NKG2D gene variation and susceptibility to viral bronchiolitis in childhood

Anu Pasanen; Minna K Karjalainen; Laura Kummola; Johannes Waage; Klaus Bønnelykke; Marja Ruotsalainen; Eija Piippo-Savolainen; Emma Goksör; Kirsi Nuolivirta; Bo Chawes; Nadja Vissing; Hans Bisgaard; Tuomas Jartti; Göran Wennergren; Ilkka Junttila; Mikko Hallman; Matti Korppi; Mika Rämet

doi:10.1038/s41390-018-0086-9

NKG2D gene variation and susceptibility to viral bronchiolitis in childhood

Anu Pasanen, Minna K Karjalainen, Laura Kummola, Johannes Waage, Klaus Bønnelykke, Marja Ruotsalainen, Eija Piippo-Savolainen, Emma Goksör, Kirsi Nuolivirta, Bo Chawes, Nadja Vissing, Hans Bisgaard, Tuomas Jartti, Göran Wennergren, Ilkka Junttila, Mikko Hallman, Matti Korppi, Mika Rämet

Department of Clinical Medicine

3 Citations (Scopus)

Abstract

Background: Genetic factors associated with bronchiolitis are inadequately characterized. We therefore inspected a selected subpopulation of our previous genome-wide association study (GWAS) of bronchiolitis for overlap with known quantitative trait loci (QTLs) to identify susceptibility loci that potentially affect mRNA and protein levels. Methods: GWAS included a Finnish–Swedish case–control population (n = 187), matched for age and site. We integrated GWAS variants (p < 10⁻⁴) with QTL data. We subsequently verified allele-specific expression of identified QTLs by flow cytometry. Association of the resulting candidate loci with bronchiolitis was tested in three additional cohorts from Finland and Denmark (n = 1201). Results: Bronchiolitis-susceptibility variant rs10772271 resided within QTLs previously associated with NKG2D (NK group 2, member D) mRNA and protein levels. Flow cytometric analysis confirmed the association with protein level in NK cells. The GWAS susceptibility allele (A) of rs10772271 (odds ratio [OR] = 2.34) corresponded with decreased NKG2D expression. The allele was nominally associated with bronchiolitis in one Finnish replicate (OR = 1.50), and the other showed directional consistency (OR = 1.43). No association was detected in Danish population Conclusions: The bronchiolitis GWAS susceptibility allele was linked to decreased NKG2D expression in the QTL data and in our expression analysis. We propose that reduced NKG2D expression predisposes infants to severe bronchiolitis.

Original language	English
Journal	Pediatric Research
Volume	84
Pages (from-to)	451-457
ISSN	0031-3998
DOIs	https://doi.org/10.1038/s41390-018-0086-9
Publication status	Published - 1 Sept 2018

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Pasanen, A., Karjalainen, M. K., Kummola, L., Waage, J., Bønnelykke, K., Ruotsalainen, M., Piippo-Savolainen, E., Goksör, E., Nuolivirta, K., Chawes, B., Vissing, N., Bisgaard, H., Jartti, T., Wennergren, G., Junttila, I., Hallman, M., Korppi, M., & Rämet, M. (2018). NKG2D gene variation and susceptibility to viral bronchiolitis in childhood. Pediatric Research, 84, 451-457. https://doi.org/10.1038/s41390-018-0086-9

Pasanen, A, Karjalainen, MK, Kummola, L, Waage, J, Bønnelykke, K, Ruotsalainen, M, Piippo-Savolainen, E, Goksör, E, Nuolivirta, K, Chawes, B, Vissing, N, Bisgaard, H, Jartti, T, Wennergren, G, Junttila, I, Hallman, M, Korppi, M & Rämet, M 2018, 'NKG2D gene variation and susceptibility to viral bronchiolitis in childhood', Pediatric Research, vol. 84, pp. 451-457. https://doi.org/10.1038/s41390-018-0086-9

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title = "NKG2D gene variation and susceptibility to viral bronchiolitis in childhood",

abstract = "Background: Genetic factors associated with bronchiolitis are inadequately characterized. We therefore inspected a selected subpopulation of our previous genome-wide association study (GWAS) of bronchiolitis for overlap with known quantitative trait loci (QTLs) to identify susceptibility loci that potentially affect mRNA and protein levels. Methods: GWAS included a Finnish–Swedish case–control population (n = 187), matched for age and site. We integrated GWAS variants (p < 10−4) with QTL data. We subsequently verified allele-specific expression of identified QTLs by flow cytometry. Association of the resulting candidate loci with bronchiolitis was tested in three additional cohorts from Finland and Denmark (n = 1201). Results: Bronchiolitis-susceptibility variant rs10772271 resided within QTLs previously associated with NKG2D (NK group 2, member D) mRNA and protein levels. Flow cytometric analysis confirmed the association with protein level in NK cells. The GWAS susceptibility allele (A) of rs10772271 (odds ratio [OR] = 2.34) corresponded with decreased NKG2D expression. The allele was nominally associated with bronchiolitis in one Finnish replicate (OR = 1.50), and the other showed directional consistency (OR = 1.43). No association was detected in Danish population Conclusions: The bronchiolitis GWAS susceptibility allele was linked to decreased NKG2D expression in the QTL data and in our expression analysis. We propose that reduced NKG2D expression predisposes infants to severe bronchiolitis.",

