Genome-wide linkage analysis of 160 North American families with celiac disease

Garner, Chad; Ding, Yuan Chun; Steele, Linda; Book, Linda S.; Leiferman, K; Zone, John J.; Neuhausen, Susan L.

doi:10.1038/sj.gene.6364361

Cited by 16 publications

(13 citation statements)

References 46 publications

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“…8 The PPP6C and PBX3 loci are located in 9q. This region showed linkage to CD in the North American population 9 but, in contrast to 2q33, no replication has been reported. Further studies are necessary to confirm this possible linkage region and, if replicated, to look for the etiologic genes.…”

Section: Resultsmentioning

confidence: 72%

Lack of replication of celiac disease risk variants reported in a Spanish population using an independent Spanish sample

et al. 2009

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Celiac disease (CD) is an inflammatory condition affecting small bowel and triggered by gluten (or related proteins) ingestion in genetic susceptible individuals. Polymorphisms in three genes, SERPINE2, PPP6C and PBX3, have recently been associated with CD in the Spanish population. However, this association could not be replicated in the UK population using imputed data. As this second study analyzed a different population, we aimed at reevaluating the role of those polymorphisms using an independent Spanish sample. We genotyped three single nucleotide polymorphisms: rs6747096 in SERPINE2, rs458046 in PPP6C and rs7040561 in PBX3, in 417 CD patients, 527 ethnically matched healthy controls and parents of 304 CD patients. A case-control study using the w 2 -test and a familial study using the transmission disequilibrium test were performed. No association was detected in those analyses. Therefore, our results seem to discard the role of the previously described polymorphisms in SERPINE2, PPP6C and PBX3 in CD susceptibility. IntroductionCeliac disease (CD) is a complex disease mediated by immune processes triggered after ingestion of gluten or related proteins in genetically susceptible individuals. 1 The genetic basis of this disease is being slowly unraveled by advances in experimental techniques. Combining two different gene-search approaches, Castellanos-Rubio et al. 2 reported new CD risk variants in the Spanish Basque population. They combined information provided by whole-genome expression profiling experiments and linkage studies (that is, functional and positional information) and found significant association with four single nucleotide polymorphisms (SNPs) located in the SERPINE2 (serine protease inhibitor, clade E, member 2), PPP6C (protein phosphatase 6, catalytic subunit) and PBX3 (pre-B-cell leukemia homeobox 3) genes.The SERPINE2 gene maps in the CD linkage region 2q33-q35 and PPP6C and PBX3 in 9q33-q34. SERPINE2 is involved in extracellular matrix production and it has been widely studied in relation to COPD (chronic obstructive pulmonary disease). 3 PPP6C encodes a protein phosphatase which seems to be involved in cell-cycle regulation. 4 Finally, PBX3 is a transcription factor implicated in basic developmental functions, including some related to immune cells. 5 The association between those genes and CD susceptibility described by Castellanos-Rubio et al. was questioned by Hunt et al., 6 who used data from a genome-wide association study performed in the British population to impute data corresponding to the previously associated SNPs. No replication was obtained and the authors suggested different possible explanations. Therefore, the debate is open because for every SNP the imputation is not 100% accurate, an issue recently discussed. 7 As an explanation of the observed discrepancies between the two studies could be owed to population or clinical heterogeneity, we aimed at evaluating the role of those SNPs in an independent Spanish sample of pediatric typical CD patients. Results and discuss...

