Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele

Morahan, Grant; Huang, Dexing; Ymer, Susie I.; Cancilla, Michael R.; Stephen, Katrina; Dabadghao, Preeti; Werther, George A.; Tait, Brian D.; Harrison, Leonard C.; Colman, Peter G

doi:10.1038/84872

Cited by 280 publications

(262 citation statements)

References 23 publications

Supporting

Mentioning

242

Contrasting

Unclassified

Order By: Relevance

“…14 The latter is of particular interest, since it has been shown to be associated with susceptibility to at least two diseases: multiple sclerosis 17 and type I diabetes mellitus. 18 To elucidate the biological significance of the 3 0 UTR polymorphism in the etiology or course of a disease, it is mandatory to study the relation between genotype and phenotype. For this reason, we studied in vitro IL-12 secretion by stimulated human monocytes in relation to this polymorphism.…”

Section: Discussionmentioning

confidence: 99%

“…18 It must be noted however that this study was done in cell lines, and focused on p40 mRNA expression rather than on p40 or p70 protein secretion, and investigated basal expression instead of stimulated expression. Interestingly, our findings in humans are in general in accordance with data we have generated in the mouse.…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…15,16 The TaqI polymorphism was recently found to be associated with susceptibility to both IDDM and MS, but the biological relevance of this polymorphism to these diseases has not been identified. 17,18 In the present study, we attempted to rectify this situation by investigating whether this polymorphism is associated with altered IL-12 secretion by monocytes. Also, given the established role of IL-12 in CD, we investigated whether this polymorphism is associated with susceptibility to this disease.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2002

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2002

View full text Add to dashboard Cite

show abstract

“…In order to avoid confounding evidence for linkage and association (linkage disequilibrium), association analyses were conducted using only one diabetic child from each family [85]. Interestingly, this strategy of searching for association in linked families was recently used to identify the newest diabetes gene, IDDM18, located at a functional (not positional) candidate gene, the interleukin 12B (IL12B) locus on chromosome 5q33-q34 [87]. Highly significant association was found between diabetes and variants in intron 4 and the 3¢ untranslated region of IL12B in the subset of affected sibpairs with increased IL12B gene sharing but not in the subset without increased IL12B gene sharing.…”

Section: Is Positional Candidate Mapping Feasible?mentioning

confidence: 99%

Genetic linkage and association studies of Type I diabetes: challenges and rewards

Field

2002

Diabetologia

104

View full text Add to dashboard Cite

Type I diabetes (formerly called insulin-dependent diabetes mellitus) results from the autoimmune destruction of the insulin-producing beta cells of the pancreas. It is now known that Type I diabetes is a genetically complex disease, i. e. a disease caused by multiple genes interacting with non-genetic (environmental and stochastic) factors. Family studies have clearly shown a genetic basis but inheritance of the disease does not follow a simple mendelian single-locus pattern. Population and family studies also suggest that most (perhaps all) affected individuals are genetically predisposed to Type I diabetes, particularly through HLA region genes. However, non-genetic factors appear to be required to precipitate the disease in these genetically susceptible persons because in monozygote (MZ) twin pairs in which one twin has Type I diabetes the MZ twin concordance rate is less than 100 %. It is not clear whether there are any purely genetic cases of Type I Diabetologia (2002) AbstractFamily and twin studies have shown clearly that Type I (insulin-dependent) diabetes mellitus has a genetic basis. However, only within the past decade has it been possible to systematically attempt to identify the genes that increase susceptibility to this disorder using linkage and association analysis of genetic markers distributed across the genome. More than 20 putative diabetes-predisposing genes have been localised in addition to HLA region susceptibility genes detected more than 25 years ago. Unfortunately, the effects of most diabetes-predisposing genes are weak, with the exception of HLA region susceptibility genes (which contribute about half of the genetic risk). The overall effects of diabetes-predisposing genes could be weak because the susceptibility gene occurs in only a small proportion of diabetic patients or the susceptibility gene (although it might be common) produces only a modest increase in risk, probably by acting in concert with other such genes to cause disease. The weak effects of these genes have made them difficult to locate, difficult to confirm in independent studies and difficult to isolate by genetic procedures. This paper summarizes the major challenges that have faced geneticists in mapping Type I diabetes genes, and reviews the progress achieved to date. The rewards of the genetic studies will be twofold: increased understanding of the causes of Type I diabetes, facilitating creation of preventative therapies, and enabling clinicians in the future to use genetic information to predict which children are predisposed to diabetes in order to target them for preventative therapies. [Diabetologia (2002) 45: 21±35]

show abstract

The Genetics of Psoriasis 2001

Nair²,

et al. 2001

View full text Add to dashboard Cite

Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele

Cited by 280 publications

References 23 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

Genetic linkage and association studies of Type I diabetes: challenges and rewards

The Genetics of Psoriasis 2001

Contact Info

Product

Resources

About