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1.
Cell ; 157(7): 1577-90, 2014 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-24949970

RESUMO

Clec16a has been identified as a disease susceptibility gene for type 1 diabetes, multiple sclerosis, and adrenal dysfunction, but its function is unknown. Here we report that Clec16a is a membrane-associated endosomal protein that interacts with E3 ubiquitin ligase Nrdp1. Loss of Clec16a leads to an increase in the Nrdp1 target Parkin, a master regulator of mitophagy. Islets from mice with pancreas-specific deletion of Clec16a have abnormal mitochondria with reduced oxygen consumption and ATP concentration, both of which are required for normal ß cell function. Indeed, pancreatic Clec16a is required for normal glucose-stimulated insulin release. Moreover, patients harboring a diabetogenic SNP in the Clec16a gene have reduced islet Clec16a expression and reduced insulin secretion. Thus, Clec16a controls ß cell function and prevents diabetes by controlling mitophagy. This pathway could be targeted for prevention and control of diabetes and may extend to the pathogenesis of other Clec16a- and Parkin-associated diseases.


Assuntos
Diabetes Mellitus Tipo 1/genética , Ilhotas Pancreáticas/patologia , Lectinas Tipo C/metabolismo , Mitofagia , Proteínas de Transporte de Monossacarídeos/metabolismo , Sequência de Aminoácidos , Animais , Proteínas de Transporte/química , Diabetes Mellitus Tipo 1/patologia , Predisposição Genética para Doença , Glucose/metabolismo , Humanos , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Lectinas Tipo C/química , Lectinas Tipo C/genética , Lisossomos/química , Lisossomos/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Dados de Sequência Molecular , Proteínas de Transporte de Monossacarídeos/química , Proteínas de Transporte de Monossacarídeos/genética , Polimorfismo de Nucleotídeo Único , Ubiquitina-Proteína Ligases
2.
Cell ; 156(1-2): 343-58, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24439387

RESUMO

Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.


Assuntos
Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , Animais , Linhagem Celular , Células Cultivadas , Sequência Conservada , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Proteínas de Homeodomínio/metabolismo , Humanos , Resistência à Insulina , PPAR gama/genética , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição/metabolismo
3.
Hum Mol Genet ; 31(19): 3377-3391, 2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-35220425

RESUMO

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 × 10-8) with GDM, mapping to/near MTNR1B (P = 4.3 × 10-54), TCF7L2 (P = 4.0 × 10-16), CDKAL1 (P = 1.6 × 10-14), CDKN2A-CDKN2B (P = 4.1 × 10-9) and HKDC1 (P = 2.9 × 10-8). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.


Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Gestacional/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Glucose , Humanos , Polimorfismo de Nucleotídeo Único/genética , Gravidez
4.
EMBO J ; 39(1): e100882, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31750562

RESUMO

Maternal drug abuse during pregnancy is a rapidly escalating societal problem. Psychostimulants, including amphetamine, cocaine, and methamphetamine, are amongst the illicit drugs most commonly consumed by pregnant women. Neuropharmacology concepts posit that psychostimulants affect monoamine signaling in the nervous system by their affinities to neurotransmitter reuptake and vesicular transporters to heighten neurotransmitter availability extracellularly. Exacerbated dopamine signaling is particularly considered as a key determinant of psychostimulant action. Much less is known about possible adverse effects of these drugs on peripheral organs, and if in utero exposure induces lifelong pathologies. Here, we addressed this question by combining human RNA-seq data with cellular and mouse models of neuroendocrine development. We show that episodic maternal exposure to psychostimulants during pregnancy coincident with the intrauterine specification of pancreatic ß cells permanently impairs their ability of insulin production, leading to glucose intolerance in adult female but not male offspring. We link psychostimulant action specifically to serotonin signaling and implicate the sex-specific epigenetic reprogramming of serotonin-related gene regulatory networks upstream from the transcription factor Pet1/Fev as determinants of reduced insulin production.


Assuntos
Diabetes Mellitus Tipo 2/etiologia , Intolerância à Glucose/etiologia , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Ilhotas Pancreáticas/patologia , Metanfetamina/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Estimulantes do Sistema Nervoso Central/toxicidade , Metilação de DNA , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Humanos , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Exposição Materna/efeitos adversos , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia
5.
Diabetologia ; 66(1): 70-81, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35900371

