Construction and analysis of tag single nucleotide polymorphism maps for six human-mouse orthologous candidate genes in type 1 diabetes.
BACKGROUND
One strategy to help identify susceptibility genes for complex, multifactorial diseases is to map disease loci in a representative animal model of the disorder. The nonobese diabetic (NOD) mouse is a model for human type 1 diabetes. Linkage and congenic strain analyses have identified several NOD mouse Idd (insulin dependent diabetes) loci, which have been mapped to small chromosome intervals, for which the orthologous regions in the human genome can be identified. Here, we have conducted re-sequencing and association analysis of six orthologous genes identified in NOD Idd loci: NRAMP1/SLC11A1 (orthologous to Nramp1/Slc11a1 in Idd5.2), FRAP1 (orthologous to Frap1 in Idd9.2), 4-1BB/CD137/TNFRSF9 (orthologous to 4-1bb/Cd137/Tnrfrsf9 in Idd9.3), CD101/IGSF2 (orthologous to Cd101/Igsf2 in Idd10), B2M (orthologous to B2m in Idd13) and VAV3 (orthologous to Vav3 in Idd18).


RESULTS
Re-sequencing of a total of 110 kb of DNA from 32 or 96 type 1 diabetes cases yielded 220 single nucleotide polymorphisms (SNPs). Sixty-five SNPs, including 54 informative tag SNPs, and a microsatellite were selected and genotyped in up to 1,632 type 1 diabetes families and 1,709 cases and 1,829 controls.


CONCLUSIONS
None of the candidate regions showed evidence of association with type 1 diabetes (P values > 0.2), indicating that common variation in these key candidate genes does not play a major role in type 1 diabetes susceptibility in the European ancestry populations studied.
Maier
Lisa M
LM
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge, UK. lisa.maier@cimr.cam.ac.uk
Smyth
Deborah J
DJ
Vella
Adrian
A
Payne
Felicity
F
Cooper
Jason D
JD
Pask
Rebecca
R
Lowe
Christopher
C
Hulme
John
J
Smink
Luc J
LJ
Fraser
Heather
H
Moule
Carolyn
C
Hunter
Kara M
KM
Chamberlain
Giselle
G
Walker
Neil
N
Nutland
Sarah
S
Undlien
Dag E
DE
Rønningen
Kjersti S
KS
Guja
Cristian
C
Ionescu-Tîrgoviste
Constantin
C
Savage
David A
DA
Strachan
David P
DP
Peterson
Laurence B
LB
Todd
John A
JA
Wicker
Linda S
LS
Twells
Rebecca C
RC
D000818:Animals; D016022:Case-Control Studies; D002874:Chromosome Mapping; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005192:Family Health; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016366:Open Reading Frames / Q000235:genetics; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D020506:Untranslated Regions / Q000235:genetics; D044465:White People / Q000235:genetics
D020506:Untranslated Regions
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