the
probands will be determined. This study combines epidemiologic,
classical genetic, and molecular genetic techniques into a powerful
methodology which utilizes simplex and multiplex families of
disease to define the genetic the genetic determinants related to
the development and prognosis of rheumatoid arthritis.