Contribution of rare and common genetic variants to early-onset type 2 diabetes

Background and aims: Early-onset type 2 diabetes (T2D) shows a more aggressive metabolic phenotype as well as an higher risk of chronic diabetes complications and premature mortality as compared to the usual T2D diagnosed in middle-aged patients. Unfortunately, the intrinsic pathogenic signatures of early-onset T2D are not completely understood. While there are several strong evidences on the contribution provided by worse behavioral and environmental risk factors, data on the genetic background are sparse and inconclusive. Both rare and common genetic variants play a role in the risk of T2D, but their contribution in shaping the age of diabetes onset is still unknown. Thus, we sought to investigate whether either both rare deleterious variants in monogenic diabetes-genes and/or common T2D susceptibility SNPs play a role in determining the risk of early-onset T2D. Materials and methods: by using the extreme-phenotype approach, 600 individuals with age at diabetes onset <35 (n=300, cases) or >65 (n=300, controls) years, as selected among 9,700 Italian patients, were investigated. All 600 DNAs were subjected to targeted resequencing of 27 monogenic diabetes-genes and to genotyping of 22 GWAS-derived T2D-SNPs then used to create an un-weighted genetic risk score (GRS). Results: Rare (i.e. minor allele frequency, MAF <1%) and possibly deleterious (i.e. with an estimated impact on protein function) alleles (n=51, carried by 47 individuals) from 27 monogenic diabetes genes significantly increased by 71% the risk of early-onset type 2 diabetes. A progressively stronger association was observed for progressively rarer variants (OR, 95% CI =2.06, 1.16-3.68, p=0.014; 2.46, 1.65-5.19 p=0.018 for MAF <0.1% and <0.01%, respectively) with ultra-rare ones (MAF<0.001%) being associated with a 6.5-fold increased risk (OR, 95% CI =6.51, 1.92-22.1, p=0.003). A similar, though less pronounced, trend was observed when previously reported MODY-causing mutations (n=8) were excluded, with only ultra-rare variants remaining significantly associated with early-onset T2D (OR, 95% CI =4.84, 1.38-16.92 p=0.01). Additionally, each allele of the GRS including 22 susceptibility SNPs for T2D increased the risk of early diabetes by approximately 20%. When the 600 study subjects were stratified according to the two geographical regions of recruitment: 324 subjects (182 cases vs. 142 controls) from Central-Southern Italy and 276 (118 vs. 158) from the Rome urban area, a similar association with early-onset T2D for both rare variants and GRS was observed in the two subgroups, with no evidence of heterogeneity, thus providing an internal validation of our findings. Conclusion: our data show for the first time a sizeable influence of both rare and possibly deleterious variants in monogenic-diabetes genes and of common type 2 diabetes susceptibility variants in increasing the risk of early-onset type 2 diabetes

Perfil hematológico, bioquímico sérico e sorológico de Felis domesticus com lagochilascariose experimental Hematological, serum biochemical and serological profile of Felis domesticus with experimental lagochilascariosis

No presente trabalho, avaliou-se o hemograma, diversas proteínas e enzimas séricas ou plasmáticas e a produção de anticorpos específicos em Felis domesticus, experimentalmente infectados por Lagochilascaris minor. Verificou-se nos animais infectados aumento de leucócitos totais, principalmente eosinófilos; queda do número de plaquetas; aumento de aspartato-aminotransferase e alanina-aminotransferase; e principalmente a presença de anticorpos IgG específicos para antígenos do parasita. A reação com extrato bruto de parasitas adultos mostrou-se mais específica, permitindo a discriminação de soros de animais: não infectados, com infecção por outros parasitas, e com lagochilascariose. Esta é a primeira descrição da padronização de uma reação sorológica para diagnóstico da lagochilascariose em Felis domesticus.<br>The present study evaluated the hemogram, different proteins, plasma enzymes, serum enzymes and specific antibody production of Felis domesticus experimentally infected by Lagochilascaris minor. The infected animals were seen to present increased total leukocytes (particularly eosinophils), decreased platelet counts, increased aspartate-aminotransferase and alanine-aminotransferase and, especially, the presence of specific IgG antibodies against antigens of the parasite. The reaction with crude extract of adult parasites was shown to be more specific, thereby enabling serum discrimination between the animals: non-infected, infected with other parasites and infected with lagochilascariosis. This is the first description of the standardization of a serological reaction for diagnosing lagochilascariosis in Felis domesticus

