Browsing by Subject "HLA"
Now showing items 1-4 of 4
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(2016)Aims/hypothesis To characterise rapid progressors to type 1 diabetes among children recruited from the general population based on HLA-conferred disease susceptibility. Methods We observed 7410 HLA-predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study from birth for development of beta cell autoimmunity and type 1 diabetes over a median follow-up time of 16.2 (range 0.9-21.1) years. Islet cell antibodies, and autoantibodies to insulin (IAA), GAD (GADA), and islet antigen 2 (IA-2A) were analysed as markers of beta cell autoimmunity. Rapid progression was defined as progression to clinical type 1 diabetes within 1.5 years after autoantibody seroconversion. We analysed the association between rapid progression and demographic and autoantibody characteristics as well as genetic markers including 25 non-HLA single nucleotide polymorphisms (SNPs) predisposing to type 1 diabetes. Results Altogether 1645 children (22%) tested positive for at least one diabetes-associated autoantibody, and 248 (15%) of the seroconverters progressed to type 1 diabetes by the end of 2015. The median time from seroconversion to diagnosis was 0.51 years in rapid progressors (n=42, 17%), and 5.4 years in slower progressors. Rapid progression was observed both among young and early pubertal children. Compared to slower progressors, rapid progressors had higher frequency of multipositivity, higher titres of ICA, IAA, and IA-2A at seroconversion, and higher prevalence of the secretor genotype in the FUT2 gene. Compared to autoantibody-positive non-progressors, rapid progressors were younger, carried more often the high-risk HLA genotype, the FUT2 secretor genotype, and a predisposing SNP in the PTPN22 gene, had higher frequency of ICA, IAA, GADA, IA-2A, and multipositivity, and higher titres of all four autoantibodies at seroconversion. Conclusions At seroconversion, individuals with rapid progression to type 1 diabetes are characterised by young age, higher autoantibody titres, positivity for multiple autoantibodies, and higher prevalence of a FUT2 SNP. The double-peak profile of seroconversion age among the rapid progressors demonstrates for the first time that rapid progression may take place not only in young children, but also in children in early puberty. Rapid progressors might benefit from careful clinical follow-up and early preventive measures.
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(2021)Henoch-Schölein purpura (HSP) is a vasculitis of small vessels and its characteristics include abnormal accumulation of IgA immunocomplexes on vessel walls as well as abnormal glycosylation patterns of IgA. HSP is an autoimmune disease like inflammatory bowel diseases (IBD). The genetic background of HSP has not been studied in Finnish population before, and only one genome-wide association study has been conducted for HSP before. Therefore investigating the Finnish genetic associations of HSP on a genome-wide level is of value. In this study the genetic background of HSP is studied with genome-wide association analyses performed on 424,041 genotyped SNPs passing quality control, HLA alleles imputed from the SNPs, and for their allele-level HLA protein sequences with the aim of replicating previous HSP associations in a Finnish cohort. There were 46 HSP individuals and 18,757 controls (216 bone marrow donors and 18,541 blood donors) passing quality control and included in the study. R package HIBAG was used for HLA imputation, and SPAtest package was used for the association analyses. In the association analyses, a region in chromosome 6 passed genome-wide significance (SNP with the smallest p-value: p 6,57 x 10-10, OR 0.14[0.1-0.2]) and the region contained both predisposing and protective associations. Of HLA alleles, DQB1*05:01, DQA1*01:01 ja DRB1*01:01 surpassed genome-wide significance level (p values 4,99 x 10-9, 1,04 x 10-8 and 2,37 x 10-8, respectively) and were positively associated with HSP. Five amino acid positions were significantly associated with HSP (p-values 3,9 x 10-10, 7,37 x 10-9, 1,26 x 10-8, 1,69 x 10-8 and 2,41 x 10-8), being both protective and predisposing to HSP. In addition, the genetic background of HSP was compared with that of IBD by comparing their GWAS results of genotyped SNPs, HLA alleles and their protein sequences. There were 49 IBD patients after quality control, and the same controls as for HSP (18,541 individuals) were included in the association analyses of IBD. The diseases seem to share some of their genetic background. According to the results, HSP seems to associate primarily with HLA class 2 and the result is also compatible with previous studies linking HSP to this region. The results also replicate previous GWAS findings in HLA class 2. According to this it is likely that the same HLA alleles are notable genetic factors in both Finnish and Spanish populations. The connection between HSP and IBD could potentially have to do with intestinal microbes aiding the onset of autoimmune diseases in genetically susceptible hosts.
