The impact of COVID‐19 varies markedly, not only between individual patients but also between different populations. We hypothesised that differences in human leukocyte antigen (HLA) genes might ...influence this variation. Using next generation sequencing, we analysed the class I and class II classical HLA genes of 147 individuals of European descent experiencing variable clinical outcomes following COVID‐19 infection. Forty‐nine of these patients were admitted to hospital with severe respiratory disease. They had no significant pre‐existing comorbidities. We compared the results to those obtained from a group of 69 asymptomatic hospital workers who evidence of COVID exposure based on blood antibody testing. Allele frequencies in both the severe and asymptomatic groups were compared to local and national healthy controls with adjustments made for age and sex. With the inclusion of hospital staff who had reported localised symptoms only (limited to loss of smell/taste, n = 13) or systemic symptoms not requiring hospital treatment (n = 16), we carried out ordinal logistic regression modelling to determine the relative influence of age, BMI, sex and the presence of specific HLA genes on symptomatology. We found a significant difference in the allele frequency of HLA‐DRB1*04:01 in the severe patient compared to the asymptomatic staff group (5.1% vs. 16.7%, P = .003 after adjustment for age and sex). There was a significantly lower frequency of the haplotype DQA1*01:01‐DQB1*05:01‐DRB1*01:01 in the asymptomatic group compared to the background population (P = .007). Ordinal logistic regression modelling confirmed the significant influence of DRB1*04:01 on the clinical severity of COVID‐19 observed in the cohorts. These alleles are found in greater frequencies in the North Western European population. This regional study provides evidence that HLA genotype influences clinical outcome in COVID‐19 infection. Validation studies must take account of the complex genetic architecture of the immune system across different geographies and ethnicities.
Low concentration of 25-hydroxyvitamin D during pregnancy may be associated with offspring autoimmune disorders. Little is known about environmental triggers except gluten for celiac disease, a ...common immune-mediated disorder where seasonality of birth has been reported as a risk factor. We therefore aimed to test whether low maternal and neonatal 25-hydroxyvitamin D predicted higher risk of childhood celiac disease.
In this Norwegian nationwide pregnancy cohort (n = 113,053) and nested case-control study, we analyzed 25-hydroxyvitamin D in maternal blood from mid-pregnancy, postpartum and cord plasma of 416 children who developed celiac disease and 570 randomly selected controls. Mothers and children were genotyped for established celiac disease and vitamin D metabolism variants. We used mixed linear regression models and logistic regression to study associations. There was no significant difference in average 25-hydroxyvitamin D between cases and controls (63.1 and 62.1 nmol/l, respectively, p = 0.28), and no significant linear trend (adjusted odds ratio per 10 nM increase 1.05, 95% CI: 0.93-1.17). Results were similar when analyzing the mid-pregnancy, postpartum or cord plasma separately. Genetic variants for vitamin D deficiency were not associated with celiac disease (odds ratio per risk allele of the child, 1.00; 95% CI, 0.90 to 1.10, odds ratio per risk allele of the mother 0.94; 95% CI 0.85 to 1.04). Vitamin D intake in pregnancy or by the child in early life did not predict later celiac disease. Adjustment for established genetic risk markers for celiac disease gave similar results.
We found no support for the hypothesis that maternal or neonatal vitamin D status is related to the risk of childhood celiac disease.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Acquired myasthenia gravis (MG) is a rare antibody-mediated autoimmune disease caused by impaired neuromuscular transmission, leading to abnormal muscle fatigability. The aetiology is complex, ...including genetic risk factors of the human leukocyte antigen (HLA) complex and unknown environmental factors. Although associations between the HLA complex and MG are well established, not all involved components of the HLA predisposition to this heterogeneous disease have been revealed. Well-powered and comprehensive HLA analyses of subgroups in MG are warranted, especially in late onset MG.
