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Metabolic and bariatric surgery (MBS) is an effective treatment for severe obesity, though individual responses vary widely, partly due to genetic predisposition. This study investigates the association of a body mass index (BMI) polygenic score (PGS) with weight loss and metabolic outcomes following surgery. A cohort of 225 patients undergoing MBS was analyzed at baseline (T0), six (T6), and twelve (T12) months, with anthropometric and biochemical parameters recorded at each time point. Total weight loss (TWL) and excess weight loss (EWL) percentages were calculated. PGS was computed using the LDpred-grid Bayesian method. The mean age was 45.9 ± 9.4 years. Males had a higher baseline prevalence of type 2 diabetes (T2D) and comorbidities (p < 0.001). Linear regression analysis confirmed an association between PGS and baseline BMI (p = 0.012). Moreover, mediation analysis revealed that baseline BMI mediated the effect of the PGS on %TWL at T12, with an indirect effect (p-value = 0.018). In contrast, high-density lipoprotein-cholesterol (HDL-C) at T6 and triglycerides (TG) at T12 showed direct associations with the PGS (p-value = 0.004 and p-value = 0.08, respectively), with no significant mediation by BMI. This study showed a BMI-mediated association of PGS with %TWL and a direct association with lipid changes, suggesting its potential integration into personalized obesity treatment.

Genetic variation plays a crucial role in individual differences in food preferences which ultimately influence food selection and health. Our current understanding of this pathway has been informed through twin studies (to assess the heritability of food preferences), candidate gene studies, and genome-wide association studies (GWAS). However, most of this literature is mainly focused on genes previously identified as having taste or smell functions. New data suggests that genes not associated with taste or smell perception may be involved in food preferences and contribute to health outcomes. This review highlights these emerging findings and suggests a polygenic risk assessment approach to explore new relationships between food preferences and health risks.

IntroductionType 1 diabetes is an autoimmune disease with an significant genetic component, played mainly by the HLA class II genes. Although evidence on the role of HLA class I genes in developing type 1 diabetes and its onset have emerged, current HLA screening is limited to determining DR3 and DR4 haplotypes. This study aimed to investigate the role of HLA genes on type 1 diabetes risk and age of onset by extensive typing.MethodsThis study included 115 children and young adults with type 1 diabetes for whom typing of HLA-A , -B , -C , -DRB1 , -DRB3/4/5 , -DQA1 , -DQB1 , -DPA1 and -DPB1 genes was conducted using Next Generation Sequencing.ResultsWe observed that 13% of type 1 diabetes subjects had non-classical HLA haplotypes that predispose to diabetes. We also found that compared to type 1 diabetes subjects with classical HLA haplotypes, non-classical HLA subjects had a significantly higher frequency of HLA-B*39:06:02 (p-value=0.01) and HLA-C*07:02:01 (p-value=0.03) alleles, known to be involved in activating the immune response. Non-classical HLA subjects also presented peculiar clinical features compared to classical HLA subjects, such as multiple diabetic antibodies and the absence of other autoimmune diseases (i.e., coeliac disease and thyroiditis). We also observed that subjects with early onset had a higher frequency of DQ2/DQ8 genotype than late-onset individuals. Moreover, subjects with late-onset had a higher frequency of alleles HLA-B*27 (p-value=0.003), HLA-C*01:02:01 (p-value=0.027) and C*02:02:02 (p-value=0.01), known to be associated with increased protection against viral infections.DiscussionThis study reveals a broader involvement of the HLA locus in the development and onset of type 1 diabetes, providing insights into new possible disease prevention and management strategies.

Diet is an essential element of treating and managing type 1 diabetes (T1D). However, limited research has examined food behaviour in children and adolescents with T1D and their relationship to glycaemic control. This study evaluated food behaviour, metabolic characteristics and their impact on the glycaemic control of children and adolescents with T1D. Two hundred and fifty-eight participants with T1D (6–15 years, duration of diabetes >1 year) were recruited. Demographic, anthropometric and clinical data were collected. Questionnaires on food neophobia and food preferences were administered. The Child Food Questionnaire (CFQ) also assessed parental feeding practices. An analysis of food behaviour showed that food neophobia was inversely associated with the liking of vegetables, fruits, fish, sweets and carbohydrates. Moreover, by analysing parental feeding practices, an inverse association of “Pressure to eat”, “Monitoring” and “Restriction” with liking for vegetables and carbohydrates emerged. Considering glycaemic control, increased food neophobia and the parent practices “Restriction”, “Pressure to eat” and “Concern about weight” were found in participants with glycated haemoglobin (HbA1c) values >8.5%. Finally, higher body mass index (BMI) and total cholesterol values were observed in subjects with HbA1c values >8.5%. These findings contribute to a better understanding of eating behaviour, metabolic status and their complex relationship with glycaemic control.

The HNF1A transcription factor, implicated in the regulation of pancreatic beta cells, as well as in glucose and lipid metabolism, is responsible for type 3 maturity-onset diabetes of the young (MODY3). HNF1A is also involved in increased susceptibility to polygenic forms of diabetes, such as type 2 diabetes (T2D) and gestational diabetes (GD), while its possible role in type 1 diabetes (T1D) is not known. In this study, 277 children and adolescents with T1D and 140 healthy controls were recruited. The following SNPs in HNF1A gene were selected: rs1169286, rs1169288, rs7979478, and rs2259816. Through linear or logistic regression analysis, we analyzed their association with T1D susceptibility and related clinical traits, such as insulin dose-adjusted glycated hemoglobin A1c (IDAA1c) and glycated hemoglobin (HbA1c). We found that rs1169286 was associated with IDAA1c and HbA1c values (p-value = 0.0027 and p-value = 0.0075, respectively), while rs1169288 was associated with IDAA1c (p-value = 0.0081). No association between HNF1A SNPs and T1D development emerged. In conclusion, our findings suggest for the first time that HNF1A variants may be a risk factor for beta cell function and glycaemic control in T1D individuals.