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(2020)Tiivistelmä – Referat – Abstract Celiac disease (CD) is a serious lifelong condition, in which the immune system attacks an individual’s own tissue when eating gluten. This leads to inflammation and damage to the small intestine. Celiac disease often goes undiagnosed because many of its symptoms are nonspecific. The prevalence of combined undiagnosed and diagnosed CD is estimated to affect 1 in 100 people throughout Europe and USA. CD is a polygenic disease, it is known that the human leukocyte antigen (HLA) system plays a crucial role. HLA-DQ2/DQ8 risk allele genotyping screening test from a whole blood sample (B -HLAKeli) is routinely used to estimate the genetic risk of a patient having CD. HLA genotyping test result is routinely used to rule out celiac disease rather than confirming it; if an individual does not have celiac disease related risk alleles, it is very unlikely that he or she has celiac disease. The Celiac disease diagnosis decision making process is based on the classic triple combination of serological antibody tests, the HLA-DQ2/DQ8 genotyping test and duodenal biopsies. The aim of this master’s thesis was to study evaluate how the two different risk classification praxis for HLA-DQx.5 allele used for celiac disease diagnostics in SYNLAB Finland and Estonia central laboratory and in SYNLAB Suomi central laboratory might influence the clinical process and final diagnosis. In SYNLAB Suomi central laboratory HLA-DQx.5 is classified and interpreted as a risk allele predisposing to celiac disease. In SYNLAB Finland and Estonia central laboratory this allele is classified as CD-non-risk-allele based on recommendations in international guideline. In addition, the aim was to get a general understanding of celiac disease prevalence and risk allele distributions among the study population. From the study population of 196 celiac disease suspect patients, 9% had a celiac disease positive laboratory result and the HLA risk genotype distribution among positive cases was well aligned with the expected values described in the literature. Study results indicated that there’s no additional clinical value if HLA-DQx.5 is classified as a celiac disease predisposing risk allele; the study data implies that it is very unlikely to find celiac disease positive cases from laboratory test perspective among HLA-DQx.5 carriers. Based on the study, approximately 7% of the celiac disease suspects carry the allele HLA-DQx.5 and therefore probably go through additional celiac disease related laboratory testing if this allele is interpreted as a risk allele. According to the study findings and general recommendations based on international guideline of celiac disease diagnosis, it seems that there is no clear clinical benefit if HLA-DQx.5 is classified as a CD risk allele.
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(2020)Tiivistelmä – Referat – Abstract Celiac disease (CD) is a serious lifelong condition, in which the immune system attacks an individual’s own tissue when eating gluten. This leads to inflammation and damage to the small intestine. Celiac disease often goes undiagnosed because many of its symptoms are nonspecific. The prevalence of combined undiagnosed and diagnosed CD is estimated to affect 1 in 100 people throughout Europe and USA. CD is a polygenic disease, it is known that the human leukocyte antigen (HLA) system plays a crucial role. HLA-DQ2/DQ8 risk allele genotyping screening test from a whole blood sample (B -HLAKeli) is routinely used to estimate the genetic risk of a patient having CD. HLA genotyping test result is routinely used to rule out celiac disease rather than confirming it; if an individual does not have celiac disease related risk alleles, it is very unlikely that he or she has celiac disease. The Celiac disease diagnosis decision making process is based on the classic triple combination of serological antibody tests, the HLA-DQ2/DQ8 genotyping test and duodenal biopsies. The aim of this master’s thesis was to study evaluate how the two different risk classification praxis for HLA-DQx.5 allele used for celiac disease diagnostics in SYNLAB Finland and Estonia central laboratory and in SYNLAB Suomi central laboratory might influence the clinical process and final diagnosis. In SYNLAB Suomi central laboratory HLA-DQx.5 is classified and interpreted as a risk allele predisposing to celiac disease. In SYNLAB Finland and Estonia central laboratory this allele is classified as CD-non-risk-allele based on recommendations in international guideline. In addition, the aim was to get a general understanding of celiac disease prevalence and risk allele distributions among the study population. From the study population of 196 celiac disease suspect patients, 9% had a celiac disease positive laboratory result and the HLA risk genotype distribution among positive cases was well aligned with the expected values described in the literature. Study results indicated that there’s no additional clinical value if HLA-DQx.5 is classified as a celiac disease predisposing risk allele; the study data implies that it is very unlikely to find celiac disease positive cases from laboratory test perspective among HLA-DQx.5 carriers. Based on the study, approximately 7% of the celiac disease suspects carry the allele HLA-DQx.5 and therefore probably go through additional celiac disease related laboratory testing if this allele is interpreted as a risk allele. According to the study findings and general recommendations based on international guideline of celiac disease diagnosis, it seems that there is no clear clinical benefit if HLA-DQx.5 is classified as a CD risk allele.
Now showing items 1-4 of 4