| 1. |
- Adamovic, Svetlana, 1965, et al.
(författare)
-
Association study of IL2/IL21 and FcgRIIa: significant association with the IL2/IL21 region in Scandinavian coeliac disease families
- 2008
-
Ingår i: Genes and immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 9:4, s. 364-367
-
Tidskriftsartikel (refereegranskat)abstract
- The first genome-wide association study performed in a UK coeliac disease (CD) case-control cohort revealed association with a linkage disequilibrium block containing the KIAA1109/Tenr/IL2/IL21 genes. Also recently, an association with a non-synonymous polymorphism in Fcitalic gammaRIIa (CD32a) was reported in CD with an unusually strong P-value. We aimed to replicate the reported associations with the single nucleotide polymorphisms rs13119723 A>G and rs6822844 G>T in the KIAA1109/Tenr/IL2/IL21 region and rs1801274 G>A in the Fcitalic gammaRIIa gene in a family sample consisting of 325 Swedish/Norwegian families using the robust transmission disequilibrium test. The family sample used in this study included 100 families with two or more children affected by CD and 225 families with one affected child. We could confirm significant association between the polymorphisms rs13119723 A>G and rs6822844 G>T located in the KIAA1109/Tenr/IL2/IL21 region and CD (P-value 0.001 and 0.002, respectively). However, we found no association with the Fcitalic gammaRIIa rs1801274 G>A polymorphism (P-value=0.3). In conclusion, our results support the KIAA1109/Tenr/IL2/IL21 region as a true CD susceptibility region.
|
|
| 2. |
- Adamovic, Svetlana, 1965, et al.
(författare)
-
Fine mapping study in Scandinavian families suggests association between coeliac disease and haplotypes in chromosome region 5q32.
- 2008
-
Ingår i: Tissue Antigens. - : Wiley. - 1399-0039 .- 0001-2815. ; 71:1, s. 27-34
-
Tidskriftsartikel (refereegranskat)abstract
- The previous genome-wide scan in Scandinavian families supported earlier evidence for linkage of a region on chromosome 5 (5q31–33) to coeliac disease. This study deals with further genetic mapping of an 18 cM region, spanning from marker GAh18A (131.87 Mb) to D5S640 (149.96 Mb). Linkage and association analyses were performed in a two-step approach. First, seven microsatellites were added. Strong evidence for linkage was obtained with a Zlr score of 3.96, Pnc = 4 × 10−5 at marker D5S436. The strongest association was with a haplotype consisting of the markers D5S2033 and D5S2490 (Pnc < 0.001). In the second step, we added 17 microsatellites and 69 single nucleotide polymorphisms (SNPs) to the analysis. These markers were located close to or within candidate genes across the region of approximately 7 Mb beneath the linkage peak marked by D5S2017 and D5S812. A substantial increase of the linkage signal with a maximum Zlr score of 4.6 at marker rs1972644 (Pnc = 2 × 10−6) was obtained and several SNPs showed association. Seven SNPs that individually showed the strongest association were genotyped in a second independent family sample set (225 trios). In the trio family sample as well as in the multiplex family sample, the strongest association was found with SNPs within the region flanked by the associated microsatellites D5S2033 and D5S2490 at 5q32.
|
|
| 3. |
- amundsen, silja, et al.
(författare)
-
A comprehensive screen for SNP associations on chromosome region 5q31-33 in Swedish/Norwegian celiac disease families.
- 2007
-
Ingår i: European Journal of Human genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 15:9, s. 980-987
-
Tidskriftsartikel (refereegranskat)abstract
- Celiac disease (CD) is a gluten-induced enteropathy, which results from the interplay between environmental and genetic factors. There is a strong human leukocyte antigen (HLA) association with the disease, and HLA-DQ alleles represent a major genetic risk factor. In addition to HLA-DQ, non-HLA genes appear to be crucial for CD development. Chromosomal region 5q31–33 has demonstrated linkage with CD in several genome-wide studies, including in our Swedish/Norwegian cohort. In a European meta-analysis 5q31–33 was the only region that reached a genome-wide level of significance except for the HLA region. To identify the genetic variant(s) responsible for this linkage signal, we performed a comprehensive single nucleotide polymorphism (SNP) association screen in 97 Swedish/Norwegian multiplex families who demonstrate linkage to the region. We selected tag SNPs from a 16 Mb region representing the 95% confidence interval of the linkage peak. A total of 1404 SNPs were used for the association analysis. We identified several regions with SNPs demonstrating moderate single- or multipoint associations. However, the isolated association signals appeared insufficient to account for the linkage signal seen in our cohort. Collective effects of multiple risk genes within the region, incomplete genetic coverage or effects related to copy number variation are possible explanations for our findings.