This case-control association study is of a large population-based Norwegian cohort of 369 MG patients and 651 healthy controls. We performed comprehensive genotyping of four classical HLA loci (HLA-A, -B, -C and -DRB1) and showed that the DRB1*15:01 allele conferred the strongest risk in late onset MG (LOMG; onset ≥ 60 years) (OR 2.38, p(c)7.4 × 10(-5)). DRB1*13:01 was found to be a protective allele for both early onset MG (EOMG) and LOMG (OR 0.31, p(c) 4.71 × 10(-4)), a finding not previously described. No significant association was found to the DRB1*07:01 allele (p(nc) = 0.18) in a subset of nonthymomatous anti-titin antibody positive LOMG as reported by others. HLA-B*08 was mapped to give the strongest contribution to EOMG, supporting previous studies.
The results from this study provide important new information concerning the susceptibility of HLA alleles in Caucasian MG, with highlights on DRB1*15:01 as being a major risk allele in LOMG.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Antigen presenting cells (APCs) in the thymus play an essential role in the establishment of central tolerance, i.e. the generation of a repertoire of functional and self-tolerant T cells to prevent ...autoimmunity. In this study, we have compared the transcriptomes of four primary APCs from human thymus (mTECs, CD19+ B cells, CD141+ and CD123+ DCs). We investigated a set of genes including the HLA genes, genes encoding transcriptional regulators and finally, tissue-enriched genes, i.e, genes with a five-fold higher expression in a particular human tissue. We show that thymic CD141+ DCs express the highest levels of all classical HLA genes and 67% (14/21) of the HLA class I and II pathway genes investigated in this study. CD141+ DCs also expressed the highest levels of the transcriptional regulator DEAF1, whereas AIRE and FEZF2 expression were mainly found in primary human mTECs. We found expression of "tissue enriched genes" from the Human Protein Atlas (HPA) in all four APC types, but the mTECs were clearly dominating in the number of uniquely expressed tissue enriched genes (20% in mTECs, 7% in CD19+ B cells, 4% in CD123+ DCs and 2% in CD141+ DCs). The tissue enriched genes also overlapped with reported human autoantigens. This is, to our knowledge, the first study that performs RNA sequencing of mTECs, CD19+ B cells, CD141+ and CD123+ DCs isolated from the same individuals and provides insight into the transcriptomes of these human thymic APCs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Circumstantial evidence links 25-hydroxy vitamin D 25(OH)D, vitamin D-binding protein (DBP), vitamin D-associated genes, and type 1 diabetes (T1D), but no studies have jointly analyzed these. We ...aimed to investigate whether DBP levels during pregnancy or at birth were associated with offspring T1D and whether vitamin D pathway genetic variants modified associations between DBP, 25(OH)D, and T1D.
From a cohort of >100,000 mother/child pairs, we analyzed 189 pairs where the child later developed T1D and 576 random control pairs. We measured 25(OH)D using liquid chromatography-tandem mass spectrometry, and DBP using polyclonal radioimmunoassay, in cord blood and maternal plasma samples collected at delivery and midpregnancy. We genotyped mother and child for variants in or near genes involved in vitamin D metabolism (
,
,
,
,
, and
). Logistic regression was used to estimate odds ratios (ORs) adjusted for potential confounders.
Higher maternal DBP levels at delivery, but not in other samples, were associated with lower offspring T1D risk (OR 0.86 95% CI 0.74-0.98 per μmol/L increase). Higher cord blood 25(OH)D levels were associated with lower T1D risk (OR = 0.87 95% CI 0.77-0.98 per 10 nmol/L increase) in children carrying the
rs11568820 G/G genotype (
= 0.01 between 25(OH)D level and rs11568820). We did not detect other gene-environment interactions.
Higher maternal DBP level at delivery may decrease offspring T1D risk. Increased 25(OH)D levels at birth may decrease T1D risk, depending on
genotype. These findings should be replicated in other studies. Future studies of vitamin D and T1D should include
genotype and DBP levels.
•We find an association between the MDM2 del1518 variant and rheumatoid arthritis.•Combinatorial genotypes the MDM2 locus may be related to rheumatoid arthritis.•Combinatorial haplotypes the MDM2 ...locus may be related to rheumatoid arthritis.•Polymorphisms of TP53 and MDM4 are not associated with rheumatoid arthritis.
In addition to being a tumour suppressor, TP53 is a suppressor of inflammation, and dysfunction of this gene has been related to autoimmune diseases. Patients with autoimmunity, such as rheumatoid arthritis (RA) have an increased risk of certain cancers, like lymphomas, indicating that some underlying mechanisms may modulate risk of both cancers and autoimmunity.
