The Missing Heritability in T1D and Potential New Targets for Prevention

Figure 3

Genomic TRBV11-2 DNA sequences from Caucasian samples in the 1000 genomes database (including HG00328 (and HG00361, HG00320, HG00111, HG00310, HG00247, HG00256, HG00231, HG00127, HG00103, HG00117, HG0032, not shown)), five expressed sequences from the dbEST (indicated with gi numbers), two alleles of TRBV11-2 from IMGT, and four of the sequences we obtained at Drexel (1231, 1201, 00275, 00040) were translated and compared. Only TRBV11-2*02 shows any nonsynonymous change (D105N, underlined, yellow highlight), and it is substantiated by one transcript (M33235). The D105N change (which is residue 98 using IMGT numbering) forms a salt bridge with a positive residue (Arg75) in the Vβ domain but is away from the pMHC (see Supplementary Figure 1 available online at http://dx.doi.org//10.1155/2013/737485). Accordingly there could be some functional/structural consequence of that SNP, but given its location (not in any CDR region) and conservative nature (Asp to Asn) it is unlikely that this is a functionally significant change. There is, however, no proof that this is the case. Nucleotide substitutions reflecting known SNPs (rs183490568, rs149749379, rs148941368, rs139187012, rs76976752, rs34112565, rs17163285, rs7777952, rs17281, rs17163283, rs17280, rs11505614, rs57147993, rs10375465, and rs17279) were commonly observed among these sequences. Using these SNPs, four haplotypes (two homozygous and two heterozygous) were observed among the four Drexel sequences.