CTLA-4 and Not CD28 Is a Susceptibility Gene for Thyroid Autoantibody Production1

• DOI: 10.1210/jcem.86.4.7372
• Publication Date: 2014-01-08T17:06:16Z
• Authors: Yaron Tomer; David A. Greenberg; Giuseppe Barbesino; Erlinda Concepcion; Terry F. Davies
• Keywords: Centimorgan; Thyroid peroxidase; Thyroglobulin; Genetic predisposition; Genetic linkage; Anti-thyroid autoantibodies; Candidate gene

One of the hallmarks human autoimmune thyroid diseases (AITDs) is production high titers autoantibodies against thyroglobulin and peroxidase that often precedes development clinical disease. A percentage family members patients with AITDs have significant antibodies (TAbs), suggesting a genetic predisposition for their development, segregation analyses favored dominant mode inheritance. The aim present study was to identify susceptibility genes TAb production. We completed genome-wide scan in 56 multiplex families (323 individuals) which all and/or detectable TAbs were considered affected. highest 2-point logarithm odds (LOD) score 3.6 obtained marker D2S325 on chromosome 2q33 at 210.9 centimorgans. This locus showed no evidence linkage Graves' disease or Hashimoto's thyroiditis (2-point LOD scores, 0.42 −0.60 thyroiditis), demonstrating gene this region conferred TAbs, but required additional environmental factors. then fine-mapped linked using 11 densely spaced microsatellite markers. Multipoint analysis these markers maximum 4.2 D2S155 209.8 centimorgans (with heterogeneity, α = 0.41). As contained CTLA-4 CD28 genes, we tested whether they 2q33. sequenced 15 individuals, new C/T single nucleotide polymorphism (SNP) identified intron 3. Analysis SNP revealed association probands (families D2S155) compared controls. analyzed known A/G49 SNP, results significantly increased frequency G allele unlinked controls (P 0.02). concluded 1) major autoantibody located 2q33; 2) most likely not gene; 3) contributed production, there it specifically diseases.