K Mustalahti

University of Tampere, Tammerfors, Province of Western Finland, Finland

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Publications (37)234.85 Total impact

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    ABSTRACT: Coeliac disease is a chronic inflammatory condition of the small intestine, triggered by dietary exposure to gluten in genetically susceptible individuals. Risk alleles at HLA-DQA1 and HLA-DQB1 are necessary for disease development, but are alone not sufficient for disease onset. We aimed to identify novel loci underlying susceptibility to coeliac disease through the use of extended Finnish and Hungarian families with multiple affected individuals. An initial whole-genome linkage approach yielded several loci that were followed up further using the Immunochip custom array. Loci with a parametric logarithm of odds (LOD) score of >1.3 were identified at 4q, 6p [human leukocyte antigen (HLA) region], 6q, 7p, 17p, 17q and at 22p. The 4q and 6q loci have been identified previously in coeliac disease risk, whereas follow-up analyses indicate that the 17p and 22p loci may be novel risk loci for coeliac disease. These loci harbour previously described risk variants for other autoimmune diseases, but their segregation patterns do not explain the linkage to coeliac disease. We followed up the linkage to the 4q region, containing the previously described interleukin (IL)2 and IL21 genes. The risk variants at 4q in the studied pedigrees are most likely distinct from previously described risk variants, indicating that the observed linkage may be due to rare high-risk variants of still unknown nature. The importance of this locus to coeliac disease risk was further shown by the finding that serum levels of IL21 were elevated in both untreated and treated coeliac patients compared to controls.
    Tissue Antigens 12/2011; 78(6):428-37. · 2.35 Impact Factor
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    ABSTRACT: Although the prevalence of celiac disease (CD) has been extensively investigated in recent years, an accurate estimate of CD frequency in the European population is still lacking. The aims of this study were: 1) to establish accurately the prevalence of CD in a large sample of the European population (Finland, Germany, Italy, and UK), including both children and adults; and 2) to investigate whether the prevalence of CD significantly varies between different areas of the European continent. Samples were drawn from the four populations. All 29,212 participants were tested for CD by tissue transglutaminase (tTG) antibody test. Positive and border-line findings were further tested for serum endomysial antibodies (EMA). All serological determinations were centrally performed. Small-bowel biopsies were recommended to autoantibody-positive individuals. Previously diagnosed cases were identified. The overall CD prevalence (previously diagnosed plus anti-tTG and EMA positives) was 1.0% (95% CI 0.9-1.1). In subjects aged 30-64 years CD prevalence was 2.4% in Finland (2.0-2.8), 0.3% in Germany (0.1-0.4), and 0.7% in Italy (0.4-1.0). Sixty-eight percent of antibody-positive individuals showed small-bowel mucosal changes typical for CD (Marsh II/III lesion). CD is common in Europe. CD prevalence shows large unexplained differences in adult age across different European countries.
    Annals of Medicine 12/2010; 42(8):587-95. · 4.73 Impact Factor
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    ABSTRACT: Human leukocyte antigen (HLA) genes, located on chromosome 6p21.3, have a crucial role in susceptibility to various autoimmune and inflammatory diseases, such as celiac disease and type 1 diabetes. Certain HLA heterodimers, namely DQ2 (encoded by the DQA1*05 and DQB1*02 alleles) and DQ8 (DQA1*03 and DQB1*0302), are necessary for the development of celiac disease. Traditional genotyping of HLA genes is laborious, time-consuming, and expensive. A novel HLA-genotyping method, using six HLA-tagging single-nucleotide polymorphisms (SNPs) and suitable for high-throughput approaches, was described recently. Our aim was to validate this method in the Finnish, Hungarian, and Italian populations. The six previously reported HLA-tagging SNPs were genotyped in patients with celiac disease and in healthy individuals from Finland, Hungary, and two distinct regions of Italy. The potential of this method was evaluated in analyzing how well the tag SNP results correlate with the HLA genotypes previously determined using traditional HLA-typing methods. Using the tagging SNP method, it is possible to determine the celiac disease risk haplotypes accurately in Finnish, Hungarian, and Italian populations, with specificity and sensitivity ranging from 95% to 100%. In addition, it predicts homozygosity and heterozygosity for a risk haplotype, allowing studies on genotypic risk effects. The method is transferable between populations and therefore suited for large-scale research studies and screening of celiac disease among high-risk individuals or at the population level.