RESUMO

AIMS/HYPOTHESES: Smoking and use of smokeless tobacco (snus) are associated with an increased risk of type 2 diabetes. We investigated whether smoking and snus use increase the risk of latent autoimmune diabetes in adults (LADA) and elucidated potential interaction with HLA high-risk genotypes. METHODS: Analyses were based on Swedish case-control data (collected 2010-2019) with incident cases of LADA (n=593) and type 2 diabetes (n=2038), and 3036 controls, and Norwegian prospective data (collected 1984-2019) with incident cases of LADA (n=245) and type 2 diabetes (n=3726) during 1,696,503 person-years of follow-up. Pooled RRs with 95% CIs were estimated for smoking, and ORs for snus use (case-control data only). The interaction was assessed by attributable proportion (AP) due to interaction. A two-sample Mendelian randomisation (MR) study on smoking and LADA/type 2 diabetes was conducted based on summary statistics from genome-wide association studies. RESULTS: Smoking (RRpooled 1.30 [95% CI 1.06, 1.59] for current vs never) and snus use (OR 1.97 [95% CI 1.20, 3.24] for ≥15 box-years vs never use) were associated with an increased risk of LADA. Corresponding estimates for type 2 diabetes were 1.38 (95% CI 1.28, 1.49) and 1.92 (95% CI 1.27, 2.90), respectively. There was interaction between smoking and HLA high-risk genotypes (AP 0.27 [95% CI 0.01, 0.53]) in relation to LADA. The positive association between smoking and LADA/type 2 diabetes was confirmed by the MR study. CONCLUSIONS/INTERPRETATION: Our findings suggest that tobacco use increases the risk of LADA and that smoking acts synergistically with genetic susceptibility in the promotion of LADA. DATA AVAILABILITY: Analysis codes are shared through GitHub ( https://github.com/jeseds/Smoking-use-of-smokeless-tobacco-HLA-genotypes-and-incidence-of-LADA ).


Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Autoimune Latente em Adultos , Tabaco sem Fumaça , Humanos , Tabaco sem Fumaça/efeitos adversos , Diabetes Autoimune Latente em Adultos/epidemiologia , Diabetes Autoimune Latente em Adultos/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Estudos Prospectivos , Fumar/efeitos adversos , Fumar/epidemiologia , Fumar/genética
6.
Diabetologia ; 65(1): 206-215, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34676424

RESUMO

AIMS/HYPOTHESIS: Data analyses from Swedish individuals with newly diagnosed diabetes have suggested that diabetes could be classified into five subtypes that differ with respect to the progression of dysglycaemia and the incidence of diabetes consequences. We assessed this classification in a multiethnic cohort of participants with established and newly diagnosed diabetes, randomly allocated to insulin glargine vs standard care. METHODS: In total, 7017 participants from the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial were assigned to the five predefined diabetes subtypes (namely, severe auto-immune diabetes, severe insulin-deficient diabetes, severe insulin-resistant diabetes, mild obesity-related diabetes, mild age-related diabetes) based on the age at diabetes diagnosis, BMI, HbA1c, fasting C-peptide levels and the presence of glutamate decarboxylase antibodies at baseline. Differences between diabetes subtypes in cardiovascular and renal outcomes were investigated using Cox regression models for a median follow-up of 6.2 years. We also compared the effect of glargine vs standard care on hyperglycaemia, defined by having a mean post-randomisation HbA1c ≥6.5%, between subtypes. RESULTS: The five diabetes subtypes were replicated in the ORIGIN trial and exhibited similar baseline characteristics in Europeans and Latin Americans, compared with the initially described clusters in the Swedish cohort. We confirmed differences in renal outcomes, with a higher incidence of events in the severe insulin-resistant diabetes subtype compared with the mild age-related diabetes subtype (i.e., chronic kidney disease stage 3A: HR 1.49 [95% CI 1.31, 1.71]; stage 3B: HR 2.25 [1.82, 2.78]; macroalbuminuria: HR 1.56 [1.22, 1.99]). No differences were observed in the incidence of retinopathy and cardiovascular diseases after adjusting for multiple hypothesis testing. Diabetes subtypes also differed in glycaemic response to glargine, with a particular benefit of receiving glargine (vs standard care) in the severe insulin-deficient diabetes subtype compared with the mild age-related diabetes subtype, with a decreased occurrence of hyperglycaemia by 13% (OR 1.36 [1.30, 1.41] on glargine; OR 1.49 [1.43, 1.57] on standard care; p for interaction subtype × intervention = 0.001). CONCLUSIONS/INTERPRETATION: Cluster analysis enabled the characterisation of five subtypes of diabetes in a multiethnic cohort. Both the incidence of renal outcomes and the response to insulin varied between diabetes subtypes. These findings reinforce the clinical utility of applying precision medicine to predict comorbidities and treatment responses in individuals with diabetes. TRIAL REGISTRATION: ORIGIN trial, ClinicalTrials.gov NCT00069784.


