Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

We evaluated the effect of maternal vitamin E supplementation on the α-tocopherol concentrations of colostrum, transitional milk and mature milk of women who had given birth prematurely. This longitudinal randomised-controlled trial divided eighty-nine women into two groups: a control group and a supplemented group. Blood and breast milk were collected from all the participants after delivery. Next, each woman in the supplemented group received 400 IU of RRR-α-tocopheryl acetate. Further breast milk samples were collected 24 h after the first collection, as well as 7 and 30 d after delivery. α-Tocopherol concentrations were determined by HPLC. The baseline α-tocopherol concentrations in the maternal serum of the two groups were similar: 1159·8 (SD 292·4) μg/dl (27·0 (SD 6·8) μmol/l) for the control group and 1128·3 (SD 407·2) μg/dl (26·2 (SD 9·5) μmol/l) for the supplemented group. None of the women was vitamin E deficient. Breast milk α-tocopherol concentrations increased by 60 % 24 h after supplementation in the intervention group and did not increase at all in the control group. α-Tocopherol concentration of the transitional milk in the supplemented group was 35 % higher compared with the control group. α-Tocopherol concentrations of the mature milk in both groups were similar. Maternal supplementation with 400 IU of RRR-α-tocopherol increased the vitamin E concentrations of the colostrum and transitional milk, but not of the mature milk. This study presents relevant information for the design of strategies to prevent and combat vitamin E deficiency in the risk group of preterm infants.

Vitamin D supplementation is widely used. However, there is no consensus on the use and dosage of this supplement and the existing recommendations arise from studies based on the benefits that this nutrient can facilitate in bones. In addition, individual genetics can influence the response to supplementation, therefore, research involving monozygotic twins aims to reduce these differences in phenotypic responses. The objective of this randomised controlled study is to examine the effect of vitamin D supplementation on body composition and the expression of the vitamin D receptor (VDR) mRnA. An intervention was performed through supplementation with cholecalciferol at the concentration of 2000 IU in 90 healthy adult monozygotic twins (male or female pairs) for 2 months. The findings showed that serum vitamin D concentration increased by 65% and VDR gene expression sixty times (p = 0.001). Changes in body composition parameters were observed regarding body fat and lean mass. our results indicate that an increase in serum vitamin D concentration may have potential therapeutic implications. Supplementation with vitamin D (cholecalciferol) has become a widely used practice, since a relationship has been demonstrated of low levels of this nutrient with the increased risk of cardiovascular diseases, the recurrence of diseases, and mortality 1,2,3. However, as there is no consensus on sufficient serum levels of vitamin D, taking into account its non-skeletal functions, it is necessary to assess whether the increase in this nutrient in individuals with 25-hydroxyvitamin D (25 (OH) D) levels above the current cutoff point, generates any health benefits 4. Vitamin D is involved in several non-skeletal functions, such as cell regulation, differentiation, and growth 3 , and adaptive and innate immunity control 5 , as well as being associated with inflammatory markers 6 , since the vitamin D receptor (VDR) is expressed in almost all human cells 7. The activity of this nutrient in the human organism involves its binding with VDR 8 , whose expression is modulated by the blood levels of the 1,25diidroxivitamin D (1,25 (OH) 2D) 9 and genetic variants 10. It is believed that there is a negative correlation between the concentration of 25 (OH) D with the body mass index (BMI) and percentage of fat mass 11. However, few studies have comprehensively evaluated the effect of

Vitamin E is important because of its antioxidant activity in situations of oxidative stress, especially postnatally. Hence, the objective was to verify whether maternal alpha-tocopherol level is associated with the alpha-tocopherol levels of the newborn and colostrum. This is a cross-sectional study of 58 women and their term newborns from a public hospital. Blood and colostrum were collected to measure alpha-tocopherol levels by high-performance liquid chromatography. Mothers with serum alpha-tocopherol levels <16.2 mmol L(-1) and newborns <11.6 mmol L(-1) were indicative of deficiency or low levels. Mothers were divided into two groups: <16.2 mmol L(-1) and those with levels ≥16.2 mmol L(-1) . The mean (95% confidence interval) serum alpha-tocopherol levels of mothers, umbilical cords and colostrum were 28 (24-32), 6 (5-8) and 39 mmol L(-1) (32-45), respectively (P < 0.001); 19% of the women and 90% of the newborns had low alpha-tocopherol levels. Maternal alpha-tocopherol level was associated with that of the umbilical cord. Newborns from mothers at risk of deficiency had low alpha-tocopherol levels (P < 0.001). Colostrum levels of vitamin E were not influenced by maternal serum. Maternal deficiency influenced the vitamin E level of the umbilical cord but does not in the colostrum, evidencing distinct transfer mechanisms via the mammary gland.

