Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Human leukocyte antigen in sickness and in health: Ankylosing spondylitis and HLA in Sweden
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.ORCID iD: 0000-0002-8414-2190
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The human leukocyte antigen (HLAplays a major role in keeping us healthy, but some of the HLA alleles can contribute to disease susceptibility. One example is HLA-B*27which confers increased susceptibility of ankylosing spondylitis and represents one of the strongest genetic associations found in any common human disease. Ankylosing spondylitis shows a strong sex ratio skew (2-3:1 male to female) and studies confirm the existence of sexual-dimorphism in the presentation of this disease. The genetic predisposition for this, however, has not previously been studied. 

A Swedish ankylosing spondylitis population was sequenced with a targeted array to investigate the existence of sex-specific associations. RUNX3 was revealed to be associated in males by a univariate test, while aggregate tests revealed the HLA gene MICB to be associated in females. Functional validation demonstrated that the risk variants in RUNX3 increase expression, and MICB changed the transcription factor binding sites. Interestingly, since the disease involves bone changes, both RUNX3 and one of the MICB variants had effect in the bone cell line, SaOS-2.

In order to help researchers obtain more controls for HLA analysis, an HLA allele bioresource (SweHLA) was generated from 1,000 Swedish genomes. The alleles were typed with three to four HLA typing software programs and results were combined by an n-1methodology. This produced high quality alleles where the bias from each software program was diminished.

The methodology from SweHLA was utilised to study HLA in ankylosing spondylitis. To investigate both sex-specific predisposition and HLA-B*27 independence, samples were subdivided into two populations (one population with mixed HLA-B*27 positive and negative samples and one with only HLA-B*27 positive samples) that in turn were grouped by sex. In the mixed population, several alleles were replicated from previous studies. This study also revealed three female-specific alleles, two of which were new and one that had previously been associated to the severity of radiological changes. The HLA-B*27 population revealed a previously unknown protective allele, HLA-A*24:02. Through deeper examination of the HLA-B*27 population, two amino acids in HLA-A, position 119 in the whole set and position 180 in the male set, were revealed to be protective.

This thesis brings new insight into the genetic predisposition for a sex-skewed disease, demonstrating how sexual-dimorphism can be reflected in the genetic predisposition, hopefully leading to more similar studies. It also highlights the importance of methodology and demonstrate the drastic biases that can be imparted by software programs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 69
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1599
Keywords [en]
Disease genetics, Ankylosing spondylitis, HLA typing, Imputation, Inference, Sex-stratified, HLA-B*27 independent, Association tests, Functional validation
National Category
Bioinformatics (Computational Biology) Medical Genetics Genetics
Research subject
Bioinformatics; Molecular Genetics
Identifiers
URN: urn:nbn:se:uu:diva-393317ISBN: 978-91-513-0760-2 (print)OAI: oai:DiVA.org:uu-393317DiVA, id: diva2:1354233
Public defence
2019-11-14, Room B41, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2019-10-23 Created: 2019-09-24 Last updated: 2019-11-12
List of papers
1. The sex-stratified genetic architecture of ankylosing spondylitis
Open this publication in new window or tab >>The sex-stratified genetic architecture of ankylosing spondylitis
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Sexual dimorphism is an emerging feature of ankylosing spondylitis (AS), a chronic rheumatic condition affecting up

to three times more men than women. Using 691 individuals from a Swedish case-control cohort, we revealed that

sex biases are also a hallmark of AS genetic predisposition, and that this multifactorial disease is in part driven by

both rare and common variants. We identified SNPs via the targeted re-sequencing of 7 270 coding and non-coding

loci, and assessed novel patterns of association with both single marker and aggregate loci SKAT tests. The male

specific RUNX3 locus (including rs7414934, OR=2.58, p=1.7x10-5) and female specific MICB SKAT locus (27

variants, p=1.2x10-6; rs3828903, OR=4.62, p=6.2x10-13) exceeded discovery thresholds. Multiple risk variants from

each locus were shown to be functionally active in immune (Jurkat), skin (HaCat) and bone (SaOS-2) cell lines.