Assuntos
Diabetes Mellitus Tipo 2 , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/uso terapêutico , Insulina Glargina/uso terapêutico , Insulina de Ação Prolongada/uso terapêutico , Resultado do Tratamento
7.
Diabetologia ; 65(1): 128-139, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34743218

RESUMO

AIMS/HYPOTHESIS: Galectin-1 modulates inflammation and angiogenesis, and cross-sectional studies indicate that galectin-1 may be a uniting factor between obesity, type 2 diabetes and kidney function. We examined whether circulating galectin-1 can predict incidence of chronic kidney disease (CKD) and type 2 diabetes in a middle-aged population, and if Mendelian randomisation (MR) can provide evidence for causal direction of effects. METHODS: Participants (n = 4022; 58.6% women) in the Malmö Diet and Cancer Study-Cardiovascular Cohort enrolled between 1991 and 1994 (mean age 57.6 years) were examined. eGFR was calculated at baseline and after a mean follow-up of 16.6 ± 1.5 years. Diabetes status was ascertained through registry linkage (mean follow-up of 18.4 ± 6.1 years). The associations of baseline galectin-1 with incident CKD and type 2 diabetes were assessed with Cox regression, adjusting for established risk factors. In addition, a genome-wide association study on galectin-1 was performed to identify genetic instruments for two-sample MR analyses utilising the genetic associations obtained from the Chronic Kidney Disease Genetics (CKDGen) Consortium (41,395 cases and 439,303 controls) and the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium (74,124 cases and 824,006 controls). One genome-wide significant locus in the galectin-1 gene region was identified (sentinel SNP rs7285699; p = 2.4 × 10-11). The association between galectin-1 and eGFR was also examined in individuals with newly diagnosed diabetes from the All New Diabetics In Scania (ANDIS) cohort. RESULTS: Galectin-1 was strongly associated with lower eGFR at baseline (p = 2.3 × 10-89) but not with incident CKD. However, galectin-1 was associated with increased risk of type 2 diabetes (per SD increase, HR 1.12; 95% CI 1.02, 1.24). Two-sample MR analyses could not ascertain a causal effect of galectin-1 on CKD (OR 0.92; 95% CI 0.82, 1.02) or type 2 diabetes (OR 1.05; 95% CI 0.98, 1.14) in a general population. However, in individuals with type 2 diabetes from ANDIS who belonged to the severe insulin-resistant diabetes subgroup and were at high risk of diabetic nephropathy, genetically elevated galectin-1 was significantly associated with higher eGFR (p = 5.7 × 10-3). CONCLUSIONS/INTERPRETATION: Galectin-1 is strongly associated with lower kidney function in cross-sectional analyses, and two-sample MR analyses suggest a causal protective effect on kidney function among individuals with type 2 diabetes at high risk of diabetic nephropathy. Future studies are needed to explore the mechanisms by which galectin-1 affects kidney function and whether it could be a useful target among individuals with type 2 diabetes for renal improvement.


Assuntos
Diabetes Mellitus Tipo 2 , Insuficiência Renal Crônica , Estudos Transversais , Diabetes Mellitus Tipo 2/genética , Feminino , Galectina 1/genética , Estudo de Associação Genômica Ampla , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/genética , Fatores de Risco
8.
Diabetologia ; 65(4): 632-643, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34951657

RESUMO

AIMS/HYPOTHESIS: Systematic studies on the phenotypic consequences of variants causal of HNF1A-MODY are rare. Our aim was to assess the phenotype of carriers of a single HNF1A variant and genetic and clinical factors affecting the clinical spectrum. METHODS: We conducted a family-based multigenerational study by comparing heterozygous carriers of the HNF1A p.(Gly292fs) variant with the non-carrier relatives irrespective of diabetes status. During more than two decades, 145 carriers and 131 non-carriers from 12 families participated in the study, and 208 underwent an OGTT at least once. We assessed the polygenic risk score for type 2 diabetes, age at onset of diabetes and measures of body composition, as well as plasma glucose, serum insulin, proinsulin, C-peptide, glucagon and NEFA response during the OGTT. RESULTS: Half of the carriers remained free of diabetes at 23 years, one-third at 33 years and 13% even at 50 years. The median age at diagnosis was 21 years (IQR 17-35). We could not identify clinical factors affecting the age at conversion; sex, BMI, insulin sensitivity or parental carrier status had no significant effect. However, for 1 SD unit increase of a polygenic risk score for type 2 diabetes, the predicted age at diagnosis decreased by 3.2 years. During the OGTT, the carriers had higher levels of plasma glucose and lower levels of serum insulin and C-peptide than the non-carriers. The carriers were also leaner than the non-carriers (by 5.0 kg, p=0.012, and by 2.1 kg/m2 units of BMI, p=2.2 × 10-4, using the first adult measurements) and, possibly as a result of insulin deficiency, demonstrated higher lipolytic activity (with medians of NEFA at fasting 621 vs 441 µmol/l, p=0.0039; at 120 min during an OGTT 117 vs 64 µmol/l, p=3.1 × 10-5). CONCLUSIONS/INTERPRETATION: The most common causal variant of HNF1A-MODY, p.(Gly292fs), presents not only with hyperglycaemia and insulin deficiency, but also with increased lipolysis and markedly lower adult BMI. Serum insulin was more discriminative than C-peptide between carriers and non-carriers. A considerable proportion of carriers develop diabetes after young adulthood. Even among individuals with a monogenic form of diabetes, polygenic risk of diabetes modifies the age at onset of diabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Fator 1-alfa Nuclear de Hepatócito , Adulto , Glicemia , Peptídeo C , Ácidos Graxos não Esterificados , Fator 1-alfa Nuclear de Hepatócito/genética , Humanos , Insulina/genética , Mutação , Fenótipo , Adulto Jovem
9.
Diabetologia ; 65(1): 65-78, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34689214

