Mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders (LSDs). MPSs are caused by excessive accumulation of mucopolysaccharides due to missing or deficiency of enzymes required for ...the degradation of specific macromolecules. MPS I-IV, MPS VI, MPS VII, and MPS IX are sub-types of mucopolysaccharidoses. Among these, MPS III (also known as Sanfilippo) and MPS IV (Morquio) syndromes are lethal and prevalent sub-types. This study aimed to identify causal genetic variants in cases of MPS III and MPS IV and characterize genotype-phenotype relations in Pakistan. We performed clinical, biochemical and genetic analysis using Whole Genome Sequencing (WGS) in 14 Pakistani families affected with MPS III or MPS IV. Patients were classified into MPS III by history of aggressive behaviors, dementia, clear cornea and into MPS IV by short trunk, short stature, reversed ratio of upper segment to lower segment with a short upper segment. Data analysis and variant selections were made based on segregation analysis, examination of known MPS III and MPS IV genes, gene function, gene expression, the pathogenicity of variants based on ACMG guidelines and
in silico
analysis. In total, 58 individuals from 14 families were included in the present study. Six families were clinically diagnosed with MPS III and eight families with MPS IV. WGS revealed variants in MPS-associated genes including
NAGLU, SGSH, GALNS, GNPTG
as well as the genes
VWA3B
,
BTD
, and
GNPTG
which have not previously associated with MPS. One family had causal variants in both
GALNS
and
BTD
. Accurate and early diagnosis of MPS in children represents a helpful step for designing therapeutic strategies to protect different organs from permanent damage. In addition, pre-natal screening and identification of genetic etiology will facilitate genetic counselling of the affected families. Identification of novel causal MPS genes might help identifying new targeted therapies to treat LSDs.
IntroductionDiabetic kidney disease is a severe complication of diabetes. The diagnosis is based on clinical characteristics such as persistently elevated albuminuria, hypertension and decline in ...kidney function, although this definition is not specific to kidney disease caused by diabetes. The only way to establish an accurate diagnosis—diabetic nephropathy—is by performing a kidney biopsy. The histological presentation of diabetic nephropathy can be associated with a heterogeneous range of histological features with many pathophysiological factors involved demonstrating the complexity of the condition. Current treatment strategies aim to slow disease progression and are not specific to the underlying pathological processes.This study will investigate the prevalence of diabetic nephropathy in individuals with type 2 diabetes (T2D) and severely elevated albuminuria. The deep molecular characterisation of the kidney biopsy and biological specimens may pave the way for improved diagnostic accuracy and a better understanding of the pathological processes involved and may also reveal new targets for individualised treatment.Methods and analysisIn the PRecIsion MEdicine based on kidney TIssue Molecular interrogation in diabetic nEphropathy 2 study, research kidney biopsies will be performed in 300 participants with T2D, urine albumin/creatinine ratio ≥700 mg/g and estimated glomerular filtration ratio >30 mL/min/1.73 m2. Cutting-edge molecular technologies will be applied to the kidney, blood, urine, faeces and saliva samples for comprehensive multi-omics profiling. The associated disease course and clinical outcomes will be assessed by annual follow-up for 20 years.Ethics and disseminationThe Danish Regional Committee on Health Research Ethics and the Knowledge Center on Data Protection (in the Capital Region of Denmark) have granted approval for the study. The results will be published in peer-reviewed journals.Trial registration numberNCT04916132.
Lactation is associated with reduced postpartum weight retention and a lower risk of several cardiometabolic disorders in population-based studies. We examined the association between lactation and ...long-term thyroid function among women with history of gestational diabetes mellitus (GDM), a high-risk population for subsequent metabolic complications. The study included 550 women who developed GDM in the Danish National Birth Cohort (1996⁻2002) and followed-up in the Diabetes & Women's Health Study (2012⁻2014). We assessed adjusted associations between cumulative lactation duration and concentrations of thyroid stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) measured at follow-up. Women with longer cumulative lactation duration tended to have higher fT3 levels (adjusted β and 95% confidence interval (CI) for ≥12 months vs. none: 0.19 (0.03⁻0.36);
-trend = 0.05). When restricted to women with a single lifetime pregnancy to control for parity (
= 70), women who lactated for >6 months (vs. none) had higher fT3 levels (0.46 pmol/L (0.12⁻0.80);
-trend = 0.02) and a higher fT3:fT4 ratio (0.61 (0.17⁻1.05);
-trend = 0.007). Our findings suggested that a longer duration of lactation may be related to greater serum fT3 levels and fT3:fT4 ratio 9⁻16 years postpartum among Danish women with a history of GDM. The association was particularly pronounced among women who only had one lifetime pregnancy.
Aims/hypothesis
Low birthweight is a risk factor for type 2 diabetes. Most previous studies are based on cross-sectional prevalence data, not designed to study the timing of onset of type 2 diabetes ...in relation to birthweight. We aimed to examine associations of birthweight with age-specific incidence rate of type 2 diabetes in middle-aged to older adults over two decades.