    Immunogenetics 05/2009; 61(4):247-56. · 2.49 Impact Factor
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    ABSTRACT: Coeliac disease is caused by dietary gluten, which triggers chronic inflammation of the small intestine in genetically predisposed individuals. In one quarter of the patients the disease manifests in the skin as dermatitis herpetiformis. Recently, a novel candidate gene, myosin IXB on chromosome 19p13, was shown to be associated with coeliac disease in the Dutch and Spanish populations. The same gene has previously been associated with inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis risk, making myosin IXB a potential shared risk factor in these inflammatory disorders. In this study, previously reported myosin IXB variants were tested for genetic linkage and association with coeliac disease in 495 Hungarian and Finnish families and in an additional 270 patients and controls. Results and The results show significant linkage (logarithm of odds (LOD) 3.76, p = 0.00002) to 19p13 which supports the presence of a genuine risk factor for coeliac disease in this locus. Myosin IXB variants were not associated with coeliac disease in this study; however, weak evidence of association with dermatitis herpetiformis was found. The association could not explain the strong linkage seen in both phenotypes, indicating that the role of other neighbouring genes in the region cannot be excluded. Therefore, more detailed genetic and functional studies are required to characterise the role of the myosin IXB gene in both coeliac disease and dermatitis herpetiformis.
    Journal of Medical Genetics 05/2008; 45(4):222-7. · 5.64 Impact Factor
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    ABSTRACT: The populations in adjacent Russian Karelia and Finland are equally exposed to grain products and share partly the same ancestry, but live in completely different socioeconomic environments. This creates an ideal epidemiological setting to study gene-environmental interactions in pathogenesis of celiac disease. The prevalence of celiac disease and predisposing human leukocyte antigen (HLA) alleles was compared between Russian Karelia and Finland. Tissue transglutaminase antibodies and HLA-DQ alleles were screened from 1988 schoolchildren from Karelia and 3654 children from Finland. Children with transglutaminase antibodies were invited to small-bowel biopsy. Results. Transglutaminase antibodies were less frequent in Russian Karelia than in Finland (0.6% versus 1.4%, P = 0.005). Immunoglobulin class G (IgG) antigliadin antibodies were also less frequent in Russian Karelia (10.2% versus 28.3%, P<0.0001). Celiac disease was confirmed by duodenal biopsy in four of the eight transglutaminase antibody-positive Karelian children, giving a prevalence of 1 in 496 compared to 1 in 107 children in Finland. The same HLA-DQ alleles were associated with celiac disease and transglutaminase antibody positivity in both populations. The prevalence of transglutaminase antibodies and celiac disease is lower in Russian Karelia than in Finland. This may be associated with a protective environment characterized by inferior prosperity and standard of hygiene in Karelia.
    Annals of Medicine 02/2008; 40(3):223-31. · 4.73 Impact Factor
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    ABSTRACT: The number of coeliac disease diagnoses has increased in the recent past and according to screening studies, the total prevalence of the disorder is around 1%. To establish whether the increased number of coeliac disease cases reflects a true rise in disease frequency. The total prevalence of coeliac disease was determined in two population-based samples representing the Finnish adult population in 1978-80 and 2000-01 and comprising 8000 and 8028 individuals, respectively. Both clinically-diagnosed coeliac disease patients and previously unrecognized cases identified by serum endomysial antibodies were taken into account. Only two (clinical prevalence of 0.03%) patients had been diagnosed on clinical grounds in 1978-80, in contrast to 32 (0.52%) in 2000-01. The prevalence of earlier unrecognized cases increased statistically significantly from 1.03% to 1.47% during the same period. This yields a total prevalence of coeliac disease of 1.05% in 1978-80 and 1.99% in 2000-01. The total prevalence of coeliac disease seems to have doubled in Finland during the last two decades, and the increase cannot be attributed to the better detection rate. The environmental factors responsible for the increasing prevalence of the disorder are issues for further studies.