Background Vitamin A deficiency is still considered to be a nutritional problem during pregnancy, lactation and early childhood. The present study aimed to assess the vitamin A status of women and their newborns in the Brazilian Northeast and to determine the association between retinol in the maternal serum, umbilical cord blood and colostrum. Methods Vitamin A status in 65 pairs of women and newborns was assessed from samples of the mother’s serum, umbilical cord serum and colostrum using high‐performance liquid chromatography. The inadequacy of the vitamin A status of mothers and infants was identified if the retinol values were <0.7 µmol L−1 in maternal serum or umbilical cord blood or <1.05 µmol L−1 in colostrum. Results The prevalence of inadequate maternal vitamin A status was 21.5% (95% CI: 11.5%–31.5%) and 13.8% [95% confidence interval (CI) = 5.4%–22.2%] based on maternal serum and colostrum, respectively. Among newborns, 41.5% (95% CI = 29.3%–53.5%) presented a low status of vitamin A based on cord serum. Multiple linear regression analysis identified that maternal serum retinol is a predictor of umbilical cord retinol (P = 0.005). Retinol in maternal serum was lower in mothers who were less educated (P = 0.04) and colostrum retinol was higher in older (P = 0.04) and multiparous (P = 0.002) mothers. Conclusions Vitamin A deficiency is a common problem among mothers attended in public hospitals in Northeast Brazil and maternal retinol concentrations are associated with retinol status in newborns. Maternal age, parity and educational level were related to the maternal vitamin A status.

Despite evidence showing that the intake of ultra-processed food has a negative impact on health, diet quality and dietary vitamin E, its impact on vitamin E nutritional status and breast milk remains unknown. This study aimed to assess the influence of the consumption of ultra-processed foods on vitamin E biomarkers of lactating women. A cross-sectional study was performed with 294 lactating women. Food consumption was obtained by 24-hour dietary recall and foods were grouped according to the NOVA classification. Levels of alpha-tocopherol were analyzed by High Performance Liquid Chromatography. Breast milk vitamin E (BMVE) adequacy was based on the quantity of the vitamin in the estimated intake volume. The Kruskal-Wallis test was used to compare the tertiles and linear regression to association between ultra-processed food consumption and biomarkers. Ultra-processed foods accounted for 16% of energy intake and vitamin E intakes by all women were considered low. Serum alpha-tocopherol was 26.55 (SD 7.98) µmol/L, 5% (n=11) showed inadequate vitamin E (<12µmol/L), and 78% had an inadequate BMVE content (< 4mg/780mL). The regression showed that a higher dietary share of ultra-processed foods was associated with lower concentrations of serum alpha-tocopherol (β=−0.168, CI=−0.047–0.010, p=0.003) and inadequate BMVE content (β=−0.144, CI=−0.505–0.063, p=0.012) (adjustment for income and maternal age). Thus, higher dietary shares of ultra-processed foods had an impact on vitamin E biomarkers, suggesting that inadequate dietary intake practices during lactation may reduce the supply of vitamin E to women and breast milk.

Objective: To determine the concentration of alpha-tocopherol in umbilical cord serum of full-term and preterm newborns, in order to assess the nutritional status of both groups in relation to the vitamin and its possible correlation with intrauterine growth.Methods: A cross-sectional observational study conducted with 140 newborns, of which 64 were preterm and 76 were full-term. They did not have any malformations, they came from healthy mothers, who were nonsmokers, and delivered a single baby. Intrauterine growth was evaluated by weight-to-gestational age at birth, using Intergrowth-21st. Thealpha-tocopherol levels of umbilical cord serum were analyzed by High Performance Liquid Chromatography.Results: The mean concentration of alpha-tocopherol in umbilical cord serum for preterm and full-term infants was 263.3±129.5 and 247.0±147.6 µg/dL (p=0.494). In the preterm group, 23% were small for gestational age, whereas in the full-term group, this percentage was only 7% (p=0.017). Low levels of vitamin E were found in 95.3% of preterm infants and 92.1% of full-term infants. There was no correlation between alpha-tocopherol levels and weight to gestational age Z score (p=0.951).Conclusions: No association was found between alpha-tocopherol levels and weight to gestational age at birth. Intrauterine growth restriction was more frequent in preterm infants and most infants had low levels of vitamin E at the time of delivery.

Objective: Dietary lipid intake is associated with serum alpha-tocopherol levels; however, its impact on human milk is unknown. The objective of this study was to evaluate the relationship between maternal intake of vitamin E, lipids, and fatty acids and the concentration of alpha-tocopherol in human milk. Methods: We conducted a longitudinal observational study, including 143 lactating women on 7, 30, and 90 days postpartum. Dietary intake was collected using 24-hour recall. On day 90, a human milk sample was collected and analyzed for alpha-tocopherol concentration. The prevalence of inadequate vitamin E intake was determined by the Estimated Average Requirement (16 mg/day), and the alpha-tocopherol concentration was analyzed by high-performance liquid chromatography. Results: Dietary intake of vitamin E was associated with the intake of lipids (r = 0.237, P = 0.004) and fatty acids (P < 0.05), and 100% of the participants had inadequate vitamin intake. Mean alpha-tocopherol concentration in the human milk samples was 7.11 (standard deviation 3.95) μmol/L and was correlated with lipid (r = 0.201, P = 0.042) and polyunsaturated fatty acid intake (r = 0.235, P = 0.017). Higher vitamin E levels were found in participants with the highest quartile of polyunsaturated fatty acid intake. Conclusions: Alpha-tocopherol concentration was associated with the dietary intake of lipids and fatty acids, demonstrating that its bioavailability is associated with fats in the mammary gland. These results suggest development of appropriate strategies to increase the levels of vitamin E in breast milk that may help to prevent and treat vitamin E deficiency.