The genetics of IgA deficiency : a ‛two-disease’ approach
Author: Wang, Ning
Date: 2014-01-17
Location: 9Q, Plan 9, Alfred Nobels allé 8, Karolinska Institutet, Huddinge
Time: 10.00
Department: Inst för laboratoriemedicin / Dept of Laboratory Medicine
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Thesis (1.358Mb)
Abstract
Selective IgA deficiency (IgAD) is the most common primary immunodeficiency disorder in Caucasians with a prevalence of approximately 1:600 in the general population. It is defined as serum IgA levels below or equal to 0.07 g/l with normal serum levels of IgM and IgG above the age of 4. Most IgAD individuals are asymptomatic, however, one-third suffer from respiratory and gastrointestinal infections and concomitant autoimmune diseases.
IgAD is associated with several classical autoimmune disorders including Graves’ disease (GD), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), celiac disease (CD) and potentially rheumatoid arthritis and myasthenia gravis (MG). As more than 95% of patients with GD are positive for thyrotropin-receptor autoantibody (TRAb), we thus investigated the prevalence of IgAD in TRAb-seropositive individuals both in Sweden and Iceland and showed that the prevalence of IgAD in the Swedish cohort is significantly higher than expected in the general population. TRAb- seropositivity is also common among IgAD individuals in both cohorts, suggesting a predisposition to GD (Paper I).
There is a markedly increased prevalence of IgAD among adults with CD. It is therefore important to validate the IgG class antibody tests for screening CD in IgAD adults. IgG anti tissue transglutaminase (anti-tTG) and anti deamidated gliadin peptides (anti-DGP) antibodies were determined in our IgAD cohort with suspected CD. IgG anti-tTG seems to be a reliable marker for CD in IgAD adults whereas the diagnostic specificity of IgG anti-DGP appears to be lower. We also found that high levels of IgG antibodies against both tTG and DGP were frequently found in IgAD adults despite adhering to a gluten free diet (Paper II). We subsequently screened IgAD among patients with SLE and T1D in different ethnical populations and the observed higher prevalence of IgAD was consistent with previous publications (Paper III).
IgAD is reported to be strongly associated with the MHC region, especially the HLA- A1, B8, DR3, DQ2 (8.1) haplotype, which is also associated with various autoimmune disorders, including GD, SLE, T1D, CD and MG. Non-MHC genes (such as IFIH1and CLEC16A) are also associated with the development of some of the above diseases as well as IgAD, indicative of a possible common genetic background (Paper III).
A high-density mapping of the HLA locus was then preformed in a combined sample of IgAD patients and matched controls from 3 independent European populations. A complex nature of the association of IgAD with the HLA locus was demonstrated. The primary association signal mapped to the HLA-DQB1*02 allele resulting from the combined independent effects of the HLA-B*0801-DRB1*0301-DQB1*0201 and DRB1*0701-DQB1*0202 haplotypes and secondary signals were associated with the DRB1*0102 and DRB1*1501 alleles. Of interest, a remarkable conservation within the HLA locus was found, regardless of ethnic background, which supports the use of large multi-ethnic populations to characterize the shared genetic association within this region. The location of association signals within several specific extended haplotypes was potentially identified, including the 8.1 haplotype in the interval between the HLA- B and HLA-DR genes (Paper IV).
Subsequently, we performed a high-throughput and high-coverage sequencing of the entire MHC region of the COX cell line, 18 IgAD patients (6 of whom have concomitant CD) and 27 healthy controls, all homozygous for the 8.1 haplotype (n=46). However, no significant difference was found between IgAD patients and IgA sufficient controls, indicating that there may be no causative/deleterious mutation located in the coding genes of the MHC region. It is thus possible that as there is no distinct “pathogenic” haplotype, that either interaction of a common allelic variant with selected non-MHC genes gives rise to the disease or that the disease-causing mutation(s) might be located in the hitherto un-sequenced regulatory regions (Paper V).
IgAD is associated with several classical autoimmune disorders including Graves’ disease (GD), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), celiac disease (CD) and potentially rheumatoid arthritis and myasthenia gravis (MG). As more than 95% of patients with GD are positive for thyrotropin-receptor autoantibody (TRAb), we thus investigated the prevalence of IgAD in TRAb-seropositive individuals both in Sweden and Iceland and showed that the prevalence of IgAD in the Swedish cohort is significantly higher than expected in the general population. TRAb- seropositivity is also common among IgAD individuals in both cohorts, suggesting a predisposition to GD (Paper I).
There is a markedly increased prevalence of IgAD among adults with CD. It is therefore important to validate the IgG class antibody tests for screening CD in IgAD adults. IgG anti tissue transglutaminase (anti-tTG) and anti deamidated gliadin peptides (anti-DGP) antibodies were determined in our IgAD cohort with suspected CD. IgG anti-tTG seems to be a reliable marker for CD in IgAD adults whereas the diagnostic specificity of IgG anti-DGP appears to be lower. We also found that high levels of IgG antibodies against both tTG and DGP were frequently found in IgAD adults despite adhering to a gluten free diet (Paper II). We subsequently screened IgAD among patients with SLE and T1D in different ethnical populations and the observed higher prevalence of IgAD was consistent with previous publications (Paper III).