author = "Anu Pasanen and Karjalainen, {Minna K} and Laura Kummola and Johannes Waage and Klaus B{\o}nnelykke and Marja Ruotsalainen and Eija Piippo-Savolainen and Emma Goks{\"o}r and Kirsi Nuolivirta and Bo Chawes and Nadja Vissing and Hans Bisgaard and Tuomas Jartti and G{\"o}ran Wennergren and Ilkka Junttila and Mikko Hallman and Matti Korppi and Mika R{\"a}met",

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doi = "10.1038/s41390-018-0086-9",

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T1 - NKG2D gene variation and susceptibility to viral bronchiolitis in childhood

AU - Pasanen, Anu

AU - Karjalainen, Minna K

AU - Kummola, Laura

AU - Waage, Johannes

AU - Bønnelykke, Klaus

AU - Ruotsalainen, Marja

AU - Piippo-Savolainen, Eija

AU - Goksör, Emma

AU - Nuolivirta, Kirsi

AU - Chawes, Bo

AU - Vissing, Nadja

AU - Bisgaard, Hans

AU - Jartti, Tuomas

AU - Wennergren, Göran

AU - Junttila, Ilkka

AU - Hallman, Mikko

AU - Korppi, Matti

AU - Rämet, Mika

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Background: Genetic factors associated with bronchiolitis are inadequately characterized. We therefore inspected a selected subpopulation of our previous genome-wide association study (GWAS) of bronchiolitis for overlap with known quantitative trait loci (QTLs) to identify susceptibility loci that potentially affect mRNA and protein levels. Methods: GWAS included a Finnish–Swedish case–control population (n = 187), matched for age and site. We integrated GWAS variants (p < 10−4) with QTL data. We subsequently verified allele-specific expression of identified QTLs by flow cytometry. Association of the resulting candidate loci with bronchiolitis was tested in three additional cohorts from Finland and Denmark (n = 1201). Results: Bronchiolitis-susceptibility variant rs10772271 resided within QTLs previously associated with NKG2D (NK group 2, member D) mRNA and protein levels. Flow cytometric analysis confirmed the association with protein level in NK cells. The GWAS susceptibility allele (A) of rs10772271 (odds ratio [OR] = 2.34) corresponded with decreased NKG2D expression. The allele was nominally associated with bronchiolitis in one Finnish replicate (OR = 1.50), and the other showed directional consistency (OR = 1.43). No association was detected in Danish population Conclusions: The bronchiolitis GWAS susceptibility allele was linked to decreased NKG2D expression in the QTL data and in our expression analysis. We propose that reduced NKG2D expression predisposes infants to severe bronchiolitis.

AB - Background: Genetic factors associated with bronchiolitis are inadequately characterized. We therefore inspected a selected subpopulation of our previous genome-wide association study (GWAS) of bronchiolitis for overlap with known quantitative trait loci (QTLs) to identify susceptibility loci that potentially affect mRNA and protein levels. Methods: GWAS included a Finnish–Swedish case–control population (n = 187), matched for age and site. We integrated GWAS variants (p < 10−4) with QTL data. We subsequently verified allele-specific expression of identified QTLs by flow cytometry. Association of the resulting candidate loci with bronchiolitis was tested in three additional cohorts from Finland and Denmark (n = 1201). Results: Bronchiolitis-susceptibility variant rs10772271 resided within QTLs previously associated with NKG2D (NK group 2, member D) mRNA and protein levels. Flow cytometric analysis confirmed the association with protein level in NK cells. The GWAS susceptibility allele (A) of rs10772271 (odds ratio [OR] = 2.34) corresponded with decreased NKG2D expression. The allele was nominally associated with bronchiolitis in one Finnish replicate (OR = 1.50), and the other showed directional consistency (OR = 1.43). No association was detected in Danish population Conclusions: The bronchiolitis GWAS susceptibility allele was linked to decreased NKG2D expression in the QTL data and in our expression analysis. We propose that reduced NKG2D expression predisposes infants to severe bronchiolitis.

U2 - 10.1038/s41390-018-0086-9

DO - 10.1038/s41390-018-0086-9

M3 - Journal article

C2 - 29967528

SN - 0031-3998

VL - 84

SP - 451

EP - 457

JO - Pediatric Research

JF - Pediatric Research

ER -

NKG2D gene variation and susceptibility to viral bronchiolitis in childhood

Abstract

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