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Association of IL23R, TNFRSF1A, and HLA-DRB1*0103 allele variants with inflammatory bowel disease phenotypes in the Finnish population.

https://arctichealth.org/en/permalink/ahliterature158286
Source
Inflamm Bowel Dis. 2008 Aug;14(8):1118-24
Publication Type
Article
Date
Aug-2008
Author
Maarit Lappalainen
Leena Halme
Ulla Turunen
Päivi Saavalainen
Elisabet Einarsdottir
Martti Färkkilä
Kimmo Kontula
Paulina Paavola-Sakki
Author Affiliation
Research Program for Molecular Medicine, Biomedicum Helsinki, Finland.
Source
Inflamm Bowel Dis. 2008 Aug;14(8):1118-24
Date
Aug-2008
Language
English
Publication Type
Article
Keywords
Colitis, Ulcerative - genetics
Crohn Disease - genetics
Female
Finland
Genetic markers
Genetic Predisposition to Disease
HLA-DR Antigens - genetics
HLA-DRB1 Chains
Humans
Inflammatory Bowel Diseases - genetics
Male
Phenotype
Polymorphism, Single Nucleotide
Receptors, Interleukin - genetics
Receptors, Tumor Necrosis Factor, Type I - genetics
Toll-Like Receptor 4 - genetics
Abstract
Crohn's disease (CD) and ulcerative colitis (UC), 2 major forms of inflammatory bowel disease (IBD), are complex disorders with significant genetic predisposition. The first CD-associated gene, CARD15/NOD2, was recently identified and since then several reports on novel IBD candidate genes have emerged. We investigated disease phenotype association to genetic variations in IL23R, ATG16L1, DLG5, ABCB1/MDR1, TLR4, TNFRSF1A, chromosome 5 risk haplotype including SLC22A4 and SLC22A5, and HLA-DRB1*0103 allele among Finnish IBD patients.
A total of 699 IBD patients were genotyped for disease-associated variants by polymerase chain reaction (PCR) and restriction enzyme digestion or Sequenom iPLEX method.
Five markers spanning the IL23R gene were associated with CD. The SNP (single nucleotide polymorphism) rs2201841 gave the strongest association (P = 0.002). The rare HLA-DRB1*0103 allele was found to associate with UC (P = 0.008), and the TNFRSF1A A36G variant was associated with familial UC (P = 0.007). Upon phenotypic analysis we detected association between familial UC and rare TNFRSF1A alleles 36G and IVS6+10G (P = 0.001 and P = 0.042, respectively). In addition, IL23R markers were associated with stricturing CD (P = 0.010-0.017), and ileocolonic CD was more prevalent in the carriers of the same 2 TNFRSF1A variants (P = 0.021 and P = 0.028, respectively). Less significant genotype-phenotype associations were observed for the TLR4 and HLA variants.
We were able to replicate the association of the IL23R variants with CD as well as HLA-DRB1*0103 with UC; confirmation of TNFRSF1A association with UC needs additional studies. Our findings also suggest that polymorphisms at IL23R and TNFRSF1A, and possibly HLA and TLR4, loci may account for phenotypic variation in IBD.
PubMed ID
18338763 View in PubMed
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Genome-wide search in Finnish families with inflammatory bowel disease provides evidence for novel susceptibility loci.