RESUMO

AIM/HYPOTHESIS: Five subgroups were described in European diabetes patients using a data driven machine learning approach on commonly measured variables. We aimed to test the applicability of this phenotyping in Indian individuals with young-onset type 2 diabetes. METHODS: We applied the European-derived centroids to Indian individuals with type 2 diabetes diagnosed before 45 years of age from the WellGen cohort (n = 1612). We also applied de novo k-means clustering to the WellGen cohort to validate the subgroups. We then compared clinical and metabolic-endocrine characteristics and the complication rates between the subgroups. We also compared characteristics of the WellGen subgroups with those of two young European cohorts, ANDIS (n = 962) and DIREVA (n = 420). Subgroups were also assessed in two other Indian cohorts, Ahmedabad (n = 187) and PHENOEINDY-2 (n = 205). RESULTS: Both Indian and European young-onset type 2 diabetes patients were predominantly classified into severe insulin-deficient (SIDD) and mild obesity-related (MOD) subgroups, while the severe insulin-resistant (SIRD) and mild age-related (MARD) subgroups were rare. In WellGen, SIDD (53%) was more common than MOD (38%), contrary to findings in Europeans (Swedish 26% vs 68%, Finnish 24% vs 71%, respectively). A higher proportion of SIDD compared with MOD was also seen in Ahmedabad (57% vs 33%) and in PHENOEINDY-2 (67% vs 23%). Both in Indians and Europeans, the SIDD subgroup was characterised by insulin deficiency and hyperglycaemia, MOD by obesity, SIRD by severe insulin resistance and MARD by mild metabolic-endocrine disturbances. In WellGen, nephropathy and retinopathy were more prevalent in SIDD compared with MOD while the latter had higher prevalence of neuropathy. CONCLUSIONS /INTERPRETATION: Our data identified insulin deficiency as the major driver of type 2 diabetes in young Indians, unlike in young European individuals in whom obesity and insulin resistance predominate. Our results provide useful clues to pathophysiological mechanisms and susceptibility to complications in type 2 diabetes in the young Indian population and suggest a need to review management strategies.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Humanos , Índia/epidemiologia , Insulina/uso terapêutico , Obesidade/complicações
10.
Diabetologia ; 65(9): 1495-1509, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35763030

RESUMO

AIMS/HYPOTHESIS: Diabetic kidney disease (DKD) is the leading cause of kidney failure and has a substantial genetic component. Our aim was to identify novel genetic factors and genes contributing to DKD by performing meta-analysis of previous genome-wide association studies (GWAS) on DKD and by integrating the results with renal transcriptomics datasets. METHODS: We performed GWAS meta-analyses using ten phenotypic definitions of DKD, including nearly 27,000 individuals with diabetes. Meta-analysis results were integrated with estimated quantitative trait locus data from human glomerular (N=119) and tubular (N=121) samples to perform transcriptome-wide association study. We also performed gene aggregate tests to jointly test all available common genetic markers within a gene, and combined the results with various kidney omics datasets. RESULTS: The meta-analysis identified a novel intronic variant (rs72831309) in the TENM2 gene associated with a lower risk of the combined chronic kidney disease (eGFR<60 ml/min per 1.73 m2) and DKD (microalbuminuria or worse) phenotype (p=9.8×10-9; although not withstanding correction for multiple testing, p>9.3×10-9). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN-RESP18, GPR158, INIP-SNX30, LSM14A and MFF; p<2.7×10-6). Integration of GWAS with human glomerular and tubular expression data demonstrated higher tubular AKIRIN2 gene expression in individuals with vs without DKD (p=1.1×10-6). The lead SNPs within six loci significantly altered DNA methylation of a nearby CpG site in kidneys (p<1.5×10-11). Expression of lead genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes (e.g. TENM2 expression correlated positively with eGFR [p=1.6×10-8] and negatively with tubulointerstitial fibrosis [p=2.0×10-9], tubular DCLK1 expression correlated positively with fibrosis [p=7.4×10-16], and SNX30 expression correlated positively with eGFR [p=5.8×10-14] and negatively with fibrosis [p<2.0×10-16]). CONCLUSIONS/INTERPRETATION: Altogether, the results point to novel genes contributing to the pathogenesis of DKD. DATA AVAILABILITY: The GWAS meta-analysis results can be accessed via the type 1 and type 2 diabetes (T1D and T2D, respectively) and Common Metabolic Diseases (CMD) Knowledge Portals, and downloaded on their respective download pages ( https://t1d.hugeamp.org/downloads.html ; https://t2d.hugeamp.org/downloads.html ; https://hugeamp.org/downloads.html ).


