The Role of the 17q21 Genotype in the Prevention of Early Childhood Asthma and Recurrent Wheeze by Vitamin D

Rachel S Kelly; Bo L Chawes; Feng Guo; Li Zhang; Kevin Blighe; Augusto A Litonjua; Benjamin A Raby; Bruce D Levy; Daniela Rago; Jakob Stokholm; Klaus Bønnelykke; Hans Bisgaard; Xiaobo Zhou; Jessica A Lasky-Su; Scott T Weiss

doi:10.1183/13993003.00761-2019

The Role of the 17q21 Genotype in the Prevention of Early Childhood Asthma and Recurrent Wheeze by Vitamin D

Rachel S Kelly, Bo L Chawes, Feng Guo, Li Zhang, Kevin Blighe, Augusto A Litonjua, Benjamin A Raby, Bruce D Levy, Daniela Rago, Jakob Stokholm, Klaus Bønnelykke, Hans Bisgaard, Xiaobo Zhou, Jessica A Lasky-Su, Scott T Weiss

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Abstract

BACKGROUND: Evidence suggests vitamin D has preventive potential for asthma, however, not all children benefit from this intervention. This study aims to investigate whether variation in the functional 17q21 SNP; rs12936231 affects the preventive potential of vitamin D against asthma.

METHODS: A combined secondary analysis of two randomised-controlled trials of prenatal vitamin D supplementation for the prevention of asthma in offspring (Vitamin D Antenatal Asthma Reduction Trial (VDAART); and Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010)) was performed stratifying by genotype and integrating metabolite data to explore underlying mechanisms.

RESULTS: The protective effect of vitamin D on asthma/wheeze was evident among children with the low-risk rs12936231 GG-genotype (HR (95%CI) 0.49 (0.26, 0.94), p=0.032), but not the high-risk CC-genotype (HR(95%CI) 1.08 (0.69,1.69), p=0.751). In VDAART, in the GG-genotype vitamin D supplementation was associated with increased plasma levels of sphingolipids, including sphingosine-1-phosphate: (sphingosine-1-phosphate (β (95% CI) 0.022 (0.001, 0.044), p=0.038)); but this was not evident with the CC-genotype, known to be associated with increased expression of ORMDL3 in bronchial epithelial cells. Sphingolipid levels were associated with decreased risk of asthma/wheeze, and there was evidence of interactions between sphingolipid levels, vitamin D and genotype (p-interactionvitaminD*genotype*age1:sphingosine-1-phosphate=0.035). In a cellular model, there was a significant difference in the induction of sphingosine-1-phosphate by vitamin D between a control Human bronchial epithelial cell-line and a cell-line overexpressing ORMDL3 (p=0.002).

CONCLUSION: Results suggest prenatal vitamin D supplementation may reduce risk of early childhood asthma/wheeze via alterations of sphingolipid metabolism dependent on 17q21 genotype.

TRIAL REGISTRATION: clinicaltrials.gov Identifiers: VDAART NCT00920621, COPSAC2010NCT00856947.

Originalsprog	Engelsk
Tidsskrift	The European Respiratory Journal
Vol/bind	54
Udgave nummer	4
ISSN	0903-1936
DOI	https://doi.org/10.1183/13993003.00761-2019
Status	Udgivet - 1 okt. 2019

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Kelly, R. S., Chawes, B. L., Guo, F., Zhang, L., Blighe, K., Litonjua, A. A., Raby, B. A., Levy, B. D., Rago, D., Stokholm, J., Bønnelykke, K., Bisgaard, H., Zhou, X., Lasky-Su, J. A., & Weiss, S. T. (2019). The Role of the 17q21 Genotype in the Prevention of Early Childhood Asthma and Recurrent Wheeze by Vitamin D. The European Respiratory Journal, 54(4). https://doi.org/10.1183/13993003.00761-2019