We genotyped 5 common genetic variants in TP53 and its main regulators MDM2 and MDM4 in a sample of 942 RA patients and 3,747 healthy controls, and mined previously published GWAS-data, to assess the potential impact of these variants on risk of RA.
For the TP53 Arg72Pro polymorphism (rs1042522), MDM4 SNP34091 (rs4245739) and MDM2 SNP285C (rs117039649), we found no association to risk of RA. For MDM2 SNP309 (rs2279744), the minor G-allele was associated with a reduced risk of RA (OR: 0.87; CI: 0.79–0.97). This association was also seen in genotype models (OR: 0.86; CI: 0.74–0.99 and OR: 0.79; CI 0.63–0.99; dominant and recessive model, respectively), but was not validated in a large GWAS data set. For MDM2 del1518 (rs3730485), the minor del-allele was associated with an increased risk of RA in the dominant model (OR: 1.18; CI: 1.02–1.38). Stratifying RA cases and controls into phylogenetic subgroups according to the combined genotypes of all three MDM2 polymorphism, we found individuals with the del158-285–309 genotype del/ins-G/G-T/T to have an increased risk of RA as compared to those with the ins/ins-G/G-G/G genotype (OR: 1.56; CI: 1.18–2.06) indicating opposite effects of the del1518 del-allele and the SNP309 G-allele.
We find a potential association between the MDM2 del1518 variant and RA, and indications that combinatorial genotypes and haplotypes in the MDM2 locus may be related to RA.
Evidence suggests a cell-mediated autoimmune pathogenesis for narcolepsy type 1 (NT1), but it is not clear whether the disease is associated with overall changes in T cell subsets. The increase in ...NT1 incidence after H1N1 vaccination campaign with the Pandemrix™ vaccine suggests that disease-relevant changes in the immune system following this vaccination were important. In this study, we aimed to investigate differentiated T cell subsets and levels of CD25 and CD69 activation markers in a cohort of mainly Pandemrix™-vaccinated NT1 patients compared with their vaccinated and unvaccinated siblings.
Peripheral blood mononuclear cells were collected in parallel and analysed with flow cytometry in 31 NT1 patients with disease onset after the 2009 influenza A (H1N1) pandemic and/or Pandemrix™ vaccination and 45 of their non-narcoleptic siblings (29/31 and 34/45 vaccinated, respectively).
We observed significantly lower effector memory CD4+ T cell levels in NT1 patients compared to their siblings, when controlling for HLA DQB1∗06:02 and vaccination status. Further, within the sibling group, vaccination status significantly affected frequencies of central memory and CD8+CD25+ T cells, and HLA DQB1∗06:02 status significantly affected frequencies of CD4+CD25+ T cells.
We confirm that NT1 is associated with lower levels of effector memory CD4+ T cells in peripheral blood. Importantly, this finding was only significant when controlling for vaccination and HLA status in both patients and controls. We thus demonstrate the importance of characterizing such factors (eg HLA and vaccination) when studying T cell subsets in NT1. This might explain earlier conflicting results.
•H1N1 Pandemrix vaccination was associated with an increase in narcolepsy type 1.•Viste et al. compared T cell composition in vaccinated NT1 patients versus siblings.•NT1 patients had lower levels of effector memory CD4 T cells compared with controls.•T cell signature in NT1 patients depends on HLA- and H1N1 vaccination status.