Clinical utility for monogenic diabetes molecular testing among patients with early-onset type 2 diabetes

Background and Aim: Type 2 diabetes (T2D) is a heterogeneous group of metabolic disorders characterized by hyperglycemia diagnosed in adulthood (generally in the middle age). Some patients however have an earlier T2D onset (i.e. &lt;35 years) and a stronger family history of diabetes. It is of note that strong family history of diabetes and disease onset at young age are also typical features of some forms of monogenic diabetes, including MODY, thus pointing the possibility of a misclassification between early-onset T2D and diabetes monogenic forms. This is a pity because molecular diagnosis of monogenic diabetes can alter both follow-up and therapeutic approaches, representing in some cases a perfect example of precision medicine. Our aim was to investigate the proportion of individuals with monogenic diabetes forms among early-onset T2D patients. Methodology: 300 T2D patients with age at onset &lt;35 years, selected among 9601 Italian patients with a clinical diagnosis of T2D, were investigated by a custom targeted NGS panel (Illumina) including 27 monogenic diabetes-genes. Possibly deleterious variants were retrieved after filtering by means of an established bioinformatic pipeline and likelihood of causality according to the ACMG criteria. Results: Among the investigated patients, 20 carried 21 possible deleterious variants in 13 genes, 15 of which were classified as Pathogenic/Likely Pathogenic and 6 as VUS. Nine variants were found in the 4 most common MODY genes, 10 in the rarer ones and 2 in genes in which recessive mutations are responsible for syndromic diabetes. Notably, only one of the 15 patients carrying Pathogenic/Likely Pathogenic variants fulfilled all the generally accepted MODY diagnostic criteria. Conclusions: Among patients clinically defined as having “early-onset” T2D, 5% were rather affected by monogenic diabetes. These results i) highlight the importance of genetic testing for monogenic diabetes among T2D patients with an early disease manifestation ii) support the notion that the prevalence of monogenic diabetes is underestimated because of misdiagnosis with early-onset T2D but also for the too stringent diagnostic criteria so far used to clinically frame some of forms of monogenic diabetes, including MODY

TRIB3 R84 variant affects glucose homeostasis by alterino the interplay between insulin sensitività and insulin secretion.

Results of studies on the genetics of complex traits need to be replicated and to reach robust statistical significance before they can be considered as established. We here tried to replicate previous association between the TRIB3 Q84R polymorphism (rs2295490) and glucose homeostasis. Methods Three samples of Europeans with fasting glucose <7.0 mmol/l, were studied. In sample 1 (n=791), the association between TRIB3 Q84R and impaired glucose regulation (IGR: either impaired fasting glucose and/or impaired glucose tolerance and/or type 2 diabetes by OGTT), insulin sensitivity (ISI) and its interplay with early phase insulin secretion (i.e. disposition index, DI), were analyzed. Sample 2 (n=374) and sample 3 (n=394) were used to replicate the association with IGR and insulin sensitivity (by glucose clamp), respectively. Genotyping was performed by TaqMan allele discrimination. Results R84 carriers were at higher risk of IGR: odds ratio (OR) for additive model=1.54, p=0.004 and 1.63, p=0.027, in sample 1 and 2. In sample 1, both ISI (p=0.005) and DI (p=0.043) were progressively reduced from QQ to QR and RR individuals. A “triangulation approach” indicated that the association with IGR was mostly mediated by DI, rather than ISI changes (i.e. being the expected ORs 1.51 and 1.25, respectively). In sample 3, glucose disposal was 7.0±3.2, 6.1±2.6, and 5.7±2.4 mg/min x Kg, p=0.022, in QQ, QR and RR individuals). Conclusions Our data confirm that the TRIB3 R84 variant affects glucose homeostasis and suggest this effect is due to alteration of the interplay between insulin sensitivity and secretion