Celiac disease (CD) is a multifactorial common disorder with several susceptibility loci. Variations in the NALP1/NLRP1 and NALP3/NLRP3 genes have been reported to confer risk for several autoimmune conditions. We hypothesized that polymorphisms in these genes, due to their role in innate immunity and inflammatory processes, may affect susceptibility to CD. Two single-nucleotide polymorphisms (SNPs) in NLRP1 (rs12150220, rs2670660) and two SNPs (rs10754558, rs35829419) in NLRP3 genes were genotyped in 504 CD Italian patients and 256 healthy controls. The minor A allele of NLRP3 rs35829419 (Q705K) polymorphism appeared to exert a protective role against the development of CD (P=0.029; odds ratio (OR)=0.56). Moreover, a particular NLRP1 haplotype was associated with predisposition to CD (P=0.003; OR=1.38), even more when present in combination with the rs35829419 major C allele (P=0.002; OR=1.42). We hypothesized that the deregulation of CIAS1/NALP3/NLRP3 and NALP1/NLRP1 inflammasomes could have a role in CD pathogenesis.

John Perry, Ken Ong and colleagues analyze genotype data on ∼370,000 women and identify 389 independent signals that associate with age at menarche, implicating ∼250 genes. Their analyses suggest causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project–imputed genotype data in up to ∼370,000 women, we identify 389 independent signals ( P < 5 × 10 −8 ) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

Age-related hearing loss (ARHL) is the most common sensory disorder in the elderly. Although not directly life threatening, it contributes to loss of autonomy and is associated with anxiety, depression and cognitive decline. To search for genetic risk factors underlying ARHL, a large whole-genome sequencing (WGS) approach has been carried out in a cohort of 212 cases and controls, both older than 50 years to select genes characterized by a burden of variants specific to cases or controls. Accordingly, the total variation load per gene was compared and two groups were detected: 375 genes more variable in cases and 371 more variable in controls. In both cases, Gene Ontology analysis showed that the largest enrichment for biological processes (fold > 5, p-value = 0.042) was the “sensory perception of sound”, suggesting cumulative genetic effects were involved. Replication confirmed 141 genes, while additional analysis based on natural selection led to a prioritization of 21 genes. The majority of them (20 out of 21) showed positive expression in mouse cochlea cDNA and were associated with two functional pathways. Among them, two genes were previously associated with hearing (CSMD1 and PTRPD) and re-sequenced in a large Italian cohort of ARHL patients (N = 389). Results led to the identification of six coding variants not detected in cases so far, suggesting a possible protective role, which requires investigation. In conclusion, we show that this multistep strategy (WGS, selection, expression, pathway analysis and targeted re-sequencing) can provide major insights into the molecular characterization of complex diseases such as ARHL.

The HNF1A transcription factor, implicated in the regulation of pancreatic beta cells, as well as in glucose and lipid metabolism, is responsible for type 3 maturity-onset diabetes of the young (MODY3). HNF1A is also involved in increased susceptibility to polygenic forms of diabetes, such as type 2 diabetes (T2D) and gestational diabetes (GD), while its possible role in type 1 diabetes (T1D) is not known. In this study, 277 children and adolescents with T1D and 140 healthy controls were recruited. The following SNPs in HNF1A gene were selected: rs1169286, rs1169288, rs7979478, and rs2259816. Through linear or logistic regression analysis, we analyzed their association with T1D susceptibility and related clinical traits, such as insulin dose-adjusted glycated hemoglobin A1c (IDAA1c) and glycated hemoglobin (HbA1c). We found that rs1169286 was associated with IDAA1c and HbA1c values (p-value = 0.0027 and p-value = 0.0075, respectively), while rs1169288 was associated with IDAA1c (p-value = 0.0081). No association between HNF1A SNPs and T1D development emerged. In conclusion, our findings suggest for the first time that HNF1A variants may be a risk factor for beta cell function and glycaemic control in T1D individuals.

Celiac disease (CD) is the most common food-sensitive enteropathy in genetically susceptible individuals. The major genetic risk factors known are specific human leukocyte antigen (HLA)-DQ haplotypes, but other genetic factors are supposed to be involved. Interleukin-18 (IL-18) is a pro-inflammatory cytokine that has an important role in the immune defense and it has the potential to influence inflammatory disorders. IL-18 is able to promote Th1 cell development and it is expressed in the mucosa of the small intestine in celiac patients. Given the IL-18 biological role, and since a few studies have previously suggested its involvement in CD, in order to investigate the role of IL18 gene in the susceptibility to CD we have performed a case–control study, analyzing two IL18 gene promoter polymorphisms, previously reported to impair the transcriptional activity of the gene, (−137G > C and −607C > A, rs187238 and rs1946518 respectively). A total of 556 CD Italian patients and 582 controls, further stratified for HLA class II (DQ) CD risk haplotypes were enrolled. The −607A > C A allele and A/A genotype, as well as the combination of this allele with the −137G allele in the AG haplotype, were associated with an increased risk towards CD development, in particular in HLA-DQ2.2 patients. Although the association was very moderate, our results indicate the possible involvement of IL18 gene in the susceptibility to CD, and for this reason we do think it should deserve further investigation.