Screening of lipids and kidney function in children and adolescents with Type 1 Diabetes: does age matter?

IntroductionThe purpose of this study was to evaluate lipid profile and kidney function in children and adolescents with Type 1 Diabetes.MethodsThis was a retrospective study including 324 children and adolescents with Type 1 Diabetes (48% females, mean age 13.1 ± 3.2 years). For all participants, demographic and clinical information were collected. The prevalence of dyslipidemia and kidney function markers were analyzed according to age. Multivariate linear regression analyses were performed to test the association of lipids or markers of renal function with demographic and clinical information (sex, age, disease duration, BMI SDS, HbA1c).ResultsIn our study the rate of dyslipidemia reached 32% in children <11 years and 18.5% in those ≥11 years. Children <11 years presented significantly higher triglyceride values. While the albumin-to-creatinine ratio was normal in all individuals, 17% had mildly reduced estimated glomerular filtration rate. Median of HbA1c was the most important determinant of lipids and kidney function, being associated with Total Cholesterol (p-value<0.001); LDL Cholesterol (p-value=0.009), HDL Cholesterol (p-value=0.045) and eGFR (p-value=0.001).ConclusionDyslipidemia could be present both in children and adolescents, suggesting that screening for markers of diabetic complications should be performed regardless of age, pubertal stage, or disease duration, to optimize glycemia and medical nutrition therapy and/or to start a specific medical treatment

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

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 similar to 370,000 women, we identify 389 independent signals (P <5 x 10(-8)) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain similar to 7.4% of the population variance in age at menarche, corresponding to similar to 25% of the estimated heritability. We implicate similar to 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

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Variant annotation was supported by software resources provided via the Caché Campus program of the InterSystems GmbH to Alexander Teumer

Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits

Hypertension affects more than one billion people worldwide. Here we identify 113 novel loci, reporting a total of 2,103 independent genetic signals (P &lt; 5 × 10−8) from the largest single-stage blood pressure (BP) genome-wide association study to date (n = 1,028,980 European individuals). These associations explain more than 60% of single nucleotide polymorphism-based BP heritability. Comparing top versus bottom deciles of polygenic risk scores (PRSs) reveals clinically meaningful differences in BP (16.9 mmHg systolic BP, 95% CI, 15.5–18.2 mmHg, P = 2.22 × 10−126) and more than a sevenfold higher odds of hypertension risk (odds ratio, 7.33; 95% CI, 5.54–9.70; P = 4.13 × 10−44) in an independent dataset. Adding PRS into hypertension-prediction models increased the area under the receiver operating characteristic curve (AUROC) from 0.791 (95% CI, 0.781–0.801) to 0.826 (95% CI, 0.817–0.836, ∆AUROC, 0.035, P = 1.98 × 10−34). We compare the 2,103 loci results in non-European ancestries and show significant PRS associations in a large African-American sample. Secondary analyses implicate 500 genes previously unreported for BP. Our study highlights the role of increasingly large genomic studies for precision health research

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

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

Genetic variation in hla-g: its influence in autoinflammatory autoimmune and viral diseases