https://arctichealth.org/en/permalink/ahliterature186275
Source
Eur J Hum Genet. 2003 Feb;11(2):112-20
Publication Type
Article
Date
Feb-2003
Author
Paulina Paavola-Sakki
Vesa Ollikainen
Tiina Heliö
Leena Halme
Ulla Turunen
Päivi Lahermo
Maarit Lappalainen
Martti Färkkilä
Kimmo Kontula
Author Affiliation
Department of Medicine, University of Helsinki, Helsinki, Finland.
Source
Eur J Hum Genet. 2003 Feb;11(2):112-20
Date
Feb-2003
Language
English
Publication Type
Article
Keywords
Female
Finland
Genetic Linkage
Genetic Predisposition to Disease
Genome, Human
Humans
Inflammatory Bowel Diseases - genetics
Lod Score
Male
Microsatellite Repeats
Abstract
Epidemiological and genetic linkage studies have indicated a strong genetic basis for development of inflammatory bowel disease (IBD) which was recently supported by discovery of the Crohn's disease (CD) susceptibility gene termed NOD2/CARD15. We carried out a genome-wide linkage study in Finnish IBD families, providing a particular advantage to map susceptibility genes for ulcerative colitis (UC) within a genetic isolate. Initially, 92 IBD families with 138 affected sib-pairs (ASPs), were genotyped for 429 markers spaced at approximately 10 cM intervals. Next, the loci on chromosomes 2p13-11, 11p12-q13, and 12p13-12 were high-density mapped in the extended family cohort of 130 families with 173 ASPs. In this study, the most significant lod scores were observed for the UC families on chromosome 2p11 (D2S2333), in the vicinity of the REG gene cluster which is strikingly overexpressed in the IBD mucosa. The maximum two-point lod score was 3.34 (dominant model), and the corresponding NPL score 2.61. For UC, the second highest two-point NPL score of 2.00 was observed at proximal 12p13, where also some evidence for linkage disequilibrium emerged (P=0.07 and P=0.007 for the basic and extended IBD cohorts, respectively). The highest two-point NPL score for the CD families was 2.34 at D12S78 (12q23) with significant evidence for linkage disequilibrium (P=0.004), and for the mixed (MX) families 2.07 at D4S406 near the linkage peak reported previously. This study confirmed several of the IBD loci that have previously been reported and gives evidence for new IBD loci on chromosomes 2p11, 11p12-q13, 12p13-12, 12q23, and 19q13.
PubMed ID
12634858 View in PubMed
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IL23R in the Swedish, Finnish, Hungarian and Italian populations: association with IBD and psoriasis, and linkage to celiac disease.

https://arctichealth.org/en/permalink/ahliterature152922
Source
BMC Med Genet. 2009;10:8
Publication Type
Article
Date
2009
Author
Elisabet Einarsdottir
Lotta L E Koskinen
Emma Dukes
Kati Kainu
Sari Suomela
Maarit Lappalainen
Fabiana Ziberna
Ilma R Korponay-Szabo
Kalle Kurppa
Katri Kaukinen
Róza Adány
Zsuzsa Pocsai
György Széles
Martti Färkkilä
Ulla Turunen
Leena Halme
Paulina Paavola-Sakki
Tarcisio Not
Serena Vatta
Alessandro Ventura
Robert Löfberg
Leif Torkvist
Francesca Bresso
Jonas Halfvarson
Markku Mäki
Kimmo Kontula
Ulpu Saarialho-Kere
Juha Kere
Mauro D'Amato
Päivi Saavalainen
Author Affiliation
Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland. elisabet.einarsdottir@helsinki.fi
Source
BMC Med Genet. 2009;10:8
Date
2009
Language
English
Publication Type
Article
Keywords
Case-Control Studies
Celiac Disease - complications - genetics
Colitis, Ulcerative - complications - genetics
Crohn Disease - complications - genetics
Finland
Genetic markers
Genetic Predisposition to Disease
Genotype
Haplotypes
Humans
Hungary
Italy
Linkage Disequilibrium
Psoriasis - complications - genetics
Receptors, Interleukin - genetics
Sweden
Abstract
Association of the interleukin-23 receptor (IL23R) with inflammatory bowel disease (IBD) has been confirmed in several populations. IL23R also associates with psoriasis, suggesting that the gene may be an important candidate for many chronic inflammatory diseases.
We studied association of single-nucleotide variants in IL23R with IBD in Swedish patients, in both Crohn's disease (CD) and ulcerative colitis (UC) subsets. The same genetic variants were also studied in Finnish patients with psoriasis or celiac disease, and in Hungarian and Italian patients with celiac disease.
Association of IL23R with IBD was replicated in our Swedish patients, and linkage and association of the IL23R region with psoriasis was found in the Finnish population. The IL23R region was also linked to celiac disease in Finnish families, but no association of IL23R variants with celiac disease was found in the Finnish, Hungarian or Italian samples.
Our study is the first to demonstrate association of IL23R with CD and UC in Swedish patients with IBD. It is also the first study to report linkage and association of the IL23R region with psoriasis in the Finnish population. Importantly, this is the first report of linkage of the IL23R region to celiac disease, a chronic inflammatory condition in which IL23R has not been previously implicated.
Notes
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PubMed ID
19175939 View in PubMed
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Novel CARD15/NOD2 mutations in Finnish patients with Crohn's disease and their relation to phenotypic variation in vitro and in vivo.