Kelly, RS, Chawes, BL, Guo, F, Zhang, L, Blighe, K, Litonjua, AA, Raby, BA, Levy, BD, Rago, D, Stokholm, J , Bønnelykke, K, Bisgaard, H, Zhou, X, Lasky-Su, JA & Weiss, ST 2019, 'The Role of the 17q21 Genotype in the Prevention of Early Childhood Asthma and Recurrent Wheeze by Vitamin D', The European Respiratory Journal, bind 54, nr. 4. https://doi.org/10.1183/13993003.00761-2019

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title = "The Role of the 17q21 Genotype in the Prevention of Early Childhood Asthma and Recurrent Wheeze by Vitamin D",

abstract = "BACKGROUND: Evidence suggests vitamin D has preventive potential for asthma, however, not all children benefit from this intervention. This study aims to investigate whether variation in the functional 17q21 SNP; rs12936231 affects the preventive potential of vitamin D against asthma.METHODS: A combined secondary analysis of two randomised-controlled trials of prenatal vitamin D supplementation for the prevention of asthma in offspring (Vitamin D Antenatal Asthma Reduction Trial (VDAART); and Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010)) was performed stratifying by genotype and integrating metabolite data to explore underlying mechanisms.RESULTS: The protective effect of vitamin D on asthma/wheeze was evident among children with the low-risk rs12936231 GG-genotype (HR (95%CI) 0.49 (0.26, 0.94), p=0.032), but not the high-risk CC-genotype (HR(95%CI) 1.08 (0.69,1.69), p=0.751). In VDAART, in the GG-genotype vitamin D supplementation was associated with increased plasma levels of sphingolipids, including sphingosine-1-phosphate: (sphingosine-1-phosphate (β (95% CI) 0.022 (0.001, 0.044), p=0.038)); but this was not evident with the CC-genotype, known to be associated with increased expression of ORMDL3 in bronchial epithelial cells. Sphingolipid levels were associated with decreased risk of asthma/wheeze, and there was evidence of interactions between sphingolipid levels, vitamin D and genotype (p-interactionvitaminD*genotype*age1:sphingosine-1-phosphate=0.035). In a cellular model, there was a significant difference in the induction of sphingosine-1-phosphate by vitamin D between a control Human bronchial epithelial cell-line and a cell-line overexpressing ORMDL3 (p=0.002).CONCLUSION: Results suggest prenatal vitamin D supplementation may reduce risk of early childhood asthma/wheeze via alterations of sphingolipid metabolism dependent on 17q21 genotype.TRIAL REGISTRATION: clinicaltrials.gov Identifiers: VDAART NCT00920621, COPSAC2010NCT00856947.",

author = "Kelly, {Rachel S} and Chawes, {Bo L} and Feng Guo and Li Zhang and Kevin Blighe and Litonjua, {Augusto A} and Raby, {Benjamin A} and Levy, {Bruce D} and Daniela Rago and Jakob Stokholm and Klaus B{\o}nnelykke and Hans Bisgaard and Xiaobo Zhou and Lasky-Su, {Jessica A} and Weiss, {Scott T}",

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year = "2019",

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doi = "10.1183/13993003.00761-2019",

language = "English",

volume = "54",

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T1 - The Role of the 17q21 Genotype in the Prevention of Early Childhood Asthma and Recurrent Wheeze by Vitamin D

