More CLEC16A gene variants associated with multiple sclerosis

Nischwitz, Sandra; Cepok, Sabine; Kroner, Antje; Wolf, Christiane; Knop, M.; Müller‐Sarnowski, Felix; Rieckmann, Peter; Hemmer, Bernhard; Ising, Marcus; Uhr, Manfred; Bettecken, T.; Holsboer, Florian; Müller‐Myhsok, Bertram; Weber, Frank

doi:10.1111/j.1600-0404.2010.01421.x

Cited by 24 publications

(16 citation statements)

References 32 publications

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“…However, when the M9 polymorphism arose, its effect on fruit mass could have been of functional significance. This pattern of few SNPs in large LD blocks has also been found in human (29)(30)(31)(32) and may be common in plants as well. The low LD yet significant association of the SNP with fruit mass led us to conduct segregation analyses; these analyses excluded the importance of M42, leaving M9 as the most significantly associated SNP of potential functional relevance (i.e., the most likely to regulate fruit mass).…”

Section: Discussionmentioning

confidence: 89%

A cytochrome P450 regulates a domestication trait in cultivated tomato

Chakrabarti

Zhang

Sauvage

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

266

239

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Domestication of crop plants had effects on human lifestyle and agriculture. However, little is known about the underlying molecular mechanisms accompanying the changes in fruit appearance as a consequence of selection by early farmers. We report the fine mapping and cloning of a tomato (Solanum lycopersicum) fruit mass gene encoding the ortholog of KLUH, SlKLUH, a P450 enzyme of the CYP78A subfamily. The increase in fruit mass is predominantly the result of enlarged pericarp and septum tissues caused by increased cell number in the large fruited lines. SlKLUH also modulates plant architecture by regulating number and length of the side shoots, and ripening time, and these effects are particularly strong in plants that transgenically down-regulate SlKLUH expression carrying fruits of a dramatically reduced mass. Association mapping followed by segregation analyses revealed that a single nucleotide polymorphism in the promoter of the gene is highly associated with fruit mass. This single polymorphism may potentially underlie a regulatory mutation resulting in increased SlKLUH expression concomitant with increased fruit mass. Our findings suggest that the allele giving rise to large fruit arose in the early domesticates of tomato and becoming progressively more abundant upon further selections. We also detected association of fruit weight with CaKLUH in chile pepper (Capsicum annuum) suggesting that selection of the orthologous gene may have occurred independently in a separate domestication event. Altogether, our findings shed light on the molecular basis of fruit mass, a key domestication trait in tomato and other fruit and vegetable crops.

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Section: Discussionmentioning

confidence: 89%

A cytochrome P450 regulates a domestication trait in cultivated tomato

Chakrabarti

Zhang

Sauvage

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

266

239

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“…Several GWAS in different autoimmune diseases such as multiple sclerosis [40,58,59], primary adrenal insufficiency [60], systemic lupus erythematosus [61,62], Celiac disease [63], Crohn’s disease [64], selective immunoglobulin A deficiency [65], alopecia areata [65], juvenile idiopathic arthritis [66], rheumatoid arthritis [54,66], and primary biliary cirrhosis [67,68] also demonstrated association of the 16p13 loci with disease risk, implying that the 16p13 region contains a key regulator of the self-reactive immune response.…”

Section: Genetic Component In Type 1 Diabetesmentioning

confidence: 99%

Genes Involved in Type 1 Diabetes: An Update

Bakay

Pandey

Hákonarson

2013

Genes

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Type 1 Diabetes (T1D) is a chronic multifactorial disease with a strong genetic component, which, through interactions with specific environmental factors, triggers disease onset. T1D typically manifests in early to mid childhood through the autoimmune destruction of pancreatic β cells resulting in a lack of insulin production. Historically, prior to genome-wide association studies (GWAS), six loci in the genome were fully established to be associated with T1D. With the advent of high-throughput single nucleotide polymorphism (SNP) genotyping array technologies, enabling investigators to perform high-density GWAS, many additional T1D susceptibility genes have been discovered. Indeed, recent meta-analyses of multiple datasets from independent investigators have brought the tally of well-validated T1D disease genes to almost 60. In this mini-review, we address recent advances in the genetics of T1D and provide an update on the latest susceptibility loci added to the list of genes involved in the pathogenesis of T1D.

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“…The most highly disease-associated single-nucleotide polymorphisms (SNPs) lie predominantly within the 60 kb intron 19 of CLEC16A (1,2,4,5,10,11), as well as within intron 10 of the same gene. The most commonly cited disease-associated SNPs within these respective introns are rs12708716 and rs8062322, which are in high linkage disequilibrium (LD) and are, therefore, likely to be tagging the same signal.…”

Section: Introductionmentioning

confidence: 99%

Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

Davison

Wallace

Cooper

et al. 2011

Human Molecular Genetics

103

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The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes.

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More CLEC16A gene variants associated with multiple sclerosis

Abstract: All described base polymorphisms are mapping to one LD block of approximately 50 kb within intron 19 of the CLEC16A gene, suggesting a pivotal role of this region for susceptibility of MS and possibly also for other autoimmune diseases.

Cited by 24 publications

References 32 publications

A cytochrome P450 regulates a domestication trait in cultivated tomato

A cytochrome P450 regulates a domestication trait in cultivated tomato

Genes Involved in Type 1 Diabetes: An Update

Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

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