Michele Rubini

Autoimmune diseases and bone density loss (osteopenia and osteoporosis) are chronic conditions of complex aetiology that affect diverse populations. Folate may be associated with a higher risk of these disorders due to its essential role in one-carbon metabolism required for nucleotide synthesis, homocysteine metabolism, and methylation processes. However, the evidence on this association is inconclusive. We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects from inception to February 2024 for systematic reviews and meta-analyses investigating the associations between folate exposure (dietary intake, supplementation, or blood concentrations) and any autoimmune diseases or skeletal outcomes. Pairs of researchers screened the retrieved syntheses, extracted the relevant data, assessed their risk of bias using the ROBIS tool, and evaluated the credibility of the evidence using predefined criteria. We found 19 reviews reporting 25 unique associations: 15 on autoimmune diseases (multiple sclerosis, inflammatory bowel disease, psoriasis, human immunodeficiency virus, vitiligo, and systemic lupus erythematosus) and 10 on skeletal outcomes (fractures and bone mineral density loss). Most of the syntheses consisted of small-scale case-control studies. The risk of bias in the included syntheses was high. Owing to the small sample sizes, all the unique associations were assessed to be at a weak level of credibility. The evidence on the relationship between folate status and autoimmune diseases or skeletal outcomes was limited in breadth and depth. Most of the 25 unique associations were reported by a single synthesis comprising small-scale studies. Subgroup analyses or dose-response analyses were severely limited or unavailable. More well-powered, prospective studies investigating the relationships between folate and autoimmune and skeletal conditions are warranted. PROSPERO: CRD42021265041.

Cardiovascular diseases (CVDs) encompass multiple subcategories of conditions, including coronary artery disease (CAD), heart failure, cerebrovascular diseases, cardiomyopathy, and peripheral artery disease. They are collectively the most prevalent chronic diseases globally as of 2019, accounting for approximately 523 million prevalent cases and 17.9 million deaths globally each year [1,2]. Metabolic diseases, an array of […]

Purpose Familial Isolated Pituitary Adenoma (FIPA) is a rare autosomal dominant condition associated with germline mutations in the Aryl Hydrocarbon Receptor-Interacting Protein (AIP) gene in ~ 20% of the cases. This study aims to characterize a novel AIP variant in a Sardinian family through genetic, clinical and immunohistochemical analyses and evaluate its pathogenicity. Methods The proband, a 17-year-old girl with an invasive prolactin (PRL)-secreting Pituitary Neuroedocrine Tumor (Pit-NET), also known as a pituitary adenoma, underwent germline AIP testing, extended to family members. All variant carriers underwent clinical and radiologic evaluation. Immunohistochemistry for AIP expression was performed on Pituitary adenoma/PitNet tissue from an affected relative. Variant pathogenicity was classified according to guidelines. Results A novel heterozygous AIP germline variant, c.479del (p.Pro160LeufsTer11 ), was identified in the proband and six relatives. Cabergoline treatment led to PRL levels normalization and tumor shrinkage in the proband. An affected cousin had an aggressive GH-secreting Pituitary adenoma/PitNet requiring multiple treatments. All other carriers had no clinical findings, and their imaging was unremarkable. The variant causes a premature stop codon leading to a truncated protein, lacking the three C-terminal tetratricopeptide repeat domains, essential for AIP protein-protein interactions and tumor suppressor function. Immunohistochemistry showed reduced AIP expression. The variant is classified as pathogenic. Conclusion This report expands the variants spectrum of AIP-related FIPA, confirming intra-familial phenotypic variability, from asymptomatic carriers to aggressive Pituitary adenoma/PitNet. Early genetic screening and surveillance are essential for timely diagnosis and personalized management.

Folate has been examined extensively in relation to carcinogenesis due to its role in one-carbon metabolism impacting the synthesis of DNA and RNA, methylation processes, and genomic integrity. Current evidence on the relationship between folate status and the risk of cancer is equivocal: low or deficient folate status may contribute to an increased risk of cancers, while high-dose folic acid supplementation may have adverse effects on carcinogenesis. We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects up to February 2024 for systematic reviews and meta-analyses investigating the associations of folate (measured as dietary intake, supplementation, or blood concentrations) with any specific cancer outcome. Screening, data extraction, and risk of bias assessment were performed in duplicate. We assessed the credibility of the evidence using predefined criteria. We found 67 syntheses, of which 57 provided meta-analyses. Over half of the syntheses had a high risk of bias. We identified 168 unique associations (unique exposure - unique outcome - unique setting) across 10 cancer types, 3 system cancers, and total cancer. Of these, we assessed 15 directional associations (colorectal, oesophageal, and total cancers) to be at a highly suggestive level of credibility, and 17 directional and 10 null associations to be at a suggestive level of credibility. The available evidence for each category of unique association was generally limited. Highly suggestive associations were found for oesophageal, colorectal, childhood brain and spinal tumours and total cancers. More robust primary studies are warranted to follow-up the signal of a positive relationship reported for prostate cancer warranting further research. Evidence was weak for all but colorectal and oesophageal cancers, or the central nervous system cancers in children. PROSPERO: CRD42021265041.

