No association of type 1 diabetes with a functional polymorphism of the LRAP gene.
OBJECTIVE
In a recent linkage analysis of genome-wide gene-expression patterns in lymphoblastoid lines, the gene encoding the leukocyte-derived arginine aminopeptidase (LRAP) was identified as having its expression levels modulated by one of the most pronounced effects in cis, mapping to a single-nucleotide polymorphism (rs2762). As this enzyme has an important role in processing antigenic peptides for the HLA I molecules, a variant that drastically modulates its expression levels might affect risk of autoimmunity. This study was designed to confirm that LRAP expression in B-cell derived lines is controlled by a haplotype marked by rs2762 and to see whether this would be the basis of an association with type 1 diabetes (T1D).


METHODS
Single-nucleotide primer extension (SNuPE) was adapted to determine the haplotype-specific expression. Genetic association was tested in 892 nuclear families with one T1D-affected offspring and two parents (2676 individuals).


RESULTS
All nine heterozygous RNA samples showed an eight-fold higher level of one haplotype over the other (7.97+/-0.99, p=1.33x10(-9)). However, no association of rs2762 with T1D was found by the transmission disequilibrium test (transmission ratio A/G=377/388, p=0.69).


CONCLUSIONS
The genetically determined LRAP expression does not play significant roles in T1D. However, this dramatic genetic effect on LRAP expression justifies further investigation of association with other phenotypes, especially autoimmune and related to host defense to specific pathogens.
Qu
Hui-Qi
HQ
Endocrine Genetics Laboratory, The McGill University Health Center, Montreal Children's Hospital, 2300 Tupper, Montréal, Que. H3H 1P3, Canada.
Marchand
Luc
L
Fréchette
Rosalie
R
Bacot
François
F
Lu
Yang
Y
Polychronakos
Constantin
C
D000293:Adolescent; D000626:Aminopeptidases / Q000096:biosynthesis / Q000235:genetics*; D017951:Antigen Presentation / Q000235:genetics*; D001402:B-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006680:HLA Antigens / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide
D006680:HLA Antigens; D000626:Aminopeptidases; C503944:ERAP2 protein, human