2012/2013L'antigene leucocitario umano (HLA)-G presenta, in condizioni fisiologiche, una ristretta espressione tessuto-specifica ed ha funzione immuno-tollerogenica. Però, la presenza della molecola HLA-G è stata associata a diverse patologie autoimmuni e virali. In questo progetto di dottorato di ricerca abbiamo analizzato la possibile associazione tra la varianti genetiche nel gene HLA-G, che si suppone regolino l'espressione di HLA-G, e la suscettibilità allo sviluppo e al decorso della malattia celiaca, del lupus eritematoso sistemico, dell'artrite reumatoide e dell'infezione dal virus dell'epatite C. Inoltre, abbiamo analizzato se variazioni all'interno del promotore di HLA-G possano alterare la sua trascrizione genica, a questo scopo è stato condotto il saggio della luciferasi. Per gli studi di associazione sono stati analizzati 800 bp del promotore, l’intero 3’UTR e la delezione di una citosina all’esone 3 (ΔC, allele HLA-G*0105N) in 402 pazienti celiaci e 509 controlli italiani; 114 pazienti con lupus eritematoso sistemico e 128 controlli sani provenienti dal Nord -Est del Brasile, 127 pazienti con artrite reumatoide e 128 controlli dal Nord-Est del Brasile, e 286 pazienti caucasici HCV positivi e 285 controlli provenienti dalla stessa area geografica. Il saggio della luciferasi è stato condotto su 9 diversi aplotipi al promotore del gene HLA-G: CCTAGGACCG, CGTAGGACCG, CTTAGGACCG, TCGGTACGAA, TGGGTACGAA, TTGGTACGAA, CCTAGGAGCG, CGTAGGAGCG, e CTTAGGAGCG. Numerosi SNPs e aplotipi del gene HLA-G sono stati associati con le malattie analizzate. Inoltre, il saggio della luciferasi ha permesso di constatare che la presenza di polimorfismi, nel promotore del gene HLA-G, altera la trascrizione genica; nello specifico, in condizioni di stress, l’allele -725 C era significativamente associato ad un aumento della trascrizione del gene rispetto agli alleli -725 G e T. I nostri i risultati indicano un'associazione tra i polimorfismi del gene HLA-G e la suscettibilità allo sviluppo delle malattie studiate, suggerendo che molecola HLA-G è coinvolta nella patogenesi di queste malattie. Inoltre, possiamo ipotizzare che il gene HLA-G sia un gene stress-inducibile e che la presenza di SNPs al promotore alterati i livelli di trascrizione del geneThe Human Leukocyte Antigen (HLA)-G present a physiological restricted tissue-specific expression and an immuno-tolerogenic functions. The HLA-G expression has been associated with various autoimmune and viral diseases. In this PhD project we analyzed the possible association between genetic variant in the HLA-G gene, supposed to regulate HLA-G expression, and the susceptibility to develop celiac disease, systemic lupus erythematosus, rheumatoid arthritis and hepatitis C virus infection. Furthermore, we analyzed if variations within the HLA-G promoter could alter its transcription, and for this reason luciferase reporter gene assays was conducted. The HLA-G 5’ upstream regulatory region (URR), 3’ untranslated region (UTR) and a cytosine deletion at exon 3 (ΔC, HLA-G*0105N allele) were analyzed in 402 celiac patients and 509 controls from Italy; 114 systemic lupus erythematosus patients and 128 healthy controls from North East Brazil; 127 rheumatoid arthritis patients and 128 controls from North East Brazil; and 286 Hepatitis C virus Caucasian patients and 285 controls from the same geographical area. The luciferase reporter gene assay was used for the HLA-G promoter CCTAGGACCG, CGTAGGACCG, CTTAGGACCG, TCGGTACGAA, TGGGTACGAA, TTGGTACGAA, CCTAGGAGCG, CGTAGGAGCG, and CTTAGGAGCG haplotypes. Several HLA-G SNPs and haplotypes were associated with the diseases analyzed. By luciferase reporter gene assay, we found that the presence of polymorphisms in the HLA-G promoter altered gene transcription, specifically -725 C allele was significantly associated with an increased of the HLA-G transcription with respect to -725 G and T alleles in stress condition. Our findings indicate an association between HLA-G gene polymorphisms and susceptibility to diseases development, suggesting that HLA-G molecule is involved in the pathogenesis of the diseases. Also, we can hypothesize that HLA-G gene is a stress-inducible gene and that the presence of SNPs to the promoter alter levels of transcription of the geneXXVI Ciclo198

HLA-G and susceptibility to develop celiac disease

The Human Leukocyte Antigen-G has immunomodulatory function and its expression has been associated with several diseases. In our study we analyzed HLA-G polymorphisms in order to evaluate their possible association with susceptibility to celiac disease development. A total of 420 celiac patients and 509 controls were genotyped for HLA-G polymorphisms. We sequenced 800bp upstream the ATG codon (5' upstream regulatory region) and the whole 3' untranslated region of the HLA-G gene, whereas the \u394C deletion at exon 3 was detected by RFLP-PCR. Five polymorphisms (namely -477 C>G, -369 C>A, 14bp del/ins, 3187 A>G, 3196 C>G) and one haplotype (TCGGTACGAAITCCCGAG) were significantly more frequent in celiac patients than controls and associated with increased disease susceptibility. The 14bp I/I, 3187 G/G, 3196 G/G genotypes and TCGGTACGAAITCCCGAG haplotype, were still significantly associated with increased disease susceptibility (and in addition also the 3003 C/C genotype) when the analysis was restricted to patients and controls presenting the DQ2.5 or DQ8 HLA-DQ celiac disease risk haplotypes. Our findings indicate an association between HLA-G gene polymorphisms and susceptibility to celiac disease development, suggesting that HLA-G molecule is possibly involved in the pathogenesis of the disease

Differences in taste and smell perception between type 2 diabetes mellitus patients and healthy controls

Background and Aims: Taste and smell senses are essential determinants of food choice which, in turn, may contribute to the development of chronic diseases, including diabetes. Although past studies have evaluated the relationship between type 2 diabetes mellitus (DM2) and senses disorders, this relationship still remains controversial. In this study, we evaluated taste and smell perception in DM2 patients and healthy controls (HC). Moreover, in DM2 patients we analyzed the association of chemosensory impairments with anthropometric and clinical outcomes (e.g. Body Mass Index (BMI), Fasting blood glucose (FBG), drugs, cardiovascular diseases (CVD) and hypertension). Methods and Results: The study included 94 DM2 patients and 244 HC. Taste recognition for 6-n-propylthiouracil (PROP), quinine, citric acid, sucrose and sodium chloride (NaCl) compounds was assessed using a filter paper method, while smell recognition of 12 odorants was performed using a sniffing sticks test. We found that a higher percentage of DM2 patients showed identification impairment in salt taste (22% vs. 5%, p-value<0.0009) and smell recognition (55% vs. 27%, p-value=0.03) compared to HC. We also observed that 65% of hypertensive DM2 subjects presented smell identification impairment respect to 18% of non-hypertensive patients (p-value=0.019). Finally, patients with impairments in both taste and smell showed elevated FBG compared to patients without impairment (149.6 vs.124.3 mg/dL, p-value=0.04). Conclusion: The prevalence of taste and smell identification impairments was higher in DM2 patients compared with HC and a possible relationship with glycemic levels emerged