Vitamin D-FUT2 interaction and risk of lower respiratory tract infections in childhood

Vitamin D levels and genetic variations of the FUT2 gene are both suggested to influence infection susceptibility in childhood. We previously showed that higher infant 25-hydroxyvitamin D (25(OH)D) levels associated with later reduced risk of infections in childhood¹ and that the FUT2 genotype on chromosome 19 holds a genetic risk for developing lower respiratory tract infections (LRTI).² Therefore, we hypothesized that an association between infant 25(OH)D levels and later risk of LRTI development could be influenced by variations in the FUT2 genotype.

We utilized data from daily longitudinally infection registrations in the Danish population-based COPSAC₂₀₁₀ cohort¹ and explored the interplay between 25(OH)D levels and variations in the FUT2 risk SNP rs601338 in relation to pneumonia risk as this was identified as a risk SNP for pneumonia.^{2, 3} Children were followed from birth until age 3 years including daily respiratory symptoms and doctor-diagnosed pneumonia episodes in diaries defined by troublesome cough accompanied by tachypnea, fever, and abnormal auscultation i.e. without confirmation by means of pathogen identification or radiologic or laboratory findings. Serum 25(OH)D levels were measured at age 6 months using the DiaSorin LIAISON Assay and divided into high (>82.7 nmol/L) vs low (<82.7 nmol/L) groups based on the median. Genotyping was performed using the Illumina BeadChip. We previously associated season of blood sample, child age and child BMI z-scores with 25(OH)D levels at 6 months and these covariates were adjusted for together with pregnancy interventions of vitamin D and fish-oil in our analyses.¹

Five hundred and fifty-three children had information on diary registered infections, 25(OH)D measurements at age 6 months and FUT2 genotyping (Table 1). We found significant interaction (p_interaction = .037) between 25(OH)D status and rs601338 genotype in a Cox regression model on risk of pneumonia until age 3 years, but no significant interaction between 25(OH)D as a continuous exposure and rs601338 genotype (p_interaction = .127) on risk of pneumonia. A genotype stratified analysis demonstrated a significant protective association between high 25(OH)D levels and risk of pneumonia episodes in the AG genotype strata (n = 274): adjusted hazard ratio: 0.52 (0.31–0.88), p = .01 and a similar trend in the homozygous low-risk AA genotype strata (n = 98): 0.59 (0.29–1.20), p = .14, whereas there was no association in the high-risk GG genotype strata (n = 181): 0.95 (0.54–1.68), p = .87 (Figure 1).

The association was observed in children having at least one low-risk A allele and not in children being homozygous for the LRTI associated GG genotype,^{2, 3} which proposes that vitamin D does not influence genetically high-risk children. A phenomenon that was also observed for 17q21 SNPs in relation to asthma risk. The FUT2 gene is responsible for coding the secretor enzyme fucosyltransferase 2 determining ABO antigen secretion status. Specific polymorphisms in the FUT2 gene are known to block production of the H-antigen located on bronchial epithelial cells⁴ and involved in the cascade of A- and B- antigen production.⁵ These glycan antigens has been suggested to play an important role for viral and bacterial infection susceptibility since pathogens specifically attach to host cell glycans.⁶ The homozygous AA genotype on the other hand is well recognized as causing the “non-secretor” phenotype inactivating the production of the ABO antigens resulting in a reduced susceptibility to both gastric and respiratory infections.⁵

We observed an almost halved risk of developing pneumonia during the first 3 years of life among children with high 25(OH)D at age 6 months having the AG genotype. The estimate was similar among the AA genotype, although the reduced sample size within this group could explain the non-significant association. The association between high 25(OH)D and a lower risk of pneumonia in these genotypes are likely to be a result of the suggested antimicrobial properties of vitamin D, which has shown to induce antimicrobial peptide production holding a role in the defense against pathogens.

In summary, this novel finding of an interaction between the well-known FUT2 risk SNP rs601338 and vitamin D status in early childhood on risk of later pneumonia development could provide basis for the development of a precision prevention strategy with early childhood vitamin D intervention against LRTI based on the genetic profile.

The guarantor of the study is NB. NB performed the statistical analyses and have written the first draft of the manuscript. JS, KB and BC have provided important intellectual input and contributed to the interpretation of the data.

NB received funding from The Capital Region Research Foundation (grant no. A7187) and The Lundbeck Foundation (R381-2021-1428). BC received funding from The European Union's Horizon 2020 research and innovation programme (grant no. 946228).

NB, JS, KB and BC all declare no conflict of interests regarding the content of this manuscript.