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/metabolismo , Quinases Semelhantes a Duplacortina , Fibrose , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Rim/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Proteínas Serina-Treonina Quinases/genética
11.
Diabetologia ; 64(9): 2026-2036, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34023962

RESUMO

AIMS/HYPOTHESIS: The study aimed to investigate the effects of HLA class I genes on susceptibility to type 1 diabetes with different onset ages, in addition to the well-established effects of HLA class II genes. METHODS: A total of 361 patients with type 1 diabetes (192 patients with onset <18 years and 169 patients with onset ≥18 years) and 500 healthy control participants from China were enrolled and genotyped for the HLA-A, -B, -C, -DQA1, -DQB1 and -DRB1 genes using next-generation sequencing. RESULTS: The susceptible DR3 (ß = -0.09, p = 0.0009) and DR4-DQ8 (ß = -0.13, p = 0.0059) haplotypes were negatively associated with onset age, while the protective DR11 (ß = 0.21, p = 0.0314) and DR12 (ß = 0.27, p < 0.0001) haplotypes were positively associated with onset age. After adjustment for linkage disequilibrium with DR-DQ haplotypes, A*11:01:01 was positively associated with onset age (ß = 0.06, p = 0.0370), while the susceptible C*15:02:01 was negatively associated with onset age (ß = -0.21, p = 0.0050). The unit for ß was double square-root (fourth root) transformed years of change in onset age associated with per copy of the HLA haplotype/allele. In addition, B*46:01:01 was protective (OR 0.41, 0.46; pc [corrected for multiple comparisons] = 0.0044, 0.0040), whereas A*24:02:01 (OR 2.71, 2.25; pc = 0.0003, 0.0002) and B*54:01:01 (OR 3.96, 3.79; pc = 0.0018, 0.0004) were predisposing in both the <18 group and the ≥18 group compared with healthy control participants. In the context of DR4-DQ4, A*11:01:01 (61.29% vs 28.26%, pc = 0.0144) was increased while the predisposing A*24:02:01 (19.35% vs 47.83%, pc = 0.0403) was decreased in patients with onset ≥18 years when compared with patients with onset <18 years. CONCLUSIONS/INTERPRETATION: In addition to DR-DQ haplotypes, novel HLA class I alleles were detected to play a role in susceptibility to type 1 diabetes with different onset ages, which could improve the understanding of disease heterogeneity and has implications for the design of future studies.


Assuntos
Diabetes Mellitus Tipo 1 , Idade de Início , Alelos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/genética , Genes MHC Classe I , Predisposição Genética para Doença/genética , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Haplótipos/genética , Humanos , Insulina/genética
12.
Diabetologia ; 64(9): 1982-1989, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34110439

RESUMO

AIMS/HYPOTHESIS: Five clusters based on clinical characteristics have been suggested as diabetes subtypes: one autoimmune and four subtypes of type 2 diabetes. In the current study we replicate and cross-validate these type 2 diabetes clusters in three large cohorts using variables readily measured in the clinic. METHODS: In three independent cohorts, in total 15,940 individuals were clustered based on age, BMI, HbA1c, random or fasting C-peptide, and HDL-cholesterol. Clusters were cross-validated against the original clusters based on HOMA measures. In addition, between cohorts, clusters were cross-validated by re-assigning people based on each cohort's cluster centres. Finally, we compared the time to insulin requirement for each cluster. RESULTS: Five distinct type 2 diabetes clusters were identified and mapped back to the original four All New Diabetics in Scania (ANDIS) clusters. Using C-peptide and HDL-cholesterol instead of HOMA2-B and HOMA2-IR, three of the clusters mapped with high sensitivity (80.6-90.7%) to the previously identified severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD) and mild obesity-related diabetes (MOD) clusters. The previously described ANDIS mild age-related diabetes (MARD) cluster could be mapped to the two milder groups in our study: one characterised by high HDL-cholesterol (mild diabetes with high HDL-cholesterol [MDH] cluster), and the other not having any extreme characteristic (mild diabetes [MD]). When these two milder groups were combined, they mapped well to the previously labelled MARD cluster (sensitivity 79.1%). In the cross-validation between cohorts, particularly the SIDD and MDH clusters cross-validated well, with sensitivities ranging from 73.3% to 97.1%. SIRD and MD showed a lower sensitivity, ranging from 36.1% to 92.3%, where individuals shifted from SIRD to MD and vice versa. People belonging to the SIDD cluster showed the fastest progression towards insulin requirement, while the MDH cluster showed the slowest progression. CONCLUSIONS/INTERPRETATION: Clusters based on C-peptide instead of HOMA2 measures resemble those based on HOMA2 measures, especially for SIDD, SIRD and MOD. By adding HDL-cholesterol, the MARD cluster based upon HOMA2 measures resulted in the current clustering into two clusters, with one cluster having high HDL levels. Cross-validation between cohorts showed generally a good resemblance between cohorts. Together, our results show that the clustering based on clinical variables readily measured in the clinic (age, HbA1c, HDL-cholesterol, BMI and C-peptide) results in informative clusters that are representative of the original ANDIS clusters and stable across cohorts. Adding HDL-cholesterol to the clustering resulted in the identification of a cluster with very slow glycaemic deterioration.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Glicemia , Peptídeo C , Humanos , Insulina
13.
EMBO J ; 36(14): 2107-2125, 2017 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-28637794