Cirurgias colorretais no Hospital Universitário da Universidade Federal de Sergipe: três anos da criação do Serviço de Coloproctologia (série histórica) Colorrectal surgery at the Federal University Hospital of Sergipe: an overview of three years after the creation of the Colorretal Group

Estudamos cirurgias colorretais do SC-HU/UFS (Serviço de Coloproctologia do Hospital Universitário da Universidade Federal de Sergipe) realizadas de janeiro de 2004 a julho de 2006, série histórica da criação da residência médica em coloproctologia. De setenta pacientes, 53(75,7%) eram do gênero masculino, 17(24,3%) feminino; idade variou de 19 a 85 anos com média de 52 anos. Os setenta pacientes foram submetidos a 102 procedimentos, com média de 1,4 cirurgias/paciente, 29(28,4%) reoperações. Dezenove(18,6%) foram reconstituições de trânsito intestinal, 15(14,8%) retossigmoidectomias, 11(10,8%) colectomias totais, 9(8,8%) colectomias direitas, 6(5,8%) amputações abdomino-perineais, 3(2,9%) proctocolectomias, 2(1,9%) colectomias esquerdas. Dezoito(17,6%) cirurgias indicadas por neoplasias de cólon, 8(7,8%) do reto e 1(0,9%) do canal anal; 10(9,9%) foram megacólon; 10(9,9%) colostomias prévias, 5(5,9%) Doença de Crohn, 5(4,9%) DDC, 3(2,9%) RCUI. Quarenta e oito(47,1%) cirurgias tiveram complicações cirúrgica: 32(31,4%) complicações da ferida operatória, 13(12,7%) abscessos abdominais, 11(10,8%) fístulas, 7(6,9%) deiscências, etc. Índice de infecção de ferida foi 26,5%. Cinqüenta e cinco pacientes(53,9%) foram submetidos à anastomose, 32(58,2%) manuais e 23(41,8%) mecânicas. Deiscência de anastomose em 7(12,7%) cirurgias: 1(3,1%) deiscência em anastomose manual e 6(26,1%), em mecânica. Óbito em 11(15,7%) pacientes. Avaliamos principais dados do trabalho objetivando definir metas, elaborar e melhorar protocolos vigentes objetivando otimizar o programa de residência médica.<br>We studied colorectal surgeries carried through by the SC-HU/UFS from January 2004 to July 2006, historical series, referring to the creation of the colorectal medical residence. Registres by seventy patients that 53(75.7%) were masculine sort and 17(24.3%) feminine; medium age is 52 years. They had been submitted to the 102 procedures, 1,4 surgeries/patients, 29 reoperations. Nineteen(18.6%) had been reconstitutions of intestinal transit, 15(14.8%) retossigmoidectomy, 11(10.8%) total colectomy, 9(8.8%) right colectomy, 6(5.8%) abdomino-perineais amputations, 3(2.9%) proctocolectomy, 2(1.9%) left colectomy. Eighteen (17.6%) surgeries were indicated for colorectal cancer, 8(7.8%) of rectum and 1(0.9%) of the anal canal; 10(9.9%) for megacólon; 10(9.9%) previous colostomy, 5(5.9%) Crohn's Disease, 5(4.9%) DDC, 3(2.9%) RCUI. Forty-eight (47.1%) surgeries have had surgical complication: 32(31.4%) ISOS, 13(12.7%) abdominal abscess, 11(10.8%) fístulas, 7(6.9%) dehiscences of anastomoses, etc. We observe wound infection in 27(26.5%) surgeries. Fifty-five(53.9%) patients had been submitted to the anastomoses, 32(58.2%) manual and 23(41.8%) stapled ones. It had dehiscence of anastomoses in 7(12.7%) surgeries: 1(3.1%) dehiscence for manual anastomoses and 6(26.1%) dehiscences for stapled anastomoses. Death in 11(15.7%) patient ones occurred. We evaluate the main data of the work objectifying to define goals, to elaborate and to improve the effective protocols, necessary to the good performance of the residence service