'Linkage analysis of thyroid antibody production: evidence for shared susceptibility to clinical autoimmune thyroid disease

Abstract

Context: Epidemiological data suggest a genetic susceptibility to thyroid antibody (TAb) production.

Objective: The objective of the study was to identify genetic loci that are linked with TAb production.

Design: The design of the study was a whole genome linkage study in families with clustering of thyroid autoimmunity.

Settings: The study took place at an academic medical center.

Participants: Participants included 102 multigenerational families (540 individuals) multiplex for autoimmune thyroid disease (AITD) and TAb production.

Main outcome measures: We computed two-point logarithm of odds (LOD) scores and multipoint heterogeneity LOD scores for 400 microsatellite markers spanning the entire human genome at an average distance of 10 cm (approximately 10 Mb).

Results: Three loci showed evidence for linkage with TAb production: 1) 2q locus, which gave a maximum multipoint heterogeneity LOD score (HLOD) of 2.8 and contained the CTLA-4 gene, previously reported to be linked and associated with clinical AITD; (2) 6p locus (HLOD 2.5), which was the same AITD-1 locus found to be linked with clinical AITD; and (3) 8q locus (HLOD 2.2), which contained the thyroglobulin gene, also previously reported to be linked and associated with AITD. All loci that were linked to TAb were also linked to AITD, suggesting that TAb and AITD share the same genetic predisposition.

Conclusions: We conclude that: 1) some of the genes/loci predisposing to TAb and AITD are shared, whereas distinct genes/loci also exist; (2) the presence of TAb in relatives of AITD patients may be associated with increased risk for the development of clinical AITD; and (3) further studies are needed to determine the predictive value of TAb levels for the development of clinical AITD in relatives of patients with familial AITD.

Figure 1

Whole genome analysis for loci linked with both GD and HT (AITD). The x-axis shows the relative marker positions on each chromosome, and the y-axis shows the LOD score obtained for each marker on every chromosome. Six loci on chromosomes 2q, 6p, 7q, 8q, 13q, and 15q showed evidence for linkage with LOD scores greater than 2.0. However, the LOD score peaks at the 7q, 13q, and 15q loci were narrow, and on multipoint analysis gave nonsignificant LOD scores (Table 2), suggesting that they were false-positive peaks. In contrast, the 2q, 6p, and 8q loci (marked by asterisk) consisted of broad peaks of positive LOD scores and remained significant in the multipoint analysis (Table 2) and therefore are likely to harbor TAb susceptibility genes.

Figure 2

Multipoint analysis for chromosomes 2 (A), 6 (B), and 8 (C). The x-axis shows the relative marker position in centimorgans, and the y-axis shows the multipoint HLOD score. The maximum multipoint HLOD scores were 2.8 for the 2q locus, 2.0 for the 6p locus, and 2.8 for the 8q locus.