Objectives Vitamin D plays an immunoregulatory activity. The aim of this study was to assess the correlation between blood serum 25(OH)D levels and Th17 and Treg circulating subsets, mainly Treg/ICOS + which seems to have a protective role in autoimmunity, in children with T1D and their healthy siblings (S). The secondary aim was to evaluate the impact of vitamin D supplementation on these subsets. Patients and Methods 22 T1D and 33 S were enrolled. Glucose, HbA1c, 25(OH)D, Th17 (CD4 +CCR6 +), Treg (CD4 +CD25 +Foxp3 +), and Treg/ICOS + cells were evaluated. According to HLA haplotypes, subjects were classified as “at risk” (HLA +), "protective haplotypes" (HLA -; "nested controls"), and “undetermined” (HLA UND). T1D and S subjects were supplemented with cholecalciferol 1,000 IU/die and evaluated after 6 months. Results Vitamin D insufficiency (74.4 %) and deficiency (43%) were frequent. S subjects with 25(OH)D levels &25 nmol/L had Th17, Treg (p&0.01) and Treg/ICOS + (p&0.05) percentages higher than subjects with 25(OH)D >75 nmol/L. Treg/ICOS + percentages (p&0.05) were higher in HLA - S subjects compared to percentages observed in their siblings with T1D. At baseline, in S subjects, a decreasing trend in Th17 and Treg/ICOS + values (p&0.05) from vitamin D deficiency to sufficiency was observed; 25(OH)D levels were negative predictors of Treg/ICOS + (R-square: 0.301) and Th17 percentages (R-square: 0.138). After 6 months, supplemented S subjects showed higher 25(OH)D levels (p&0.0001), and lower Th17 (p&0.0001) and Treg/ICOS+ (p&0.05) percentages than at baseline; supplemented T1D patients only had a decrease in Th17 levels (p&0.05). Conclusion serum 25(OH)D levels seem to affect Th17 and Treg cell subsets in S subjects, consistent with its immunomodulating role. HLA role should be investigated in a larger population.

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Normal tissue radiosensitivity is thought to be influenced by an individual’s genetic background. However, the specific genetic variants underlying the risk of late skin reactions following radiotherapy for breast cancer remain elusive. To unravel the genetic basis for radiation-induced late skin toxicity, we carried out targeted next-generation sequencing of germline DNA samples from 48 breast cancer patients with extreme late skin toxicity phenotypes, consisting of 24 cases with grade 2–3 subcutaneous fibrosis and/or grade 2–3 telangiectasia (LENT-SOMA scales) and 24 controls with grade 0 fibrosis and grade 0 telangiectasia. In this exploratory study, a total of five single-nucleotide variants (SNVs) located in three genes (TP53, ERCC2, and LIG1) reached nominal levels of statistical significance (p < 0.05). In the replication study, which consisted of an additional 45 cases and 192 controls, none of the SNVs identified by targeted NGS achieved nominal replication. Nevertheless, TP53 rs1042522 (G > C, Pro72Arg) in the replication cohort had an effect (OR per C allele: 1.52, 95%CI: 0.82–2.83, p = 0.186) in the same direction as in the exploratory cohort (OR per C allele: 4.70, 95%CI: 1.51–14.6, p = 0.007) and was found be nominally associated to the risk of radiation-induced late skin toxicity in the overall combined cohort (OR per C allele: 1.79, 95%CI: 1.06–3.02, p = 0.028). These results raise the possibility of an association between TP53 rs1042522 and risk of radiation-induced late skin toxicity in breast cancer patients; however, large replication studies are warranted for conclusive evidence.

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Known multiple sclerosis (MS) susceptibility variants can only explain half of the disease’s estimated heritability, whereas low-frequency and rare variants may partly account for the missing heritability. Thus, here we sought to determine the occurrence of rare functional variants in a large Italian MS multiplex family with five affected members. For this purpose, we combined linkage analysis and next-generation sequencing (NGS)-based whole exome and whole genome sequencing (WES and WGS, respectively). The genetic burden attributable to known common MS variants was also assessed by weighted genetic risk score (wGRS). We found a significantly higher burden of common variants in the affected family members compared to that observed among sporadic MS patients and healthy controls (HCs). We also identified 34 genes containing at least one low-frequency functional variant shared among all affected family members, showing a significant enrichment in genes involved in specific biological processes—particularly mRNA transport—or neurodegenerative diseases. Altogether, our findings point to a possible pathogenic role of different low-frequency functional MS variants belonging to shared pathways. We propose that these rare variants, together with other known common MS variants, may account for the high number of affected family members within this MS multiplex family.