|
|
| 4. |
- Amundsen, S. S., et al.
(författare)
-
Association analysis of MYO9B gene polymorphisms with celiac disease in a Swedish/Norwegian cohort
- 2006
-
Ingår i: Hum Immunol. - : Elsevier BV. - 0198-8859. ; 67:4-5, s. 341-5
-
Tidskriftsartikel (refereegranskat)abstract
- Association between myosin IXB (MYO9B) gene variants and celiac disease (CD) has been reported in a study of a Dutch cohort. Six single nucleotide polymorphisms (SNPs) within the 3' part of the MYO9B gene showed significant genetic association and formed an associated haplotype. The current study aimed to replicate these findings in a Swedish/Norwegian cohort. Genotyping of the three SNPs which tagged the associated haplotype was performed in a CD family dataset (n = 326) and in an additional set of healthy controls (n = 562). Although our material provided reasonable power to detect the previously observed association, we were unable to replicate association with these SNPs. Lack of reproducibility could be explained by no or negligible contribution of MYO9B to the genetic predisposition to CD in the Swedish/Norwegian population. Alternatively, it might be due to variable linkage disequilibria in distinct populations in the tested SNPs and a causative mutation yet to be identified or to false positive findings (type I error) in the Dutch study.
|
|
| 5. |
- Amundsen, Silja Svanström, et al.
(författare)
-
Four novel coeliac disease regions replicated in an association study of a Swedish-Norwegian family cohort.
- 2010
-
Ingår i: Genes and immunity. - : Springer Science and Business Media LLC. - 1476-5470 .- 1466-4879. ; 11:1, s. 79-86
-
Tidskriftsartikel (refereegranskat)abstract
- Recent genome-wide association studies have identified 1q31 (RGS1), 2q11-12 (IL18RAP), 3p21 (CCR1/CCR3/CCR2), 3q25-26 (IL12A/SCHIP1), 3q28 (LPP), 4q27 (IL2/IL21), 6q25 (TAGAP) and 12q24 (SH2B3) as susceptibility regions for coeliac disease (CD). We have earlier replicated association with the IL2/IL21 region. This study aimed at replicating the remaining regions in a family cohort using the transmission disequilibrium test, which is not prone to population stratification as a source of false-positive results. Nine single nucleotide polymorphisms (SNPs) within these regions were genotyped in 325 Swedish-Norwegian CD families. We found significant associations with the same alleles in the regions 1q31 (rs2816316; P(nc)=0.0060), 3p21 (rs6441961; P(nc)=0.0006), 3q25-26 (rs17810564; P(nc)=0.0316 and rs9811792; P(nc)=0.0434) and 3q28 (rs1464510; P(nc)=0.0037). Borderline, but non-significant, associations were found for rs917997 (IL18RAP), whereas no evidence for association could be obtained for rs13015714 (IL18RAP) or rs1738074 (TAGAP). The lack of replication of the latter SNPs could be because of limited power. rs3184504 (SH2B3) was not analysed because of assay failure. The most significantly associated region, 3p21 (CCR1/CCR3/CCR2), was further analysed by typing of 30 SNPs, with the aim of identifying the causal variant responsible for the initial association. Several SNPs showed association with CD, but none displayed associations stronger than rs6441961, nor did any of them add to the effect initially marked by rs6441961 in a conditional analysis. However, differential effects of rs6441961(*)C carrying haplotypes were indicated, and we thus cannot exclude the possibility that our inability to obtain evidence for multiple independent effects in the CCR1/CCR3/CCR2 gene region was related to a power issue.
|
|
| 6. |
- Amundsen, S. S., et al.
(författare)
-
Genetic analysis of the CD28/CTLA4/ICOS (CELIAC3) region in coeliac disease.
- 2004
-
Ingår i: Tissue antigens. - : Wiley. - 0001-2815 .- 1399-0039. ; 64:5, s. 593-9
-
Tidskriftsartikel (refereegranskat)abstract
- In order to extend our previous findings of genetic linkage to the CD28/CTLA4/ICOS region on chromosome 2q33 (CELIAC3) in coeliac disease (CD), we have investigated 22 genetic markers in 325 Norwegian/Swedish multiplex and simplex CD families. We found both linkage and association with several markers, primarily in the multiplex material. We observed strong linkage disequilibrium (LD) between SNPs (Single Nucleotide Polymorphisms) within an LD block delimited by MH30 and D2S72. A haplotype of this region marked by the alleles -1147*T: + 49*A:CT60*G:CT61*A was significantly associated with CD, suggesting that one or more polymorphisms of this haplotype, possibly -1147*T, are involved in CD susceptibility. The CT60 SNP, a polymorphism found to be most strongly associated with some other immune-mediated diseases, was not associated with CD, as this SNP was part of both associated and non-associated haplotypes. Moreover, our results suggest that CELIAC3 harbours several independent loci contributing to CD susceptibility.
|
|
| 7. |
- Bjornvold, M., et al.
(författare)
-
FOXP3 polymorphisms in type 1 diabetes and coeliac disease
- 2006
-
Ingår i: J Autoimmun. - : Elsevier BV. - 0896-8411. ; 27:2, s. 140-4
-
Tidskriftsartikel (refereegranskat)abstract
- The FOXP3 gene encodes a transcription factor thought to be essential for the development and function of T regulatory cells. Two previous studies have tested common polymorphisms in FOXP3 for association with type 1 diabetes (T1D) with conflicting results. The aim of our study was to see whether there is any evidence of association between the FOXP3 polymorphisms previously reported to be associated with T1D, in a Caucasian population regarding T1D and coeliac disease (CD). We further looked for evidence of interaction between FOXP3 polymorphisms and HLA-DR3 in conferring susceptibility to T1D. Initially, we analysed two microsatellites in the FOXP3 gene in 363 T1D nuclear families. Our results indicated an association between FOXP3 and T1D (global p=0.004) and a possible interaction between FOXP3 and the HLA-DR3-DQ2 susceptibility haplotype. We then genotyped an additional independent set of 826 T1D patients and 1459 controls as well as one CD dataset consisting of 325 families. A similar tendency was revealed in the CD family material (pnc=0.055 for the associated allele). On the other hand, we were unable to reproduce our initial findings in the T1D case-control dataset (global p=0.6). Our results suggest that the tested FOXP3 markers do not have any major impact on susceptibility for these diseases.
|
|
| 8. |
|
|
| 9. |
- Gudjonsdottir, Audur, 1959, et al.
(författare)
-
Association Between Genotypes and Phenotypes in Coeliac Disease.
- 2009
-
Ingår i: Journal of pediatric gastroenterology and nutrition. - 1536-4801 .- 0277-2116. ; 49:2, s. 165-169
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:: Coeliac disease (CD) is a genetically driven immunological intolerance to dietary gluten with a wide range of clinical presentations. The aim of this study was to investigate the heritability of the phenotype in CD and the influence on the phenotype of different genes associated with the disease. PATIENTS AND METHODS:: One hundred and seven families with at least 2 siblings with CD were collected. The patients were grouped in symptom grades on the basis of the clinical presentation, the age at diagnosis, and sex. Stratification analyses of the human leucocyte antigen-DQA1 and human leucocyte antigen-DQB1 genotypes, the CTLA4 +49A/G polymorphism, the CTLA4 haplotype MH30*G:-1147*T:+49*A:CT60*G:CT61*A and the 5q31-33 loci were done. RESULTS:: The heritability of the phenotype was estimated to be 0.45. Significant association and linkage was found between the clinical presentation and the CTLA4 +49A/G polymorphism but not for the other genotypes. No correlation was found between genotypes and age at diagnosis or sex. CONCLUSIONS:: Our results indicate that the heritability is determiner of the phenotype in CD. The CTLA4 +49A/G polymorphism is correlated to the clinical presentation: the AA genotype is associated with clinically silent disease.
