Parameters for reliable results in genetic association studies in common disease

Dahlman, Ingrid; Eaves, Iain A.; Kosoy, Roman; Morrison, V. Anne; Heward, J. M.; Gough, Stephen; Allahabadia, Amit; Franklyn, Jayne A.; Tuomilehto, Jaakko; Tuomilehto‐Wolf, Eva; Cucca, Francesco; Guja, Cristian; Ionescu-Tîrgovişte, C; Stevens, Helen; Carr, Philippa; Nutland, Sarah; McKinney, Patricia A.; Shield, Julian; Wang, William Y.S.; Cordell, Heather J.; Walker, Neil M.; Todd, John A.; Concannon, Patrick

doi:10.1038/ng825

Cited by 213 publications

(144 citation statements)

References 10 publications

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“…The relatively small sample size in combination with the rare frequency of the variant allele may not have been powerful enough to detect such an association. As was recently shown for IDDM, 18,24 large-scale family-based linkage studies are necessary to establish the role of the IL-12 genes in the susceptibility to CD. These efforts are currently underway.…”

Section: Discussionmentioning

confidence: 99%

A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion

et al. 2002

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Interleukin-12 (IL-12) is a key cytokine for the induction of Th1 immune responses. We evaluated whether a TaqI polymorphism in the 3 0 UTR of the IL-12 p40 gene affects secretion of IL-12 in vitro, and whether this polymorphism is associated with susceptibility to Crohn's disease (CD). IL-12 p40 and p70 secretion by monocytes in relation to genotype was determined in 63 healthy donors. Genotype and allele frequencies of the TaqI polymorphism in 150 CD patients were compared with 145 ethnically matched healthy controls (HC). No significant association was found between genotype and IL-12 p40 secretion after stimulation of monocytes with SAC+IFNg. In contrast, increasing IL-12 p70 secretion was found across the categories of noncarriers, heterozygotes and homozygotes for the variant allele (median values 7 SEM: 147 7 27, 282 7 51 and 482 7 34 pg/ ml, respectively; Po0.005). The allele and genotype frequencies of this polymorphism in patients with CD did not differ statistically significantly from HC. The presence of a TaqI polymorphism in the IL12 p40 3 0 UTR correlates with increased in vitro IL-12 p70, but not p40 secretion. While this polymorphism does not appear to be correlated with susceptibility to CD in the limited population of patients tested here, it could influence the occurrence of the disease in certain subsets of patients.

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Section: Discussionmentioning

confidence: 99%

A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion

et al. 2002

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“…Even with a plausible biological rationale for the candidacy of a gene such as IL4RA, P values in the order of 10 À5 are desirable to ensure a relatively low falsepositive rate for disease association studies and Po10 À7 -10 À8 for genome-wide association studies. [34][35][36] Obviously, a second independent even larger data set will need to be genotyped for this SNP to test if the T allele of the -3223 C4T SNP does indeed protect from T1D. New collections of families (http://www.t1dgc.org) and case-controls are under way (http://www.childhooddiabetes.org.uk).…”

Section: Discussionmentioning

confidence: 99%

Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene

et al. 2003

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Variations in the interleukin 4 receptor A (IL4RA) gene have been reported to be associated with atopy, asthma, and allergy, which may occur less frequently in subjects with type 1 diabetes (T1D). Since atopy shows a humoral immune reactivity pattern, and T1D results from a cellular (T lymphocyte) response, we hypothesised that alleles predisposing to atopy could be protective for T1D and transmitted less often than the expected 50% from heterozygous parents to offspring with T1D. We genotyped seven exonic single nucleotide polymorphisms (SNPs) and the -3223 C4T SNP in the putative promoter region of IL4RA in up to 3475 T1D families, including 1244 Finnish T1D families. Only the À3223 C4T SNP showed evidence of negative association (P ¼ 0.014). There was some evidence for an interaction between À3233 C4T and the T1D locus IDDM2 in the insulin gene region (P ¼ 0.001 in the combined and P ¼ 0.02 in the Finnish data set). We, therefore, cannot rule out a genetic effect of IL4RA in T1D, but it is not a major one.

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“…152 In a recent comprehensive review of over 600 positive case-control studies, only six positive associations were found to have been consistently replicated. 153 A follow-up meta-analysis of a selection of the positive associations by the same authors found that eight of 25 associations were statistically significant.…”

Section: Disease Associations-conclusionmentioning

confidence: 99%

Is there a future for TNF promoter polymorphisms?

2004

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The in vitro study of TNF promoter polymorphism (SNP) function was stimulated by the numerous case-control (association) studies of the polymorphisms in relation to human disease and the appearance of several studies claiming to show a functional role for these SNPs provided a further impetus to researchers interested in the role of TNF in their disease of interest. In this review we consider case-control studies, concentrating on the autoimmune and inflammatory diseases rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis, and asthma, and on infectious diseases including malaria, hepatitis B and C infection, leprosy and sepsis/septic shock. We also review the available evidence on the functional role of the various TNF promoter polymorphisms. In general, case-control studies have produced mixed results, with little consensus in most cases on whether any TNF polymorphisms are actually associated with disease, although results have been more consistent in the case of infectious diseases, particularly malaria. Functional studies have also produced mixed results but recent work suggests that the much studied À308G/A polymorphism is not functional, while the function of other TNF polymorphisms remains controversial. Studies of the TNF region are increasingly using extended haplotypes that can better capture the variation of the MHC region.

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Parameters for reliable results in genetic association studies in common disease

Cited by 213 publications

References 10 publications

A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion

A TaqI polymorphism in the 3′UTR of the IL-12 p40 gene correlates with increased IL-12 secretion

Testing the possible negative association of type 1 diabetes and atopic disease by analysis of the interleukin 4 receptor gene

Is there a future for TNF promoter polymorphisms?

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