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Association of the Cytotoxic T Lymphocyte-Associated Antigen 4 Gene with Type 1 Diabetes: Evidence for Independent Effects of Two Polymorphisms on the Same Haplotype Block

Endocrine Genetics Laboratory, Department of Pediatrics, Division of Pediatric Endocrinology, McGill University Health Sciences Center, Montréal, Québec, Canada H3H 1P3

Address all correspondence and requests for reprints to: Dr. Constantin Polychronakos, McGill University Health Center (Montreal Children’s Hospital), 2300 Tupper, Montréal, Québec, Canada H3H 1P3. E-mail: constantin.polychronakos{at}mcgill.ca.

A recent study mapped the known association of type 1 diabetes with the cytotoxic T lymphocyte-associated antigen 4 gene to a polymorphism at the 3'end (+6230G>A), but could not rule out additional contribution from the 5' end of the gene. To examine this possibility, we analyzed four polymorphisms at the 5'-flanking region for effects independent of +6230G>A. We confirm, by the transmission disequilibrium test, in 496 family trios overtransmission of the susceptibility allele (G) at +6230 (217/168; P = 0.013). Of the four promoter polymorphisms, one (–319C>T) showed overtransmission of the C allele (97/58; P = 0.0017). Because the undertransmitted T at the promoter is in linkage disequilibrium with the overtransmitted G at +6230G>A, the effect observed at the promoter cannot be accounted for by linkage disequilibrium with the +6230G>A. We confirm this by showing that parents heterozygous at the promoter but homozygous at +6230 overtransmit the C promoter allele even more significantly (53/24; P = 9 x 10^–4). In vitro, the T promoter allele directs higher luciferase expression in Jurkat cells by 42% (P = 0.006), a difference also found in lymphocyte mRNA from eight individuals heterozygous at the promoter, but homozygous at +6230 (P = 1.3 x 10^–4). Thus, the +6230G>A cannot be the sole functional variant. Either the two polymorphisms define a haplotype carrying the (yet unexamined) functional variant or the –319C>T contributes to the genetic association independently, a possibility suggested by the functional evidence we present.

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