    Alimentary Pharmacology & Therapeutics 12/2007; 26(9):1217-25. · 5.48 Impact Factor
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    K Mustalahti
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    ABSTRACT: Celiac disease is multifaced autoimmune disorder with several extraintestinal manifestations and connections to other autoimmune diseases and other conditions. The recognition of the complex clinical picture of the disease helps doctors to search and diagnose celiac disease even if the gastrointestinal symptoms are lacking. Individuals at risk for celiac disease should be thoroughly investigated and individuals with unusual manifestations of the disease should be screened actively.
    The Indian Journal of Pediatrics 09/2006; 73(8):711-6. · 0.72 Impact Factor
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    ABSTRACT: The exclusion of oats from the diet in coeliac disease is controversial. To study the long-term safety of oats in the treatment of children with coeliac disease. Altogether 32 children with coeliac disease were enrolled in a 2-year controlled trial. Twenty-three children in remission were randomized either to oats or gluten challenge; when small bowel histological relapse was evident after gluten challenge, a gluten-free diet including oats was started. Furthermore, nine newly detected coeliac patients adopted an oat-containing gluten-free diet. Small bowel mucosal morphology, CD3+, alphabeta+ and gammadelta+ intraepithelial lymphocytes, human leucocyte antigen (HLA) DR expression and coeliac serology were determined. After the trial, the children were allowed to eat oats freely; follow-up was extended up to 7 years. In coeliac children in remission, oats had no detrimental effect on intestinal histology or serology during the 2-year trial. In contrast, the gluten-challenge group relapsed after 3-12 months. Complete recovery from the disease was accomplished in all relapsed and newly detected patients on an oat-containing gluten-free diet. After the trial, 86% of the children preferred to consume oats and they all remained in remission. In most children with coeliac disease, long-term consumption of oats is well tolerated, and it does not result in small bowel mucosal deterioration or immune activation.
    Alimentary Pharmacology & Therapeutics 06/2006; 23(10):1463-72. · 5.48 Impact Factor
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    ABSTRACT: There are only a few studies which have assessed the impact of asthma on the quality of life (QoL) compared to healthy children. In this study we wanted to compare QoL between asthmatic and healthy children in a population based setting. We surveyed 2159 children aged 11-15 yr with a Child Health Questionnaire; a generic QoL measure for children. This method gives a profile of the QoL consisting of 11 scales giving a range from 0 to 100. Asthma was defined based on the ISAAC questionnaire on asthma and asthma symptoms. In all, 192 children (8.9%) reported to have asthma diagnosed by a doctor and 61 of them (2.8% of all children) had been symptomatic during the previous month. Among these symptomatic children significantly impaired QoL was observed in 8 of the 11 scales compared to non-asthmatics. The most affected scales were those defining the physical part of child's QoL: Mean General Health scores were 60 for asthmatic and 74 for non-asthmatic children and mean Bodily Pain scores 71 and 86, respectively. Symptoms during longer periods were associated with an overall decreased QoL. In conclusion, a child's asthma impairs the QoL and especially the physical dimensions.
    Pediatric Allergy and Immunology 07/2005; 16(4):332-40. · 3.86 Impact Factor
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    N Woolley, K Mustalahti, M Mäki, J Partanen
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    ABSTRACT: Coeliac disease (CD) is an intestinal disorder caused by intolerance to dietary gluten in susceptible individuals. The HLA-DQ genes are major risk factors for CD, but other genes also play an important role in the disease susceptibility. Immune-mediated mechanisms are known to underlie the pathogenesis of CD. We studied single-nucleotide polymorphisms in transforming growth factor (TGF)-beta1, interleukin (IL)-10, IL-6, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha genes in the Finnish population using family-based association approach. In addition, we genotyped a trinucleotide repeat polymorphism in the major histocompatibility complex (MHC) class I chain-related protein A (MICA) gene, located in the human leucocyte antigen (HLA) region in the vicinity of TNF-alpha. To control the effect of linkage disequilibrium between HLA-DQ genes and MICA and TNF-alpha, an HLA-stratified association analysis was performed. We did not find evidence of association between TGF-beta1, IL-10, IL-6 and IFN-gamma polymorphisms and CD susceptibility. No association was found for any of the MICA alleles independently of DQ genes, whereas TNF-alpha-308 A allele was slightly overrepresented on chromosomes carried by CD patients compared with control chromosomes, indicating that either TNF-alpha, or another gene in linkage disequilibrium with it, could confer increased susceptibility to CD. This result supports the earlier findings that the HLA region harbours a novel susceptibility factor in addition to HLA-DQ.
