Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes

E. Zeggini; C. J. Groves; J. R.C. Parkinson; S. Halford; K. R. Owen; T. M. Frayling; M. Walker; G. A. Hitman; J. C. Levy; S. O'Rahilly; A. T. Hattersley; M. I. McCarthy

doi:10.1007/s00125-005-1902-4

Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes

E. Zeggini, C. J. Groves, J. R.C. Parkinson, S. Halford, K. R. Owen, T. M. Frayling, M. Walker, G. A. Hitman, J. C. Levy, S. O'Rahilly, A. T. Hattersley, M. I. McCarthy

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

Abstract

Aims/hypothesis: The proinflammatory cytokine TNF-α has been implicated in the pathogenesis of insulin resistance and type 2 diabetes, and variation in the gene encoding TNF-α (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. Materials and 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/interpretation: 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.

Original language	English
Pages (from-to)	2013-2017
Number of pages	5
Journal	Diabetologia
Volume	48
Issue number	10
DOIs	https://doi.org/10.1007/s00125-005-1902-4
State	Published - Oct 2005
Externally published	Yes

Keywords

Association
Linkage disequilibrium
Lymphotoxin α
TNF
Tumour necrosis factor

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00125-005-1902-4

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Zeggini, E., Groves, C. J., Parkinson, J. R. C., Halford, S., Owen, K. R., Frayling, T. M., Walker, M., Hitman, G. A., Levy, J. C., O'Rahilly, S., Hattersley, A. T., & McCarthy, M. I. (2005). Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes. Diabetologia, 48(10), 2013-2017. https://doi.org/10.1007/s00125-005-1902-4

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title = "Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes",

abstract = "Aims/hypothesis: The proinflammatory cytokine TNF-α has been implicated in the pathogenesis of insulin resistance and type 2 diabetes, and variation in the gene encoding TNF-α (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. Materials and 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/interpretation: 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.",

keywords = "Association, Linkage disequilibrium, Lymphotoxin α, TNF, Tumour necrosis factor",

author = "E. Zeggini and Groves, {C. J.} and Parkinson, {J. R.C.} and S. Halford and Owen, {K. R.} and Frayling, {T. M.} and M. Walker and Hitman, {G. A.} and Levy, {J. C.} and S. O'Rahilly and Hattersley, {A. T.} and McCarthy, {M. I.}",

note = "Funding Information: Acknowledgements The work was supported by Diabetes UK, who were also responsible for funding the collection of many of the samples used. A. T. Hattersley is a Wellcome Trust Research Leave Fellow.",

year = "2005",

month = oct,

doi = "10.1007/s00125-005-1902-4",

language = "English",

volume = "48",

pages = "2013--2017",

journal = "Diabetologia",

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TY - JOUR

T1 - Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes

AU - Zeggini, E.

AU - Groves, C. J.

AU - Parkinson, J. R.C.

AU - Halford, S.

AU - Owen, K. R.

AU - Frayling, T. M.

AU - Walker, M.

AU - Hitman, G. A.

AU - Levy, J. C.

AU - O'Rahilly, S.

AU - Hattersley, A. T.

AU - McCarthy, M. I.

N1 - Funding Information: Acknowledgements The work was supported by Diabetes UK, who were also responsible for funding the collection of many of the samples used. A. T. Hattersley is a Wellcome Trust Research Leave Fellow.

PY - 2005/10

Y1 - 2005/10

N2 - Aims/hypothesis: The proinflammatory cytokine TNF-α has been implicated in the pathogenesis of insulin resistance and type 2 diabetes, and variation in the gene encoding TNF-α (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. Materials and 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/interpretation: 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.

AB - Aims/hypothesis: The proinflammatory cytokine TNF-α has been implicated in the pathogenesis of insulin resistance and type 2 diabetes, and variation in the gene encoding TNF-α (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. Materials and 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/interpretation: 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.

KW - Association

KW - Linkage disequilibrium

KW - Lymphotoxin α

KW - TNF

KW - Tumour necrosis factor

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U2 - 10.1007/s00125-005-1902-4

DO - 10.1007/s00125-005-1902-4

M3 - Article

C2 - 16132956

AN - SCOPUS:26244448474

SN - 0012-186X

VL - 48

SP - 2013

EP - 2017

JO - Diabetologia

JF - Diabetologia

IS - 10

ER -

Large-scale studies of the association between variation at the TNF/LTA locus and susceptibility to type 2 diabetes

Abstract

Keywords

UN SDGs

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