IgAD is reported to be strongly associated with the MHC region, especially the HLA- A1, B8, DR3, DQ2 (8.1) haplotype, which is also associated with various autoimmune disorders, including GD, SLE, T1D, CD and MG. Non-MHC genes (such as IFIH1and CLEC16A) are also associated with the development of some of the above diseases as well as IgAD, indicative of a possible common genetic background (Paper III).
A high-density mapping of the HLA locus was then preformed in a combined sample of IgAD patients and matched controls from 3 independent European populations. A complex nature of the association of IgAD with the HLA locus was demonstrated. The primary association signal mapped to the HLA-DQB1*02 allele resulting from the combined independent effects of the HLA-B*0801-DRB1*0301-DQB1*0201 and DRB1*0701-DQB1*0202 haplotypes and secondary signals were associated with the DRB1*0102 and DRB1*1501 alleles. Of interest, a remarkable conservation within the HLA locus was found, regardless of ethnic background, which supports the use of large multi-ethnic populations to characterize the shared genetic association within this region. The location of association signals within several specific extended haplotypes was potentially identified, including the 8.1 haplotype in the interval between the HLA- B and HLA-DR genes (Paper IV).
Subsequently, we performed a high-throughput and high-coverage sequencing of the entire MHC region of the COX cell line, 18 IgAD patients (6 of whom have concomitant CD) and 27 healthy controls, all homozygous for the 8.1 haplotype (n=46). However, no significant difference was found between IgAD patients and IgA sufficient controls, indicating that there may be no causative/deleterious mutation located in the coding genes of the MHC region. It is thus possible that as there is no distinct “pathogenic” haplotype, that either interaction of a common allelic variant with selected non-MHC genes gives rise to the disease or that the disease-causing mutation(s) might be located in the hitherto un-sequenced regulatory regions (Paper V).
List of papers:
I. Association of immunoglobulin A deficiency and elevated thyrotropinreceptor autoantibodies in two Nordic countries. Jorgensen GH, Ornolfsson AE, Johannesson A, Gudmundsson S, Janzi M, Wang N, Hammarström L, Ludviksson BR. Hum Immunol. 2011 Feb; 72(2):166-72.
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II. Serologic assessment for celiac disease in IgA deficient adults. Wang N, Truedsson L, Elvin K, Andersson BA, Rönnelid J, MinchevaNilsson L, Lindqvist A, Ludvigsson JF, Hammarström L, Dahle C. [Submitted]
III. Selective IgA deficiency in autoimmune diseases. Wang N, Shen N, Vyse TJ, Anand V, Gunnarson I, Sturfelt G, Rantapää-Dahlqvist S, Elvin K, Truedsson L, Andersson BA, Dahle C, Ortqvist E, Gregersen PK, Behrens TW, Hammarström L. Mol Med. 2011; 17(11-12):1383-96.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency. Ferreira RC, Pan-Hammarström Q, Graham RR, Fontán G, Lee AT, Ortmann W, Wang N, Urcelay E, Fernández-Arquero M, Núñez C, Jorgensen G, Ludviksson BR, Koskinen S, Haimila K, Padyukov L, Gregersen PK, Hammarström L, Behrens TW. PLoS Genet. 2012 Jan; 8(1):e1002476.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Sequencing of the MHC region in IgA deficient individuals homozygous for HLA-A1, B8, DR3, DQ2 haplotype - a comparison with IgA sufficient blood donors. Wang N, Cao H, Zhang T, Xu Y, Wang G, Hammarström L. [Manuscript]
I. Association of immunoglobulin A deficiency and elevated thyrotropinreceptor autoantibodies in two Nordic countries. Jorgensen GH, Ornolfsson AE, Johannesson A, Gudmundsson S, Janzi M, Wang N, Hammarström L, Ludviksson BR. Hum Immunol. 2011 Feb; 72(2):166-72.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Serologic assessment for celiac disease in IgA deficient adults. Wang N, Truedsson L, Elvin K, Andersson BA, Rönnelid J, MinchevaNilsson L, Lindqvist A, Ludvigsson JF, Hammarström L, Dahle C. [Submitted]
III. Selective IgA deficiency in autoimmune diseases. Wang N, Shen N, Vyse TJ, Anand V, Gunnarson I, Sturfelt G, Rantapää-Dahlqvist S, Elvin K, Truedsson L, Andersson BA, Dahle C, Ortqvist E, Gregersen PK, Behrens TW, Hammarström L. Mol Med. 2011; 17(11-12):1383-96.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency. Ferreira RC, Pan-Hammarström Q, Graham RR, Fontán G, Lee AT, Ortmann W, Wang N, Urcelay E, Fernández-Arquero M, Núñez C, Jorgensen G, Ludviksson BR, Koskinen S, Haimila K, Padyukov L, Gregersen PK, Hammarström L, Behrens TW. PLoS Genet. 2012 Jan; 8(1):e1002476.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Sequencing of the MHC region in IgA deficient individuals homozygous for HLA-A1, B8, DR3, DQ2 haplotype - a comparison with IgA sufficient blood donors. Wang N, Cao H, Zhang T, Xu Y, Wang G, Hammarström L. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Hammarström, Lennart
Issue date: 2015-09-04
Rights:
Publication year: 2014
ISBN: 978-91-7549-424-1
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