    Scandinavian Journal of Immunology 02/2005; 61(1):51-6. · 1.88 Impact Factor
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    ABSTRACT: Oesophagitis and gastro-oesophageal reflux have been implicated recently in the manifestations of coeliac disease. The aim was to investigate this association in a primary-care setting. First, the prevalence of coeliac disease was calculated in 1198 adults with oesophagitis, in 2541 adults with reflux symptoms and in 200 adults suffering from dysphagia; 5459 patients with a history consistent with dyspepsia and 709 patients with a suspicion of coeliac disease served as controls. Second, the prevalence of oesophagitis was estimated in 382 untreated and 232 treated coeliac patients; controls here comprised 5404 patients with dyspeptic symptoms and 2525 patients with reflux symptoms. Third, oesophagitis and oesophageal reflux symptoms were investigated before and after a gluten-free diet was followed in 67 adults with coeliac disease. The diagnosis of coeliac disease was based on small-bowel histology; histological exclusion of the disease was unambiguous in all controls. Oesophagitis was identified by endoscopic inspection. Altogether, 0.9% of patients with oesophagitis and 0.6% of those with oesophageal reflux symptoms had coeliac disease. The corresponding percentages were 1.0% in patients with dyspepsia and 12% with suspicion of coeliac disease. The prevalence of oesophagitis was 5.2% in untreated coeliac disease, 5.6% in treated coeliac disease, 7.0% in patients with dyspepsia, and 27% in symptomatic reflux disease. In coeliac patients, the reflux symptoms were mild but nevertheless were alleviated on a gluten-free diet. This study does not support the conception that patients with reflux oesophagitis should be screened vigorously for coeliac disease. The association between these two conditions is, at most, weak, but a gluten-free diet may still bring symptomatic relief for reflux symptoms in coeliac disease.
    European Journal of Gastroenterology & Hepatology 10/2004; 16(9):917-20. · 2.15 Impact Factor
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    ABSTRACT: An interesting candidate gene region for coeliac disease (CD), a common multifactorial disease, is a segment on 2q33-37 harbouring the genes for the CD28, cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), inducible costimulator (ICOS), and programmed death-1 (PD-1), all receptors that regulate lymphocyte activation. Several studies have suggested a role for this locus in immune-mediated diseases. To study further our previous finding of genetic linkage of this region to CD, we studied 25 polymorphic markers to identify the putative disease-associated polymorphism. Transmission/disequilibrium test in 106 Finnish families with CD indicated that only four polymorphisms, all located in the ICOS gene, showed evidence for genetic association. Strong linkage disequilibrium (LD), based on the analysis of 424 haplotypes, encompassed not only the associated ICOS markers but also many polymorphisms in the CTLA4 gene. Our results demonstrate that due to LD, it appears not easy to identify the genuine susceptibility factor in this region without larger multipopulation studies. Furthermore, the results did not support the evidence that polymorphisms in CTLA4 were the major susceptibility locus for CD.