Multiple sclerosis (MS) is a complex disease of the central nervous system of unknown etiology. The human leukocyte antigen (HLA) locus on chromosome 6 confers a considerable part of the ...susceptibility to MS, and the most important factor is the class II allele HLA-DRB1*15:01. In addition, we and others have previously established a protective effect of HLA-A*02. Here, we genotyped 1,784 patients and 1,660 healthy controls from Scandinavia for the HLA-A, HLA-B, HLA-C and HLA-DRB1 genes and investigated their effects on MS risk by logistic regression. Several allele groups were found to exert effects independently of DRB1*15 and A*02, in particular DRB1*01 (OR = 0.82, p = 0.034) and B*12 (including B*44/45, OR = 0.76, p = 0.0028), confirming previous reports. Furthermore, we observed interaction between allele groups: DRB1*15 and DRB1*01 (multiplicative: OR = 0.54, p = 0.0041; additive: AP = 0.47, p = 4 × 10(-06)), DRB1*15 and C*12 (multiplicative: OR = 0.37, p = 0.00035; additive: AP = 0.58, p = 2.6 × 10(-05)), indicating that the effect size of these allele groups varies when taking DRB1*15 into account. Analysis of inferred haplotypes showed that almost all DRB1*15 bearing haplotypes were risk haplotypes, and that all A*02 bearing haplotypes were protective as long as they did not carry DRB1*15. In contrast, we found one class I haplotype, carrying A*02-C*05-B*12, which abolished the risk of DRB1*15. In conclusion, these results confirms a complex role of HLA class I and II genes that goes beyond DRB1*15 and A*02, in particular by including all three classical HLA class I genes as well as functional interactions between DRB1*15 and several alleles of DRB1 and class I genes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•Largest ME/CFS genetic study to date.•Three different cohorts totaling >2500 patients.•First Immunochip study in ME/CFS.•Possible implication of TPPP genetic region.
Myalgic ...encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease of unknown etiology and pathogenesis, which manifests in a variety of symptoms like post-exertional malaise, brain fog, fatigue and pain. Hereditability is suggested by an increased disease risk in relatives, however, genome-wide association studies in ME/CFS have been limited by small sample sizes and broad diagnostic criteria, therefore no established risk loci exist to date. In this study, we have analyzed three ME/CFS cohorts: a Norwegian discovery cohort (N = 427), a Danish replication cohort (N = 460) and a replication dataset from the UK biobank (N = 2105). To the best of our knowledge, this is the first ME/CFS genome-wide association study of this magnitude incorporating 2532 patients for the genome-wide analyses and 460 patients for a targeted analysis. Even so, we did not find any ME/CFS risk loci displaying genome-wide significance. In the Norwegian discovery cohort, the TPPP gene region showed the most significant association (rs115523291, P = 8.5 × 10−7), but we could not replicate the top SNP. However, several other SNPs in the TPPP gene identified in the Norwegian discovery cohort showed modest association signals in the self-reported UK biobank CFS cohort, which was also present in the combined analysis of the Norwegian and UK biobank cohorts, TPPP (rs139264145; P = 0.00004). Interestingly, TPPP is expressed in brain tissues, hence it will be interesting to see whether this association, with time, will be verified in even larger cohorts. Taken together our study, despite being the largest to date, could not establish any ME/CFS risk loci, but comprises data for future studies to accumulate the power needed to reach genome-wide significance.
Multiple immune-related genes are encoded in the HLA complex on chromosome 6p21. The 8.1 ancestral haplotype (AH8.1) include the classical HLA alleles HLA-B*08:01 and HLA-DRB1*03:01, and has been ...associated with a large number of autoimmune diseases, but the underlying mechanisms for this association are largely unknown. Given the recently established links between the gut microbiota and inflammatory diseases, we hypothesized that the AH8.1 influences the host gut microbial community composition. To study this further, healthy individuals were selected from the Norwegian Bone Marrow Donor Registry and categorized as either I. AH8.1 homozygote (n=34), II. AH8.1 heterozygote (n=38), III. Non AH8.1 heterozygote or IV. HLA-DRB1 homozygote but non AH8.1 (n=15). Bacterial DNA from stool samples were subjected to sequencing of the V3-V5 region of the 16S rRNA gene on the 454 Life Sciences platform and data analyzed using Mothur and QIIME. The results showed that the abundances of different taxa were highly variable within all pre-defined AH8.1 genotype groups. Using univariate non-parametric statistics, there were no differences regarding alpha or beta diversity between AH8.1 carriers (categories I and II) and non-carriers (categories III and IV), however four different taxa (Prevotellaceae, Clostridium XVIII, Coprococcus, Enterorhabdus) had nominally significant lower abundances in AH8.1 carriers than non-carriers. After including possible confounders in a multivariate linear regression, only the two latter genera remained significantly associated. In conclusion, the overall contribution of the AH8.1 haplotype to the variation in gut microbiota profile of stool in the present study was small.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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