LINKAGE ANALYSIS OF CANDIDATE GENES IN AUTOIMMUNE THYROID-DISEASE - II - SELECTED GENDER-RELATED GENES AND THE X-CHROMOSOME

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are autoimmune t hyroid diseases (AITD) in which multiple genetic factors are suspected to play an important role. Until now, only a few minor risk factors f or these diseases have been identified. Susceptibility seems to be str onger in women, pointing toward a possible role for genes related to s ex steroid action or mechanisms related to genes on the X-chromosome. We have studied a total of 45 multiplex families, each containing at l east 2 members affected with either GD (55 patients) or HT (72 patient s), and used linkage analysis to target as candidate susceptibility lo ci genes involved in estrogen activity, such as the estrogen receptor alpha and beta and the aromatase genes. We then screened the entire X- chromosome using a set of polymorphic microsatellite markers spanning the whole chromosome. We found a region of the X-chromosome (Xq21.33-2 2) giving positive logarithm of odds (LOD) scores and then reanalyzed this area with dense markers in a multipoint analysis. Our results exc luded linkage to the estrogen receptor alpha and aromatase genes when either the patients with GD only, those with HT only, or those with an y AITD were considered as affected. Linkage to the estrogen receptor b eta could not be totally ruled out, partly due to incomplete mapping i nformation for the gene itself at this time. The X-chromosome data rev ealed consistently positive LOD scores (maximum of 1.88 for marker DXS 8020 and GD patients) when either definition of affectedness was consi dered. Analysis of the family data using a multipoint analysis with ei ght closely linked markers generated LOD scores suggestive of linkage to GD in a chromosomal area (Xq21.33-22) extending for about 6 cM and encompassing four markers. The maximum LOD score (2.5) occurred at DXS 8020. In conclusion, we ruled out a major role for estrogen receptor c t and the aromatase genes in the genetic predisposition to AITD. Estro gen receptor beta remains a candidate locus. We found a locus on Xq21. 33-22 linked to GD that may help to explain the female predisposition to GD. Confirmation of these data in HT may require study of an extend ed number of families because of possible heterogeneity.