    Genes and Immunity 04/2004; 5(2):85-92. · 3.79 Impact Factor
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    ABSTRACT: Evidence suggests the acceptability of oats in a gluten-free diet in coeliac disease. We investigated the impact of an oats-containing diet on quality of life and gastrointestinal symptoms. Thirty-nine coeliac disease patients on a gluten-free diet were randomized to take either 50 g of oats-containing gluten-free products daily or to continue without oats for 1 year. Quality of life was assessed using the Psychological General Well-Being questionnaire and gastrointestinal symptoms using the Gastrointestinal Symptom Rating Scale. Small-bowel mucosal villous architecture, CD3+, alphabeta+, gammadelta+ intraepithelial lymphocytes, serum endomysial and tissue transglutaminase antibodies were investigated. Twenty-three subjects were randomized to the oats-containing diet and 16 to the traditional gluten-free diet. All adhered strictly to their respective diet. Quality of life did not differ between the groups. In general, there were more gastrointestinal symptoms in the oats-consuming group. Patients taking oats suffered significantly more often from diarrhoea, but there was a simultaneous trend towards a more severe average constipation symptom score. The villous structure did not differ between the groups, but the density of intraepithelial lymphocytes was slightly but significantly higher in the oats group. The severity of symptoms was not dependent on the degree of inflammation. Antibody levels did not increase during the study period. The oats-containing gluten-free diet caused more intestinal symptoms than the traditional diet. Mucosal integrity was not disturbed, but more inflammation was evident in the oats group. Oats provide an alternative in the gluten-free diet, but coeliac patients should be aware of the possible increase in intestinal symptoms.
    Scandinavian Journal of Gastroenterology 02/2004; 39(1):27-31. · 2.33 Impact Factor
  • Journal of Pediatric Gastroenterology and Nutrition 01/2004; 39. · 2.87 Impact Factor
  • The American Journal of Gastroenterology 01/2004; 98(12):2808-9. · 9.21 Impact Factor
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    ABSTRACT: Wheat, rye, and barley proteins induce celiac disease, an autoimmune type of gastrointestinal disorder, in genetically susceptible persons. Because the disease may be underdiagnosed, we estimated the prevalence of the disease and tested the hypothesis that assays for serum autoantibodies can be used to detect untreated celiac disease and that positive findings correlate with specific HLA haplotypes. Serum samples were collected from 3654 students (age range, 7 to 16 years) in 1994 and screened in 2001 for endomysial and tissue transglutaminase antibodies. HLA typing was also performed on stored blood samples. All antibody-positive subjects were asked to undergo small-bowel biopsy in 2001. Of the 3654 subjects, 56 (1.5 percent) had positive antibody tests, as determined in 2001. Results of the two antibody tests were highly concordant. As of 1994, none of the subjects had received a clinical diagnosis of celiac disease, but 10 who had positive tests for both antibodies in serum obtained in 1994 received the diagnosis between 1994 and 2001. Of the 36 other subjects with positive antibody assays who agreed to undergo biopsy in 2001, 27 had evidence of celiac disease on biopsy. Thus, the estimated biopsy-proved prevalence was 1 case in 99 children. All but two of the antibody-positive subjects had either the HLA-DQ2 or the HLA-DQ8 haplotype. The prevalence of the combination of antibody positivity and an HLA haplotype associated with celiac disease was 1 in 67. The presence of serum tissue transglutaminase and endomysial autoantibodies is predictive of small-bowel abnormalities indicative of celiac disease. There is a good correlation between autoantibody positivity and specific HLA haplotypes. We estimate that the prevalence of celiac disease among Finnish schoolchildren is at least 1 case in 99 children.
    New England Journal of Medicine 07/2003; 348(25):2517-24. · 54.42 Impact Factor
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    ABSTRACT: Although HLA-DQ genes are the major celiac disease (CD) susceptibility genes, results from Finnish families suggest that not all DQ2-encoding haplotypes confer equal susceptibility to CD, implying the effect of other gene(s) in the HLA region. The aim of the present work was to extend and confirm the aforementioned results in a southern European population ( Italian) and to better localize the additional risk factor/s. The association of nine loci spanning the HLA region from DR to HFE, 4.5-Mb telomeric of HLA-A, was tested. The analysis was performed by comparing marker frequencies in DR3-DQ2 haplotypes transmitted and non-transmitted to the affected offspring in 156 Italian CD families selected for having at least one DR3-positive parent. The same analysis was performed independently in 101 Finnish CD families selected with the same criteria. Three alleles, MICA-A5.1, MICB-CA24 and MIB-350, all characteristic of the B8-DR3 extended haplotype, showed a significantly increased frequency in DR3 transmitted haplotypes in the Italian families. DR3 haplotypes carrying the combination of these alleles conferred an approximate fourfold increased CD risk. B8-DR3 transmitted haplotypes were significantly more conserved telomerically down to the MIC-Class I region. Similar results were seen in the Finnish families. The major conclusion that holds true in both populations is that, while DQ2 is an absolute requirement for the development of CD, the presence of an additional genetic factor within the MIC-Class I region confers an approximate 4-fold increased risk of the disease.