|
|
| 10. |
- Gudjonsdottir, Audur, 1959
(författare)
-
Clinical and genetical aspects of Celiac Disease
- 2008
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Celiac disease (CD), or gluten-sensitive enteropathy, is one of the most common chronic diseases in childhood but is diagnosed in all ages. CD is a genetically driven immunological intolerance to dietary gluten. Th e treatment is a gluten-free diet. Th e diagnostic criteria are the ESPGHAN criteria, which include the histological characteristics of villous atrophy, crypt hyperplasia and increased number of intraepithelial lymphocytes (IEL). Th e clinical manifestations in CD range from severely aff ected young children to children and adults with milder symptoms as well as patients with silent CD. Th ere is a strong heredity in CD with the well-known HLA components DQ2 and DQ8. Th e genetics in CD are believed to confer up to 40% HLA genetics and otherwise non-HLA genetics. Th e knowledge of the genotype-phenotype association in CD is limited. Th e aim of this study has been to estimate the risk of a third sibling being aff ected in CD sib-pair families, identify the chromosomal region containing susceptibility genes in CD and study the genotype-phenotype association in CD. Material was collected from 107 families with at least two aff ected siblings, making a total of 224 CD siblings, as well as their healthy siblings and parents. Screening for CD was performed in these apparently healthy members and the estimated risk for CD in the third sibling and parent was then calculated. Th irteen new CD cases were diagnosed, six siblings and seven parents. Th e estimated sibling risk was 26.3% and the parent risk was 12.9%. Th e risk of a sibling of two aff ected siblings having CD was approximately three times higher compared to siblings of one aff ected sibling. Considering the high level of knowledge of CD in these families, the number of undiagnosed cases was surprisingly high. We suggested that serological screening should be off ered all fi rst-degree relatives of CD patients. Genome-wide linkage scan was performed in the same material. Th is work showed signifi cant evidence of linkage to CD with an interesting region on chromosome 5q31-33 and on chromosome 11q. Simplex CD family material was collected for further genetic association studies. Th e phenotype-genotype association was examined in two studies. An investigation was made of a possible interaction between the phenotypes and HLA class II risk alleles, the CTLA4 +49 A/G polymorphism, the haplotype MH30*G:-1147*T:+49*A:CT60*G:CT61*A and the 5q31-33 locus, in CD. Th e patients were grouped according to symptoms at presentation, the age at diagnosis and gender. Th e heritability of the phenotype was estimated to be 0.45. Th e AA genotype at the CTLA4 +49A/G polymorphism was associated with clinically silent disease. No other correlations were found between genotypes and clinical presentation, age at diagnosis or gender. A genotype-phenotype analysis was made of phenotypes in DQ2-negative CD patients in the largest DQ2-negative CD group that has been published compared to DQ2-positive CD controls in a European population. Th e fi nding was that the clinical presentation diff ered signifi cantly between DQ2-negative and DQ2-positive CD patients in Italy and Sweden. In both samples there was an association between DQ2-negative cases and classic symptoms. In the Italian sample there was also an association between silent grade and DQ2-negative cases. Autoimmune disease was signifi cantly overrepresented in DQ8-positive patients. Th is thesis shows that the risk for third sibling and parents is, as expected, increased in sib-pair families, as the expected risk of being aff ected in polygenic diseases is higher in families with multiple cases compared to single-case families. Th e genome scan indicated signifi cant linkage to 11q and 5q, which makes these regions interesting for further fi ne mapping of these regions using association analysis. Genotype-phenotype analysis of both HLA and non-HLA locus showed some signifi cant correlation between silent CD and both CTLA4 +49 AA genotype and the DQ2-negatives. In addition, an association was shown between classic symptom grade and DQ2-negative cases.
|
|
