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. 2019 May;59(5):1836-1842.
doi: 10.1111/trf.15222. Epub 2019 Mar 3.

The nonconservative CD177 single-nucleotide polymorphism c.1291G>A is a genetic determinant for human neutrophil antigen-2 atypical/low expression and deficiency

Jianming Wu  1 , Yunfang Li  1 , Randy M Schuller  2 , Ling Li  3 , Anne-Sophie Litmeyer  4 , Gregor Bein  4 , Ulrich J Sachs  4 , Behnaz Bayat  4
Affiliations

The nonconservative CD177 single-nucleotide polymorphism c.1291G>A is a genetic determinant for human neutrophil antigen-2 atypical/low expression and deficiency

Jianming Wu et al. Transfusion. 2019 May.

Abstract

Background: Human neutrophil antigen-2 (HNA-2) is exclusively expressed on neutrophils. HNA-2-deficient individuals (HNA-2 null) are susceptible to produce isoantibodies. The nonsense CD177 coding single-nucleotide polymorphism (SNP) c.787A>T has been demonstrated as the primary genetic mechanism for HNA-2 deficiency. We hypothesized that the other genetic variants also contribute to HNA-2 expression variation and deficiency.

Study design and methods: The deficiency, density, and percentage of HNA-2 antigen on neutrophils from 292 healthy blood donors were determined in flow cytometry. CD177 genotypes were determined by genomic DNA sequence analyses. The full-length CD177 cDNAs were amplified and sequenced. Additionally, the whole CD177 genomic sequence in eight HNA-2-null immunized women and four HNA-2-positive donors were analyzed with next-generation sequencing. The associations of CD177 SNP genotypes with HNA-2 expression variation were statistically analyzed.

Results: A functional CD177 SNP c.1291G>A was identified in the current study. Atypical (trimodal) HNA-2 expression phenotype was consistently observed in donors carrying the heterozygous c.1291G/A genotype. Phenotype-genotype analyses of SNP c.787A>T and SNP c.1291G>A revealed that all homozygous 787T-1291G (TG/TG) genotype donors were HNA-2 null in healthy blood donors. On the other hand, five of eight HNA-2-immunized females were homozygous for the 787T-1291G (TG/TG) genotype while the other three HNA-2-immunized females had the 787T-1291G/787A-1291A (TG/AA) genotype and the lowest HNA-2 expression was observed in healthy subjects with the 787T-1291G/787A-1291A (TG/AA) and 787A-1291A/787A-1291A (AA/AA) genotype.

Conclusion: The CD177 SNP c.1291G>A is a genetic determinant for the atypical and low HNA-2 expression, which also contributes to HNA-2 deficiency phenotype.

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Conflict of interest statement

Competing financial interests: The authors have disclosed no conflicts of interest.

Figures

Fig. 1.
Fig. 1.. Relationship between CD177 SNP c.787A>T-1291G>A genotypes and heterogeneous HNA-2 expression.
A). HNA-2 expression is absent on neutrophils from homozygous 787T-1291G (TG/TG) donors. B). Neutrophils from homozygous 787A-1291G (AG/AG) donors typically express high density of HNA-2. C). Atypical (tri-modal) HNA-2 expression pattern is always displayed on neutrophils from heterozygous 787A-1291G/787A-1291A (AG/AA) donors. D). Neutrophils from homozygous 787A-1291A (AA/AA) donors express a significantly lower level of HNA-2 compared to homozygous 787A-1291G (AG/AG) donors.
Fig. 2.
Fig. 2.. Non-conservative CD177 SNP c.1291G>A within the hydrophobic region for GPI-signal of HNA-2 processing.
CD177 SNP c.1291G>A causes the residue 431G to 431R substitution. Chromatograms of three SNP c.1291G>A genotypes (homozygous 1291A/A, heterozygous 1291A/G, and homozygous 1291G/G) were shown.
Fig. 3.
Fig. 3.. CD177 SNP c.787A>T and 1291G>A genotypes are associated with variable HNA-2 expressions in normal healthy blood donors.
A). SNP c.787A>T and c.1291G>A genotypes were associated with the percentage of HNA-2+ neutrophils. All homozygous 787T-1291G/787T-1291 (TG/TG) genotype donors were HNA-2 null. Heterozygous 787T-1291G/787A-1291G (TG/AG) donors had significantly lower percentages of HNA-2+ neutrophils than the homozygous 787A-1291G/787A-1291G (AG/AG) donors (P < 0.0001). Heterozygous 787T-1291G/787A-1291A (TG/AA) donors had significantly higher percentages of HNA-2+ neutrophils than the heterozygous 787T-1291G/787A-1291G (TG/AG) donors (P = 0.0148). B). SNP 787A>T and 1291G>A genotypes were associated with HNA-2 expression levels on HNA-2+ neutrophils. Neutrophils from the homozygous 787A-1291A/787A-1291A (AA/AA) donors expressed significantly lower levels of HNA-2 than those from the homozygous 787A-1291G/787A-1291A (AG/AG) donors (P = 0.001). Neutrophils from the heterozygous 787T-1291G/787A-1291A (TG/AA) donors also had much lower levels of HNA-2 expressions than those from heterozygous 787T-1291G/787A-1291G (TG/AG) donors (P = 0.0007). Neutrophils from heterozygous 787A-1291G/787A-1291A (AG/AA) donors also expressed significantly lower levels of HNA-2 than those from the homozygous 787A-1291G/787A-1291G (AG/AG) donors (P < 0.0001).
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