    Tissue Antigens 05/2003; 61(4):308-16. · 2.35 Impact Factor
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    ABSTRACT: Coeliac disease has a large variation in clinical outcome. In addition to the classical disease with malabsorption, many individuals have a silent form, in which subject symptoms are missing but autoantibodies and mucosa lesions are identical to the symptomatic disease. To investigate whether differences in HLA DR-DQ genes explain the variation in outcome. HLA DQ alleles were determined in 28 multiplex families with sibling pairs in which one had the symptomatic disease but the other had the silent form. No differences in the distribution of HLA DR-DQ haplotypes could be observed. The clinically diagnosed coeliac disease seemed to have earlier onset than silent coeliac disease. Results indicate that the major genetic susceptibility locus, HLA DQ, does not determine the exact clinical outcome of coeliac disease.
    Digestive and Liver Disease 01/2003; 34(12):842-5. · 2.89 Impact Factor
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    ABSTRACT: Background. Coeliac disease has a large variation in clinical outcome. In addition to the classical disease with malabsorption, many individuals have a silent form, in which subjective symptoms are missing but autoantibodies and mucosa lesions are identical to the symptomatic disease.Aim. To investigate whether differences in HLA DR-DQ genes explain the variation in outcome.Materials and methods. HLA DQ alleles were determined in 28 multiplex families with sibling pairs in which one had the symptomatic disease but the other had the silent form.Results. No differences in the distribution of HLA DR-DQ haplotypes could be observed. The clinically diagnosed coeliac disease seemed to have earlier onset than silent coeliac disease.Conclusions. Results indicate that the major genetic susceptibility locus, HLA DO, does not determine the exact clinical outcome of coeliac disease.
    Digestive and Liver Disease 12/2002; · 2.89 Impact Factor
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    ABSTRACT: Gluten sensitive enteropathy has various manifestations, of which the two major forms are classical coeliac disease (cCD) and dermatitis herpetiformis (DH). In cCD predominantly the small intestine is affected, whereas in DH also the skin is affected showing typical rash and IgA deposits. The symptoms in both forms are dependent on gluten intake. The factors diversifying these two clinical outcomes are unknown. In the present report we evaluated the role of the major genetic susceptibility locus, HLA DQ, in 25 families, in which both forms of the disease, cCD and DH, occurred in siblings. By using the family-based approach it can be assumed that within each family variation in environmental factors is substantially lower than in the standard case-control setting, and also the problems related to population stratification can be avoided. Results from the Finnish family material with 25 discordant and 85 concordant sib pairs, and from additional case-control material comprising 71 unrelated Hungarian DH and 68 cCD patients, together indicated that the HLA DQ locus did not differ between the two major outcomes of gluten sensitive enteropathy. The non-HLA DR;DQ factors are critical for the different clinical manifestations of gluten sensitivity.
    Annals of Human Genetics 12/2002; 66(Pt 5-6):387-92. · 1.93 Impact Factor

Publication Stats

2k Citations
234.85 Total Impact Points

Institutions

  • 1999–2011
    • University of Tampere
      • • Medical School
      • • Paediatric Research Centre
      • • Institute of Medical Technology
      Tammerfors, Province of Western Finland, Finland
  • 2001–2005
    • Finnish Red Cross Blood Service
      Helsinki, Southern Finland Province, Finland
  • 2004
    • Tampere University Hospital (TAUH)
      Tammerfors, Province of Western Finland, Finland