RESUMO

Ca2+-sensor proteins are generally implicated in insulin release through SNARE interactions. Here, secretagogin, whose expression in human pancreatic islets correlates with their insulin content and the incidence of type 2 diabetes, is shown to orchestrate an unexpectedly distinct mechanism. Single-cell RNA-seq reveals retained expression of the TRP family members in ß-cells from diabetic donors. Amongst these, pharmacological probing identifies Ca2+-permeable transient receptor potential vanilloid type 1 channels (TRPV1) as potent inducers of secretagogin expression through recruitment of Sp1 transcription factors. Accordingly, agonist stimulation of TRPV1s fails to rescue insulin release from pancreatic islets of glucose intolerant secretagogin knock-out(-/-) mice. However, instead of merely impinging on the SNARE machinery, reduced insulin availability in secretagogin-/- mice is due to ß-cell loss, which is underpinned by the collapse of protein folding and deregulation of secretagogin-dependent USP9X deubiquitinase activity. Therefore, and considering the desensitization of TRPV1s in diabetic pancreata, a TRPV1-to-secretagogin regulatory axis seems critical to maintain the structural integrity and signal competence of ß-cells.


Assuntos
Regulação da Expressão Gênica , Células Secretoras de Insulina/fisiologia , Proteínas/metabolismo , Secretagoginas/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Sobrevivência Celular , Perfilação da Expressão Gênica , Humanos , Camundongos , Camundongos Knockout , Secretagoginas/deficiência , Análise de Célula Única
14.
Am J Hum Genet ; 102(5): 760-775, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29706349

RESUMO

Finland provides unique opportunities to investigate population and medical genomics because of its adoption of unified national electronic health records, detailed historical and birth records, and serial population bottlenecks. We assembled a comprehensive view of recent population history (≤100 generations), the timespan during which most rare-disease-causing alleles arose, by comparing pairwise haplotype sharing from 43,254 Finns to that of 16,060 Swedes, Estonians, Russians, and Hungarians from geographically and linguistically adjacent countries with different population histories. We find much more extensive sharing in Finns, with at least one ≥ 5 cM tract on average between pairs of unrelated individuals. By coupling haplotype sharing with fine-scale birth records from more than 25,000 individuals, we find that although haplotype sharing broadly decays with geographical distance, there are pockets of excess haplotype sharing; individuals from northeast Finland typically share several-fold more of their genome in identity-by-descent segments than individuals from southwest regions. We estimate recent effective population-size changes through time across regions of Finland, and we find that there was more continuous gene flow as Finns migrated from southwest to northeast between the early- and late-settlement regions than was dichotomously described previously. Lastly, we show that haplotype sharing is locally enriched by an order of magnitude among pairs of individuals sharing rare alleles and especially among pairs sharing rare disease-causing variants. Our work provides a general framework for using haplotype sharing to reconstruct an integrative view of recent population history and gain insight into the evolutionary origins of rare variants contributing to disease.


Assuntos
Doença/genética , Genética Populacional , Haplótipos/genética , Finlândia , Fluxo Gênico , Variação Genética , Geografia , Migração Humana , Humanos , Parto , Densidade Demográfica , Fatores de Tempo
15.
Eur Respir J ; 57(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33243845

RESUMO

There is currently limited understanding of the genetic aetiology of obstructive sleep apnoea (OSA). We aimed to identify genetic loci associated with OSA risk, and to test if OSA and its comorbidities share a common genetic background.We conducted the first large-scale genome-wide association study of OSA using the FinnGen study (217 955 individuals) with 16 761 OSA patients identified using nationwide health registries.We estimated 0.08 (95% CI 0.06-0.11) heritability and identified five loci associated with OSA (p<5.0×10-8): rs4837016 near GAPVD1 (GTPase activating protein and VPS9 domains 1), rs10928560 near CXCR4 (C-X-C motif chemokine receptor type 4), rs185932673 near CAMK1D (calcium/calmodulin-dependent protein kinase ID) and rs9937053 near FTO (fat mass and obesity-associated protein; a variant previously associated with body mass index (BMI)). In a BMI-adjusted analysis, an association was observed for rs10507084 near RMST/NEDD1 (rhabdomyosarcoma 2 associated transcript/NEDD1 γ-tubulin ring complex targeting factor). We found high genetic correlations between OSA and BMI (rg=0.72 (95% CI 0.62-0.83)), and with comorbidities including hypertension, type 2 diabetes, coronary heart disease, stroke, depression, hypothyroidism, asthma and inflammatory rheumatic disease (rg>0.30). The polygenic risk score for BMI showed 1.98-fold increased OSA risk between the highest and the lowest quintile, and Mendelian randomisation supported a causal relationship between BMI and OSA.Our findings support the causal link between obesity and OSA, and the joint genetic basis between OSA and comorbidities.


