Genetic mapping at 3-kilobase resolution reveals inositol 1,4,5-triphosphate receptor 3 as a risk factor for type 1 diabetes in Sweden.
We mapped the genetic influences for type 1 diabetes (T1D), using 2,360 single-nucleotide polymorphism (SNP) markers in the 4.4-Mb human major histocompatibility complex (MHC) locus and the adjacent 493 kb centromeric to the MHC, initially in a survey of 363 Swedish T1D cases and controls. We confirmed prior studies showing association with T1D in the MHC, most significantly near HLA-DR/DQ. In the region centromeric to the MHC, we identified a peak of association within the inositol 1,4,5-triphosphate receptor 3 gene (ITPR3; formerly IP3R3). The most significant single SNP in this region was at the center of the ITPR3 peak of association (P=1.7 x 10(-4) for the survey study). For validation, we typed an additional 761 Swedish individuals. The P value for association computed from all 1,124 individuals was 1.30 x 10(-6) (recessive odds ratio 2.5; 95% confidence interval [CI] 1.7-3.9). The estimated population-attributable risk of 21.6% (95% CI 10.0%-31.0%) suggests that variation within ITPR3 reflects an important contribution to T1D in Sweden. Two-locus regression analysis supports an influence of ITPR3 variation on T1D that is distinct from that of any MHC class II gene.
Roach
Jared C
JC
Institute for Systems Biology, Seattle, WA 98103, USA. jroach@systemsbiology.org
Deutsch
Kerry
K
Li
Sarah
S
Siegel
Andrew F
AF
Bekris
Lynn M
LM
Einhaus
Derek C
DC
Sheridan
Colleen M
CM
Glusman
Gustavo
G
Hood
Leroy
L
Lernmark
Ake
A
Janer
Marta
M
D000293:Adolescent; D000328:Adult; D015220:Calcium Channels / Q000235:genetics*; D002503:Centromere; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping / Q000379:methods*; D002896:Chromosomes, Human, Pair 6; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006239:Haplotypes; D006801:Humans; D007223:Infant; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D013548:Sweden
D015220:Calcium Channels; C506926:ITPR1 protein, human; C506929:ITPR3 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear