Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes.
OBJECTIVE
The proinflammatory cytokine TNF-alpha has been implicated in the pathogenesis of insulin resistance and type 2 diabetes, and variation in the gene encoding TNF-alpha (TNF) has shown inconsistent associations with susceptibility to both conditions. Additionally, the coding non-synonymous variant T60N in the neighbouring LTA gene has been reported to be associated with type 2 diabetes. The present study aimed to obtain a robust assessment of the role of variation in the tightly linked TNF/LTA region in diabetes susceptibility by genotyping TNF and LTA variants in large case-control resources.


METHODS
The G-308A and G-238A TNF promoter variants and the LTA T60N polymorphism were genotyped in two UK case samples that were ascertained for positive family history and/or early onset of type 2 diabetes (combined n=858) and in 1,257 ethnically matched controls.


RESULTS
There were no significant associations between the T60N, G-308A or G-238A genotype and type 2 diabetes in the combined analysis (exact Cochran-Mantel-Haenszel statistic for ordered genotypes for T60N, p=0.69; for G-308A, p=0.51; for G-238A, p=0.16).


CONCLUSIONS
The present study, one of the largest association analyses yet reported at this locus, provides no evidence that the specific TNF or LTA variants examined influence susceptibility to type 2 diabetes. More comprehensive studies of the TNF/LTA locus in substantially larger sample sets are required to establish whether genome sequence variation at this locus truly influences susceptibility to type 2 diabetes.
Zeggini
E
E
Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital Site, Old Road, Headington, Oxford OX3 7LJ, UK.
Groves
C J
CJ
Parkinson
J R C
JR
Halford
S
S
Owen
K R
KR
Frayling
T M
TM
Walker
M
M
Hitman
G A
GA
Levy
J C
JC
O'Rahilly
S
S
Hattersley
A T
AT
McCarthy
M I
MI
D000328:Adult; D017668:Age of Onset; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology* / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology
D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha