scholarly journals Validation of Single Nucleotide Variant Assays for Human Leukocyte Antigen Haplotypes HLA-B*15:02 and HLA-A*31:01 Across Diverse Ancestral Backgrounds

2021 ◽  
Vol 12 ◽  
Author(s):  
Amanda Buchner ◽  
Xiuying Hu ◽  
Katherine J. Aitchison
Keyword(s):  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Single Nucleotide Variant ◽  
Taqman Assay ◽  
Slight Reduction ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Leukocyte Antigen ◽  
Efficient Detection ◽  
Hla Haplotypes

The human leukocyte antigen haplotypes HLA-B*15:02 and HLA-A*31:01 have been linked to life-threatening adverse drug reactions to the anticonvulsants carbamazepine and oxcarbazepine. Identification of these haplotypes via pharmacogenetic techniques facilitates implementation of precision medicine to prevent such reactions. Using reference samples from diverse ancestral origins, we investigated the test analytical validity (i.e., ability to detect whether or not the haplotypes were present or absent) of TaqMan assays for single nucleotide variants previously identified as potentially being able to “tag” these haplotypes. A TaqMan custom assay for rs10484555 and an inventoried assay for rs17179220 and were able to identify with 100% sensitivity and 100% specificity HLA-B*15:02 and HLA-A*31:01 respectively. A custom assay for rs144012689 that takes into account a neighboring single nucleotide variant with manual calling was also able to identify HLA-B*15:02 with 100% sensitivity and 100% specificity. A custom assay for rs106235 identified HLA-A*31:01 with 100% sensitivity and 95% specificity. The slight reduction in specificity for the latter was owing to another haplotype (HLA-A*33:03) also being detected. While any positive call using the rs106235 assay could therefore be further investigated, as the presence of the HLA-A*31:01 haplotype confers adverse drug reaction risk, the absence of false negatives (indexed by sensitivity) is more important than false positives. In summary, we present validated TaqMan assay methodology for efficient detection of HLA haplotypes HLA-B*15:02 and HLA-A*31:01. Our data are relevant for other genotyping technologies that identify, or have the potential to identify, these haplotypes using single nucleotide variants.

scholarly journals The Phenotype of Celiac Disease Has Low Concordance between Siblings, Despite a Similar Distribution of HLA Haplotypes

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 479 ◽  
Author(s):  
Saana Kauma ◽  
Katri Kaukinen ◽  
Heini Huhtala ◽  
Laura Kivelä ◽  
Henna Pekki ◽  
...  
Keyword(s):  
Celiac Disease ◽  
Environmental Factors ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Similar Distribution ◽  
Intestinal Malabsorption ◽  
Sibling Pairs ◽  
Leukocyte Antigen ◽  
Intestinal Symptoms ◽  
Hla Haplotypes

The factors determining the presentation of celiac disease are unclear. We investigated the phenotypic concordance and the distribution of human leukocyte antigen (HLA) risk haplotypes in affected siblings. One hundred sibling pairs were included. Clinical and histological parameters and HLA haplotypes were compared between the first diagnosed indexes and their siblings. The phenotype was categorized into gastrointestinal, extra-intestinal, malabsorption/anemia, and asymptomatic. The phenotype was fully concordant in 21 pairs. The most common concordant phenotype was gastrointestinal (14 pairs). Indexes had more anemia/malabsorption and extra-intestinal symptoms than siblings (45% vs. 20%, p < 0.001 and 33% vs. 12%, p < 0.001, respectively). Twenty siblings and none of the indexes were asymptomatic. The indexes were more often women (81% vs. 63%, p = 0.008). They were also more often seronegative (11% vs. 0%, p = 0.03) and younger (37 vs. 43 year, p < 0.001), and had more severe histopathology (total/subtotal atrophy 79% vs. 58%, p = 0.047) at diagnosis. The indexes and siblings were comparable in other disease features. Pairs with discordant presentation had similar HLA haplotypes more often than the concordant pairs. The phenotype was observed to vary markedly between siblings, with the indexes generally having a more severe presentation. HLA did not explain the differences, suggesting that non-HLA genes and environmental factors play significant roles.

scholarly journals Effective Detection of Human Leukocyte Antigen Risk Alleles in Celiac Disease Using Tag Single Nucleotide Polymorphisms

PLoS ONE ◽  
2008 ◽  
Vol 3 (5) ◽  
pp. e2270 ◽  
Author(s):  
Alienke J. Monsuur ◽  
Paul I. W. de Bakker ◽  
Alexandra Zhernakova ◽  
Dalila Pinto ◽  
Willem Verduijn ◽  
...  
Keyword(s):  
Celiac Disease ◽  
Single Nucleotide Polymorphisms ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Leukocyte Antigen ◽  
Risk Alleles

Human leukocyte antigen (HLA) haplotypes and clozapine induced agranulocytosis

1997 ◽  
Vol 42 (1) ◽  
pp. 102S
Author(s):  
St. Theodoropoulou ◽  
K. Tarassi ◽  
L. Lykouras ◽  
J. Hatzimanolis ◽  
G. Papageorgiou ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Hla Haplotypes

scholarly journals Donor human leukocyte antigen-G single nucleotide polymorphisms are associated with post-lung transplant mortality

2019 ◽  
Vol 54 (2) ◽  
pp. 1802126 ◽  
Author(s):  
Julieta Lazarte ◽  
Jin Ma ◽  
Tereza Martinu ◽  
Liran Levy ◽  
William Klement ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Lung Transplantation ◽  
Human Leukocyte Antigen ◽  
Mortality Risk ◽  
Lung Transplant ◽  
Multivariable Analysis ◽  
Human Leukocyte ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Leukocyte Antigen

Human leukocyte antigen (HLA)-G is a non-classical HLA that inhibits immune responses. Its expression is modified by single nucleotide polymorphisms (SNPs), which are associated with transplant outcomes. Our aim was to investigate the association of donor and recipient HLA-G SNPs with chronic lung allograft dysfunction (CLAD) and mortality after lung transplantation.In this single-centre study, we examined 11 HLA-G SNPs in 345 consecutive recipients and 297 donors of a first bilateral lung transplant. A multivariable Cox proportional hazards model assessed associations of SNPs with death and CLAD. Transbronchial biopsies (TBBx) and bronchoalveolar lavage (BAL) samples were examined using quantitative PCR, ELISA and immunofluorescence.Over a median of 4.75 years, 142 patients (41%) developed CLAD; 170 (49%) died. Multivariable analysis revealed donor SNP +3142 (GG+CG versus CC) was associated with increased mortality (hazard ratio 1.78, 95% CI 1.12–2.84; p=0.015). In contrast, five donor SNPs, -201(CC), -716(TT), -56(CC), G*01:03(AA) and 14 bp INDEL, conferred reduced mortality risk. Specific donor–recipient SNP pairings reduced CLAD risk. Predominantly epithelial HLA-G expression was observed on TBBx without rejection. Soluble HLA-G was present in higher concentrations in the BAL samples of patients who later developed CLAD.Specific donor SNPs were associated with mortality risk after lung transplantation, while certain donor–recipient SNP pairings modulated CLAD risk. TBBx demonstrated predominantly epithelial, and therefore presumably donor-derived, HLA-G expression in keeping with these observations. This study is the first to demonstrate an effect of donor HLA-G SNPs on lung transplantation outcome.

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