Differential patterns of genetic predisposition may point to alternative disease mechanisms in male and female

patients. Genetic and functional analyses demonstrated that risk alleles should not be considered in isolation and that

associated variants would likely affect gene regulation across multiple tissues. This work illustrates the need to

consider the contribution of sex to the genetics of AS and the duality that individual loci may play in the key clinical outcomes of disease.

Keywords
ankylosing spondylitis, SKAT, RUNX3, MICB
National Category
Genetics
Research subject
Molecular Genetics; Molecular Genetics
Identifiers
urn:nbn:se:uu:diva-390455 (URN)
Available from: 2019-08-10 Created: 2019-08-10 Last updated: 2019-09-24
2. SweHLA: the high confidence HLA typing bio-resource drawn from 1,000 Swedish genomes
Open this publication in new window or tab >>SweHLA: the high confidence HLA typing bio-resource drawn from 1,000 Swedish genomes
Show others...
(English)In: Article in journal (Other academic) Submitted
Abstract [en]

There is a need to accurately call human leukocyte antigen (HLA) genes from existing short-read sequencing data, however there is no single solution that matches the gold standard of Sanger sequenced lab typing. Here we aimed to combine results from available software programs, minimising the biases of applied algorithm and HLA reference. The result is a robust HLA population resource for the published 1,000 Swedish genomes, and a framework for future HLA interrogation. HLA 2-field alleles were called using four imputation and inference methods for the classical eight genes (class I: HLA-A, -B, -C; class II: HLA-DPA1, -DPB1, -DQA1, -DQB1, -DRB1). A high confidence population set (SweHLA) was determined using an n-1 concordance rule for class I (four software) and class II (three software) alleles. Results were compared across populations and individual programs benchmarked to SweHLA. Per allele, 875 to 988 of the 1,000 samples were genotyped in SweHLA; 920 samples had at least seven loci. While a small fraction of reference alleles were common to all software (class I=1.9% and class II=4.1%), this did not affect the overall call rate. Gene-level concordance was high compared to European populations (>0.83%), with COX and PGF the dominant SweHLA haplotypes. We noted that 15/18 discordant alleles (delta allele frequency >2) were previously reported as disease-associated. These differences could in part explain across-study genetic replication failures, reinforcing the need to use multiple software solutions. SweHLA demonstrates a way to use existing NGS data to generate a population resource agnostic to individual HLA software biases.

National Category
Medical Genetics Bioinformatics (Computational Biology) Genetics
Research subject
Bioinformatics; Molecular Genetics; Medical Genetics
Identifiers
urn:nbn:se:uu:diva-393313 (URN)
Available from: 2019-09-19 Created: 2019-09-19 Last updated: 2019-09-24
3. HLA-A confers protection in HLA-B*27 positive ankylosing spondylitis
Open this publication in new window or tab >>HLA-A confers protection in HLA-B*27 positive ankylosing spondylitis
Show others...
(English)In: Article in journal (Other academic) Submitted
Keywords
Ankylosing spondylitis, HLA-typing, Gene polymorphism
National Category
Medical Genetics Genetics Bioinformatics (Computational Biology)
Research subject
Bioinformatics; Molecular Genetics; Medical Genetics
Identifiers
urn:nbn:se:uu:diva-393316 (URN)
Available from: 2019-09-19 Created: 2019-09-19 Last updated: 2019-10-02

Open Access in DiVA

fulltext(1453 kB)59 downloads
File information
File name FULLTEXT01.pdfFile size 1453 kBChecksum SHA-512
969df0e2c0320ce9cf38637a91c783655a92fe036f38c28a6a07cc8e2a75ace0a43b1857d1ae629cb82543b021ab92266f25a3d7d914b4e0adb33f1c43e9979d
Type fulltextMimetype application/pdf
Buy this publication >>

Search in DiVA

By author/editor
Nordin, Jessika
By organisation
Department of Medical Biochemistry and Microbiology
Bioinformatics (Computational Biology)Medical GeneticsGenetics

Search outside of DiVA

GoogleGoogle Scholar
Total: 59 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 240 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf