Linkage Analysis of Candidate Genes in Autoimmune Thyroid Disease. II. Selected Gender-Related Genes and the X-Chromosome

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Abstract
Hashimoto's thyroiditis (HT) and Graves' disease (GD) are auto- immune thyroid diseases (AITD) in which multiple genetic factors are suspected to play an important role. Until now, only a few minor risk factors for these diseases have been identified. Susceptibility seems to be stronger in women, pointing toward a possible role for genes related to sex steroid action or mechanisms related to genes on the X-chromosome. We have studied a total of 45 multiplex families, each containing at least 2 members affected with either GD (55 patients) or HT (72 patients), and used linkage analysis to target as candidate suscep- tibility loci genes involved in estrogen activity, such as the estrogen receptor a and b and the aromatase genes. We then screened the entire X-chromosome using a set of polymorphic microsatellite mark- ers spanning the whole chromosome. We found a region of the X- chromosome (Xq21.33-22) giving positive logarithm of odds (LOD) scores and then reanalyzed this area with dense markers in a mul- tipoint analysis. Our results excluded linkage to the estrogen receptor a and aro- matase genes when either the patients with GD only, those with HT only, or those with any AITD were considered as affected. Linkage to the estrogen receptor b could not be totally ruled out, partly due to incomplete mapping information for the gene itself at this time. The X-chromosome data revealed consistently positive LOD scores (max- imum of 1.88 for marker DXS8020 and GD patients) when either definition of affectedness was considered. Analysis of the family data using a multipoint analysis with eight closely linked markers gen- erated LOD scores suggestive of linkage to GD in a chromosomal area (Xq21.33-22) extending for about 6 cM and encompassing four mark- ers. The maximum LOD score (2.5) occurred at DXS8020. In conclusion, we ruled out a major role for estrogen receptor a and the aromatase genes in the genetic predisposition to AITD. Estrogen receptor b 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 extended number of families because of possible heterogeneity. (J Clin Endo- crinol Metab 83: 3290 -3295, 1998)

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