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Section: Resultsmentioning

confidence: 72%

Lack of replication of celiac disease risk variants reported in a Spanish population using an independent Spanish sample

et al. 2009

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“…Probands were CD patients with a reported family history of CD from the Pediatric Gastroenterology Clinic of the Soroka University Medical Center, Israel, the only hospital in the Negev region. Families were ascertained through sequential sampling of first-degree relatives of CD cases, with diagnostic criteria as described in Garner et al 14 The results of the multipoint linkage analysis are shown in Figure 1 Multipoint linkage results for autosomal chromosomes. Genotypes from a 10-cM density microsatellite marker genome scan of 405 short-tandem repeat (STR) markers were analyzed.…”

Section: Resultsmentioning

confidence: 99%

“…There have been multiple genome-wide linkage studies to identify loci for CD (reviewed in van Heel et al, 13 Garner et al, 14 Eller et al…”

Section: Introductionmentioning

confidence: 99%

An autosomal genome-wide screen for celiac disease in Bedouin families

et al. 2007

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Celiac disease is a common, familial autoimmune disease caused by exposure to gliadin in wheat, and related prolamins in barley and rye. The prevalence of the disease is approximately 1:133. Celiac disease can cause significant morbidity. The only treatment is a gluten-free diet. A genome-wide search of 405 microsatellite markers was performed on samples from 18 Bedouin families with a minimum of two cases of celiac disease. Non-parametric and parametric (including both dominant and recessive models of inheritance) linkage analyses were performed. The most significant genome-wide linkage evidence was at chromosome 3p26 with an HLod of 3.21, under the dominant model. The only other HLod or NPL greater than 2 was at 4q35, with an HLod of 2.15 under a dominant model. The region at 3p26, previously reported in two linkage analyses, harbors interleukin receptor genes, plausible candidates for celiac disease.

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“…Owing to their inherent features, tandem repeats have been widely used in genetic fingerprinting and as the genetic markers in linkage studies to locate the chromosomal regions harboring the mutations or genes for monogenic or familial disorders, complex diseases and quantitative traits. [41][42][43][44] Although tandem repeats are more informative than SNPs at the individual marker level, their number is far less than the several million SNPs in the human genome. Thus, tandem repeats are not ideal genetic markers for applications that require high marker density or resolution, such as genome-wide association studies (GWASs), in which several hundred thousand of SNPs are needed.…”

Section: The Evolution Of Genetic Markers In Disease Gene Mappingmentioning

confidence: 99%

“…However, microsatellites were widely used as the genetic markers in linkage studies. [41][42][43][44] These genetic variations have been used as the markers in human genetic studies for more than 20 years until the completion of the Human Genome Project 50 and the finding of millions of SNPs by the International SNP Map Working Group and other studies. 5,6 Thereafter, SNPs became the primary markers in genetic association studies, and also replaced microsatellites in some linkage studies.…”

Section: The Evolution Of Genetic Markers In Disease Gene Mappingmentioning

confidence: 99%

The discovery of human genetic variations and their use as disease markers: past, present and future

Loy

Salim

et al. 2010

J Hum Genet

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The field of human genetic variations has progressed rapidly over the past few years. It has added much information and deepened our knowledge and understanding of the diversity of genetic variations in the human genome. This significant progress has been driven mainly by the developments of microarray and next generation sequencing technologies. The array-based methods have been widely used for large-scale copy number variation (CNV) detection in the human genome. The arrival of next generation sequencing technologies, which enabled the completion of several whole genome resequencing studies, has also resulted in a massive discovery of genetic variations. These studies have identified several hundred thousand short indels and a total of thousands of CNVs and other structural variations in the human genome. The discovery of these 'newer' types of genetic variations, indels, CNVs and copy neutral variations (inversions and translocations) has also widened the scope of genetic markers in human genetic and disease gene mapping studies. The aim of this review article is to summarize the latest developments in the discovery of human genetic variations and address the issue of inadequate coverage of genetic variations in the current genome-wide association studies, which mainly focuses on common SNPs. Finally, we also discuss the future directions in the field and their impacts on next generation genome-wide association studies.

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Genome-wide linkage analysis of 160 North American families with celiac disease

Cited by 16 publications

References 46 publications

Lack of replication of celiac disease risk variants reported in a Spanish population using an independent Spanish sample

Lack of replication of celiac disease risk variants reported in a Spanish population using an independent Spanish sample

An autosomal genome-wide screen for celiac disease in Bedouin families

The discovery of human genetic variations and their use as disease markers: past, present and future

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