https://arctichealth.org/en/permalink/ahliterature160792
Source
Inflamm Bowel Dis. 2008 Feb;14(2):176-85
Publication Type
Article
Date
Feb-2008
Author
Maarit Lappalainen
Paulina Paavola-Sakki
Leena Halme
Ulla Turunen
Martti Färkkilä
Heikki Repo
Kimmo Kontula
Author Affiliation
Research Program for Molecular Medicine, Biomedicum Helsinki, Finland.
Source
Inflamm Bowel Dis. 2008 Feb;14(2):176-85
Date
Feb-2008
Language
English
Publication Type
Article
Keywords
Case-Control Studies
Crohn Disease - epidemiology - genetics
European Continental Ancestry Group - genetics
Female
Finland - epidemiology
Founder Effect
Genetic Predisposition to Disease - epidemiology - genetics
Humans
Interleukin-8 - blood
Male
Middle Aged
Mutation
Nod2 Signaling Adaptor Protein - genetics
Phenotype
Abstract
Three mutations (R702W, G908R, and 1007fs) of the CARD15/NOD2 gene associate with Crohn's disease (CD). Despite a strong linkage of CD to the inflammatory bowel disease (IBD) 1 region, only 16% of the Finnish CD patients carry 1 of these 3 mutations, pointing to the possibility of yet undetected founder mutations in the genetically isolated Finns. The aim of this study was to screen for CARD15 mutations in Finnish CD patients and to assess their functional consequences and relation to clinical phenotype.
We performed CARD15 mutation screening in 240 CD probands. For functional studies, blood mononuclear cells were cultured alone or with muramyl dipeptide (MDP) and IL-8 levels were determined.
We identified 30 different variants, including 12 new ones. Allele frequencies for the R702W, G908R, and 1007fs mutations were 3.3%, 0.4%, and 4.8%, respectively. The 1007fs variant was the only 1 associated significantly with CD. Five novel variants (R38M, W355X, P727L, W907R, R1019X) were found in 5 patients. The biochemical nature of these new mutations, data obtained by cross-species comparisons, as well as low IL-8 production favors their pathogenic role. All 5 patients with novel mutations presented a complicated form of ileal or ileocolonic disease.
In conclusion, we identified 5 novel CARD15 mutations with an apparent pathophysiological role, but could not identify a putative Finnish founder mutation. It is still possible that regulatory mutations present in the flanking or intronic areas of the CARD15 gene contribute to the genetic susceptibility of CD. Homozygosity or compound heterozygosity for CARD15 gene mutations must be considered especially in complicated CD patients.
PubMed ID
17941079 View in PubMed
Less detail

PepT1 oligopeptide transporter (SLC15A1) gene polymorphism in inflammatory bowel disease.

https://arctichealth.org/en/permalink/ahliterature150812
Source
Inflamm Bowel Dis. 2009 Oct;15(10):1562-9
Publication Type
Article
Date
Oct-2009
Author
Marco Zucchelli
Leif Torkvist
Francesca Bresso
Jonas Halfvarson
Anna Hellquist
Francesca Anedda
Ghazaleh Assadi
Gunnar B Lindgren
Monika Svanfeldt
Martin Janson
Colin L Noble
Sven Pettersson
Maarit Lappalainen
Paulina Paavola-Sakki
Leena Halme
Martti Färkkilä
Ulla Turunen
Jack Satsangi
Kimmo Kontula
Robert Löfberg
Juha Kere
Mauro D'Amato
Author Affiliation
Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
Source
Inflamm Bowel Dis. 2009 Oct;15(10):1562-9
Date
Oct-2009
Language
English
Publication Type
Article
Keywords
Adult
Case-Control Studies
Cohort Studies
Colitis, Ulcerative - genetics
Crohn Disease - genetics
Female
Finland
Genotype
Humans
Male
Middle Aged
NF-kappa B - genetics - metabolism
Nod2 Signaling Adaptor Protein - genetics - metabolism
Polymorphism, Single Nucleotide - genetics
Sweden
Symporters - genetics
Abstract
Human polymorphisms affecting gut epithelial barrier and interactions with bacteria predispose to the inflammatory bowel diseases (IBD) Crohn's disease (CD) and ulcerative colitis (UC). The intestinal transporter PepT1, encoded by the SLC15A1 gene, mediates intracellular uptake of bacterial products that can induce inflammation and NF-kappaB activation upon binding to NOD2, a protein often mutated in CD. Hence, we tested SLC15A1 polymorphisms for association with IBD.
Twelve SLC15A1 single nucleotide polymorphisms (SNPs) were genotyped in 1783 individuals from 2 cohorts of Swedish and Finnish IBD patients and controls. An in vitro system was set up to evaluate the potential impact of SLC15A1 polymorphism on PepT1 transporter function by quantification of NOD2-mediated activation of NF-kappaB.
The common allele (C) of a coding polymorphism (rs2297322, Ser117Asn) was associated with CD susceptibility both in Sweden and in Finland, but with genetic effects in opposite directions (risk and protection, respectively). The best evidence of association was found in both populations when the analysis was performed on individuals not carrying NOD2 common risk alleles (Sweden allelic P = 0.0007, OR 1.97, 95% confidence interval [CI] 1.34-2.92; Finland genotype P = 0.0013, OR 0.63, 95% CI 0.44-0.90). The PepT1 variant encoded by the C allele (PepT1-Ser117) was associated with reduced signaling downstream of NOD2 (P
PubMed ID
19462432 View in PubMed
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Polycystic liver disease is genetically heterogeneous: clinical and linkage studies in eight Finnish families.

https://arctichealth.org/en/permalink/ahliterature187367
Source
J Hepatol. 2003 Jan;38(1):39-43
Publication Type
Article
Date
Jan-2003
Author
Pia Tahvanainen
Esa Tahvanainen
Hanna Reijonen
Leena Halme
Helena Kääriäinen
Krister Höckerstedt
Author Affiliation
Department of Human Molecular Genetics, National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, Finland.
Source
J Hepatol. 2003 Jan;38(1):39-43
Date
Jan-2003
Language
English
Publication Type
Article
Keywords
Adult
Chromosome Mapping
Chromosomes, Human, Pair 19 - genetics
Cysts - genetics - physiopathology - surgery - ultrasonography
Decompression, Surgical
Female
Finland
Genetic Linkage
Genetic Variation
Humans
Liver Diseases - genetics - physiopathology - surgery - ultrasonography
Male
Pedigree
Severity of Illness Index
Abstract
Polycystic liver disease (PCLD), a dominantly inherited condition separate from polycystic kidney disease (PKD), has recently been found to be linked to a locus on chromosome 19p13.2-13.1 in two North American families. Our aim was to study whether there is clinical or genetic heterogeneity within PCLD families.
We collected clinical data of eight Finnish PCLD families and performed both linkage analysis and an extended admixture test. We used genetic markers located on chromosome 19p13.2-13.1 and, in addition, on the three known PKD loci on chromosomes 4q21-q23 (PKD2), 6p21 (ARPKD) and 16p13.3-p13.12 (PKD1).
There were a total of 33 PCLD patients among which the severity of the disease varied greatly even within families. Seven patients had disabling symptoms requiring cyst decompression while ten patients were found only when the symptomless family members were studied by abdominal ultrasound. When genetic homogeneity was assumed, the PCLD locus on chromosome 19p13.2-13.1 was excluded but when genetic heterogeneity was allowed, five families out of seven showed linkage to that locus. All three PKD loci were excluded.
Most Finnish PCLD families are linked to chromosome 19p13.2-13.1 but there exists also a second PCLD locus yet to be found.
PubMed ID
12480558 View in PubMed
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7 records – page 1 of 1.