Folate is required for one-carbon metabolism, a network of reactions involving the transfer and utilisation of one-carbon units for key biological reactions, including the biosynthesis of DNA and RNA, amino acid metabolism, and methylation processes [1]. It is thus essential for normal growth and development and in human health throughout the lifecycle. Clinical deficiency of […]

Background/Objectives: We investigated maternal and parent-of-origin (PoO) gene-environment interaction effects on the risk of nonsyndromic orofacial clefts for two maternal environmental factors: periconceptional smoking and folic acid supplementation. Methods: Genome-wide single nucleotide polymorphisms (SNPs) genotypes and TopMed-imputed genotypes were obtained for case-parent triads from the EUROCRAN and ITALCLEFT studies. Candidate regions were selected around target SNPs from a previous genome-wide association study, resulting in 12 (726 SNPs) and 11 regions (730 SNPs) for maternal and PoO effects, respectively. Log-linear models were used to analyze 404 case-parent triads and 40 case-parent dyads. p-values were combined across regions. Results: None of the interactions reached statistical significance after correction for the number of regions tested. Nominally significant (pooled p-values < 0.05) interactions pointed to regions in or close to genes LRRC7 (maternal gene-folate interaction), NCKAP5 (PoO-smoking interaction), and IFT43 and GPATCH2L (PoO-folate interaction). Conclusions: Our results suggested that the genetic effects in or around these genes were heightened under periconceptional exposure to tobacco or no folic acid supplementation. The involvement of these genes in orofacial cleft development, in conjunction with environmental exposures, should be further studied.

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease with a prevalence of 1%. Currently, RA treatment aims to achieve low disease activity or remission. Failure to achieve this goal causes disease progression with a poor prognosis. When treatment with first-line drugs fails, treatment with tumor necrosis factor-α (TNF-α) inhibitors may be prescribed to which many patients do not respond adequately, making the identification of response markers urgent. This study investigated the association of two RA-related genetic polymorphisms, c.665C>T (historically referred to as C677T) and c.1298A>C, in the MTHFR gene as response markers to an anti-TNF-α therapy. A total of 81 patients were enrolled, 60% of whom responded to the therapy. Analyses showed that both polymorphisms were associated with a response to therapy in an allele dose-dependent manner. The association for c.665C>T was significant for a rare genotype (p = 0.01). However, the observed opposite trend of association for c.1298A>C was not significant. An analysis revealed that c.1298A>C, unlike c.665C>T, was also significantly associated with the drug type (p = 0.032). Our preliminary results showed that the genetic polymorphisms in the MTHFR gene were associated with a response to anti-TNF-α therapy, with a potential significance for the anti-TNF-α drug type. This evidence suggests a role for one-carbon metabolism in anti-TNF-α drug efficacy and contributes to further personalized RA interventions.

Background: Methotrexate (MTX) is considered the first choice among disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA) treatment. However, response to it varies as approximately 40% of the patients do not respond and would lose the most effective period of treatment time. Therefore, having a predictive biomarker before starting MTX treatment is of utmost importance. Methylation of long interspersed nucleotide element-1 (LINE-1) is generally considered a surrogate marker for global genomic methylation, which has been reported to associate with disease activity after MTX therapy. Methods: We performed a prospective study on 273 naïve early RA (ERA) patients who were treated with MTX, followed up to 12 months, and classified according to their therapy response. The baseline LINE-1 methylation levels in peripheral blood mononuclear cells (PBMC) of cases were assessed by bisulfite pyrosequencing. Results: Baseline LINE-1 methylation level per se turned out not to predict the response to the therapy, nor did age, sex, body mass index, or smoking status. However, if cases were stratified according to positivity to rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) or seronegativity, we observed an opposite association between baseline LINE-1 methylation levels and optimal response to MTX therapy among responders. The best response to MTX therapy was associated with hypermethylated LINE-1 among double-positive ERA cases (p-value: 0.002) and with hypomethylated LINE-1 in seronegative ERA patients (p-value: 0.01). Conclusion: The LINE-1 methylation level in PBMCs of naïve ERA cases associates with the degree of response to MTX therapy in an opposite way depending on the presence of RF and ACPA antibodies. Our results suggest LINE-1 methylation level as a new epigenetic biomarker for predicting the degree of response to MTX in both double-positive and seronegative ERA patients.