Assuntos
Diabetes Mellitus Tipo 2 , Hipertensão , Apneia Obstrutiva do Sono , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Humanos , Fatores de Risco
16.
Diabetes Metab Res Rev ; 37(6): e3419, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33119194

RESUMO

BACKGROUND: Middle Eastern immigrants to Europe represent a high risk population for type 2 diabetes. We compared prevalence of novel subgroups and assessed risk of diabetic macro- and microvascular complications between diabetes patients of Middle Eastern and European origin. METHODS: This study included newly diagnosed diabetes patients born in Sweden (N = 10641) or Iraq (N = 286), previously included in the All New Diabetes in Scania cohort. The study was conducted between January 2008 and August 2016. Patients were followed to April 2017. Incidence rates in diabetic macro- and microvascular complications were assessed using cox-regression adjusting for the confounding effect of age at onset, sex, anthropometrics, glomerular filtration rate (eGFR) and HbA1c. FINDINGS: In Iraqi immigrants versus native Swedes, severe insulin-deficient diabetes was almost twice as common (27.9 vs. 16.2% p < 0.001) but severe insulin-resistant diabetes was less prevalent. Patients born in Iraq had higher risk of coronary events (hazard ratio [HR] 1.84, 95% CI 1.06-3.12) but considerably lower risk of chronic kidney disease (CKD) than Swedes (HR 0.19; 0.05-0.76). The lower risk in Iraqi immigrants was partially attributed to better eGFR. Genetic risk scores (GRS) showed more genetic variants associated with poor insulin secretion but lower risk of insulin resistance in the Iraqi than native Swedish group. INTERPRETATION: People with diabetes, born in the Middle East present with a more insulin-deficient phenotype and genotype than native Swedes. They have a higher risk of coronary events but lower risk of CKD. Ethnic differences should be considered in the preventive work towards diabetes and its complications.


Assuntos
Complicações do Diabetes , Diabetes Mellitus Tipo 2 , Emigrantes e Imigrantes , Resistência à Insulina , Insuficiência Renal Crônica , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Receptores ErbB , Etnicidade , Humanos , Insulina , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Fatores de Risco , Suécia/epidemiologia
17.
Diabetes Metab Res Rev ; 37(1): e3357, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32463555

RESUMO

BACKGROUND: The aim of this study was to investigate differences in clinical features and HLA genotypes between adult-onset and childhood-onset patients with type 1 diabetes in a Chinese population. MATERIALS AND METHODS: This study enrolled 716 Han Chinese patients with type 1 diabetes from Guangdong (258 childhood-onset and 458 adult-onset) to compare their clinical features. Of them 214 patients with classical type 1 diabetes (100 childhood-onset and 114 adult-onset) were selected for HLA DR and DQ genotyping by next-generation sequencing. RESULTS: Adult-onset patients were characterized by longer duration of symptoms before diagnosis, lower frequency of DKA at disease onset, less frequent autoantibody positivity, higher serum C-peptide concentrations, and better glycemic control. These findings were replicated in the restricted cohort of 214 patients with classical type 1 diabetes. Compared with childhood-onset patients, adult-onset patients had a lower frequency of the DR9 haplotype, as well as lower frequency of high-risk DR3/DR4 and DR3/DR9 genotypes, but higher frequency of DR3/DR3 genotype and DR3/X, DR4/X or DR9/X (X, non-risk) genotypes. CONCLUSIONS: Adult-onset type 1 diabetic patients with susceptible haplotypes (DR3, DR4 or DR9) were more likely to carry protective DR-DQ haplotypes than childhood-onset patients, which suggested the association between less risk DR-DQ genotypes and the less severe clinical manifestation in adult-onset patients.


Assuntos
Diabetes Mellitus Tipo 1 , Antígenos HLA-DQ , Antígenos HLA-DR , Adulto , Idade de Início , Criança , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Genótipo , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Humanos , Gravidade do Paciente , Medição de Risco
18.
Eur J Nutr ; 60(2): 769-779, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32444887

RESUMO

PURPOSE: Red meat consumption is positively associated with type 1 (T1D) and type 2 (T2D) diabetes. We investigated if red meat consumption increases the risk of latent autoimmune diabetes in adults (LADA) and T2D, and potential interaction with family history of diabetes (FHD), HLA and TCF7L2 genotypes. METHODS: Analyses were based on Swedish case-control data comprising incident cases of LADA (n = 465) and T2D (n = 1528) with matched, population-based controls (n = 1789; n = 1553 in genetic analyses). Multivariable-adjusted ORs in relation to self-reported processed and unprocessed red meat intake were estimated by conditional logistic regression models. Attributable proportion (AP) due to interaction was used to assess departure from additivity of effects. RESULTS: Consumption of processed red meat was associated with increased risk of LADA (per one servings/day OR 1.27, 95% CI 1.07-1.52), whereas no association was observed for unprocessed red meat. For T2D, there was no association with red meat intake once BMI was taken into account. The combination of high (> 0.3 servings/day vs. less) processed red meat intake and high-risk HLA-DQB1 and -DRB1 genotypes yielded OR 8.05 (95% CI 4.86-13.34) for LADA, with indications of significant interaction (AP 0.53, 95% CI 0.32-0.73). Results were similar for the combination of FHD-T1D and processed red meat. No interaction between processed red meat intake and FHD-T2D or risk variants of TCF7L2 was seen in relation to LADA or T2D. CONCLUSION: Consumption of processed but not unprocessed red meat may increase the risk of LADA, especially in individuals with FHD-T1D or high-risk HLA genotypes.


Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Autoimune Latente em Adultos , Carne Vermelha , Adulto , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Dieta , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Carne , Suécia/epidemiologia
19.
BMC Endocr Disord ; 21(1): 32, 2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33639916

RESUMO

BACKGROUND: Insulin resistance (IR) in skeletal muscle is a key feature of the pre-diabetic state, hypertension, dyslipidemia, cardiovascular diseases and also predicts type 2 diabetes. However, the underlying molecular mechanisms are still poorly understood. METHODS: To explore these mechanisms, we related global skeletal muscle gene expression profiling of 38 non-diabetic men to a surrogate measure of insulin sensitivity, i.e. homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: We identified 70 genes positively and 110 genes inversely correlated with insulin sensitivity in human skeletal muscle, identifying autophagy-related genes as positively correlated with insulin sensitivity. Replication in an independent study of 9 non-diabetic men resulted in 10 overlapping genes that strongly correlated with insulin sensitivity, including SIRT2, involved in lipid metabolism, and FBXW5 that regulates mammalian target-of-rapamycin (mTOR) and autophagy. The expressions of SIRT2 and FBXW5 were also positively correlated with the expression of key genes promoting the phenotype of an insulin sensitive myocyte e.g. PPARGC1A. CONCLUSIONS: The muscle expression of 180 genes were correlated with insulin sensitivity. These data suggest that activation of genes involved in lipid metabolism, e.g. SIRT2, and genes regulating autophagy and mTOR signaling, e.g. FBXW5, are associated with increased insulin sensitivity in human skeletal muscle, reflecting a highly flexible nutrient sensing.


Assuntos
Perfilação da Expressão Gênica/métodos , Resistência à Insulina/genética , Músculo Esquelético/metabolismo , Adulto , Células Cultivadas , Estudos de Coortes , Feminino , Expressão Gênica , Humanos , Masculino , Reação em Cadeia da Polimerase em Tempo Real/métodos , Comportamento Sedentário
20.
Diabetologia ; 63(5): 1043-1054, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31974732

RESUMO

AIMS/HYPOTHESIS: Evidence that glucose-dependent insulinotropic peptide (GIP) and/or the GIP receptor (GIPR) are involved in cardiovascular biology is emerging. We hypothesised that GIP has untoward effects on cardiovascular biology, in contrast to glucagon-like peptide 1 (GLP-1), and therefore investigated the effects of GIP and GLP-1 concentrations on cardiovascular disease (CVD) and mortality risk. METHODS: GIP concentrations were successfully measured during OGTTs in two independent populations (Malmö Diet Cancer-Cardiovascular Cohort [MDC-CC] and Prevalence, Prediction and Prevention of Diabetes in Botnia [PPP-Botnia]) in a total of 8044 subjects. GLP-1 (n = 3625) was measured in MDC-CC. The incidence of CVD and mortality was assessed via national/regional registers or questionnaires. Further, a two-sample Mendelian randomisation (2SMR) analysis between the GIP pathway and outcomes (coronary artery disease [CAD] and myocardial infarction) was carried out using a GIP-associated genetic variant, rs1800437, as instrumental variable. An additional reverse 2SMR was performed with CAD as exposure variable and GIP as outcome variable, with the instrumental variables constructed from 114 known genetic risk variants for CAD. RESULTS: In meta-analyses, higher fasting levels of GIP were associated with risk of higher total mortality (HR[95% CI] = 1.22 [1.11, 1.35]; p = 4.5 × 10-5) and death from CVD (HR[95% CI] 1.30 [1.11, 1.52]; p = 0.001). In accordance, 2SMR analysis revealed that increasing GIP concentrations were associated with CAD and myocardial infarction, and an additional reverse 2SMR revealed no significant effect of CAD on GIP levels, thus confirming a possible effect solely of GIP on CAD. CONCLUSIONS/INTERPRETATION: In two prospective, community-based studies, elevated levels of GIP were associated with greater risk of all-cause and cardiovascular mortality within 5-9 years of follow-up, whereas GLP-1 levels were not associated with excess risk. Further studies are warranted to determine the cardiovascular effects of GIP per se.


Assuntos
Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/mortalidade , Polipeptídeo Inibidor Gástrico/metabolismo , Glucose/metabolismo , Adulto , Idoso , Feminino , Genótipo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores dos Hormônios Gastrointestinais/metabolismo
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