AU - Kelly, Rachel S

AU - Chawes, Bo L

AU - Guo, Feng

AU - Zhang, Li

AU - Blighe, Kevin

AU - Litonjua, Augusto A

AU - Raby, Benjamin A

AU - Levy, Bruce D

AU - Rago, Daniela

AU - Stokholm, Jakob

AU - Bønnelykke, Klaus

AU - Bisgaard, Hans

AU - Zhou, Xiaobo

AU - Lasky-Su, Jessica A

AU - Weiss, Scott T

PY - 2019/10/1

Y1 - 2019/10/1

N2 - BACKGROUND: Evidence suggests vitamin D has preventive potential for asthma, however, not all children benefit from this intervention. This study aims to investigate whether variation in the functional 17q21 SNP; rs12936231 affects the preventive potential of vitamin D against asthma.METHODS: A combined secondary analysis of two randomised-controlled trials of prenatal vitamin D supplementation for the prevention of asthma in offspring (Vitamin D Antenatal Asthma Reduction Trial (VDAART); and Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010)) was performed stratifying by genotype and integrating metabolite data to explore underlying mechanisms.RESULTS: The protective effect of vitamin D on asthma/wheeze was evident among children with the low-risk rs12936231 GG-genotype (HR (95%CI) 0.49 (0.26, 0.94), p=0.032), but not the high-risk CC-genotype (HR(95%CI) 1.08 (0.69,1.69), p=0.751). In VDAART, in the GG-genotype vitamin D supplementation was associated with increased plasma levels of sphingolipids, including sphingosine-1-phosphate: (sphingosine-1-phosphate (β (95% CI) 0.022 (0.001, 0.044), p=0.038)); but this was not evident with the CC-genotype, known to be associated with increased expression of ORMDL3 in bronchial epithelial cells. Sphingolipid levels were associated with decreased risk of asthma/wheeze, and there was evidence of interactions between sphingolipid levels, vitamin D and genotype (p-interactionvitaminD*genotype*age1:sphingosine-1-phosphate=0.035). In a cellular model, there was a significant difference in the induction of sphingosine-1-phosphate by vitamin D between a control Human bronchial epithelial cell-line and a cell-line overexpressing ORMDL3 (p=0.002).CONCLUSION: Results suggest prenatal vitamin D supplementation may reduce risk of early childhood asthma/wheeze via alterations of sphingolipid metabolism dependent on 17q21 genotype.TRIAL REGISTRATION: clinicaltrials.gov Identifiers: VDAART NCT00920621, COPSAC2010NCT00856947.

AB - BACKGROUND: Evidence suggests vitamin D has preventive potential for asthma, however, not all children benefit from this intervention. This study aims to investigate whether variation in the functional 17q21 SNP; rs12936231 affects the preventive potential of vitamin D against asthma.METHODS: A combined secondary analysis of two randomised-controlled trials of prenatal vitamin D supplementation for the prevention of asthma in offspring (Vitamin D Antenatal Asthma Reduction Trial (VDAART); and Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC2010)) was performed stratifying by genotype and integrating metabolite data to explore underlying mechanisms.RESULTS: The protective effect of vitamin D on asthma/wheeze was evident among children with the low-risk rs12936231 GG-genotype (HR (95%CI) 0.49 (0.26, 0.94), p=0.032), but not the high-risk CC-genotype (HR(95%CI) 1.08 (0.69,1.69), p=0.751). In VDAART, in the GG-genotype vitamin D supplementation was associated with increased plasma levels of sphingolipids, including sphingosine-1-phosphate: (sphingosine-1-phosphate (β (95% CI) 0.022 (0.001, 0.044), p=0.038)); but this was not evident with the CC-genotype, known to be associated with increased expression of ORMDL3 in bronchial epithelial cells. Sphingolipid levels were associated with decreased risk of asthma/wheeze, and there was evidence of interactions between sphingolipid levels, vitamin D and genotype (p-interactionvitaminD*genotype*age1:sphingosine-1-phosphate=0.035). In a cellular model, there was a significant difference in the induction of sphingosine-1-phosphate by vitamin D between a control Human bronchial epithelial cell-line and a cell-line overexpressing ORMDL3 (p=0.002).CONCLUSION: Results suggest prenatal vitamin D supplementation may reduce risk of early childhood asthma/wheeze via alterations of sphingolipid metabolism dependent on 17q21 genotype.TRIAL REGISTRATION: clinicaltrials.gov Identifiers: VDAART NCT00920621, COPSAC2010NCT00856947.

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DO - 10.1183/13993003.00761-2019

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SN - 0903-1936

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JO - The European Respiratory Journal

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The Role of the 17q21 Genotype in the Prevention of Early Childhood Asthma and Recurrent Wheeze by Vitamin D

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