Methods
Adults aged 30–60 years enrolled in the Danish Inter99 cohort in 1999–2001 (baseline examination), with information on birthweight from original birth records from 1939–1971 and without diabetes at baseline, were eligible. Birth records were linked with individual-level data on age at diabetes diagnosis and key covariates. Incidence rates of type 2 diabetes as a function of age, sex and birthweight were modelled using Poisson regression, adjusting for prematurity status at birth, parity, polygenic scores for birthweight and type 2 diabetes, maternal and paternal diabetes history, socioeconomic status and adult BMI.
Results
In 4590 participants there were 492 incident type 2 diabetes cases during a mean follow-up of 19 years. Type 2 diabetes incidence rate increased with age, was higher in male participants, and decreased with increasing birthweight (incidence rate ratio 95% CI per 1 kg increase in birthweight 0.60 0.48, 0.75). The inverse association of birthweight with type 2 diabetes incidence was statistically significant across all models and in sensitivity analysis.
Conclusions/interpretation
A lower birthweight was associated with increased risk of developing type 2 diabetes independent of adult BMI and genetic risk of type 2 diabetes and birthweight.
Graphical Abstract
Background
Women with gestational diabetes mellitus (GDM) may be at an increased risk of liver complications because chronic hyperglycemia is a risk factor for liver fat accumulation and potential ...liver dysfunction. Large prospective studies examining liver fat accumulation following a GDM pregnancy are lacking.
Methods
The Diabetes & Women's Health Study (2012‐2014) examined the association between GDM and subsequent fatty liver scores among 607 women with and 619 women without GDM in the Danish National Birth Cohort. Nine to 16 years postpartum, a clinical examination was performed, with measurement of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ‐glutamyl transferase, from which fatty liver scoring indices were calculated to assess liver fat score, fatty liver index, hepatic steatosis index, and liver fat percentage. Relative risks (RR) with 95% confidence intervals (CI) for elevated liver scoring indices by GDM status were assessed adjusting for major risk factors, including prepregnancy body mass index.
Results
Women with prior GDM had higher adjusted ALT and AST levels than women without GDM (by 6.7% 95% CI 1.7‐12.0 and 4.8% 95% CI 0.6‐9.1, respectively). Women with GDM also had adjusted increased risks for elevated liver fat score (RR 2.34; 95% CI 1.68‐3.27), fatty liver index (RR 1.59; 95% CI 1.27‐1.99), and hepatic steatosis index (RR 1.44; 95% CI 1.21‐1.71).
Conclusions
Women with GDM during pregnancy were at an increased risk for fatty liver 9 to 16 years postpartum. Gestational diabetes mellitus may serve as another risk indicator for the early identification and prevention of liver fat accumulation.
摘要
背景
妊娠期糖尿病(gestational diabetes mellitus，GDM)女性发生肝脏并发症的风险可能增加，因为慢性高血糖是肝脏脂肪蓄积及潜在肝功能异常的危险因素。目前评估GDM患者产后肝脏脂肪蓄积的大型前瞻性研究不足。
方法
糖尿病与女性健康研究(The Diabetes & Women's Health Study, 2012‐2014)使用丹麦国家出生队列，在607例合并GDM的女性和619例无GDM的女性中调查了GDM与后续脂肪肝评分之间的相关性。在产后9‐16年进行临床检查，测定丙氨酸氨基转移酶(alanine aminotransferase，ALT)、天冬氨酸氨基转移酶(aspartate aminotransferase，AST)和γ‐谷氨酰转移酶，由此计算脂肪肝评分指标，评估肝脏脂肪评分、脂肪肝指数、肝脏脂肪变性指数以及肝脏脂肪百分比。校正主要风险因素(包括妊娠前体重指数)后，根据GDM状态评估导致肝脏评分指标升高的相对风险(relative risk，RR)及其95%可信区间(confidence interval，CI)。
结果
既往患GDM的女性校正的ALT及AST水平均高于无GDM的女性(分别高出6.7%95% CI: 1.7‐12.0与4.8%95% CI: 0.6‐9.1)。GDM女性的校正后肝脏脂肪评分(RR 2.34；95% CI: 1.68‐3.27)、脂肪肝指数(RR 1.59；95% CI: 1.27‐1.99)及肝脏脂肪变性指数(RR 1.44；95% CI: 1.21‐1.71)升高的风险也增加。
结论
妊娠期合并GDM的女性在产后9‐16年发生脂肪肝的风险增加。GDM可作为早期发现和预防肝脏脂肪蓄积的另一个风险指标。
Highlights
Liver scoring indices were significantly elevated in women with gestational diabetes 9 to 16 years after the index pregnancy.
Alanine aminotransferase and aspartate aminotransferase levels were higher and liver fat percentage was greater in women with than without gestational diabetes.
Women with gestational diabetes may be at a higher risk for liver fat accumulation, regardless of and prior to the development of overt diabetes later in life.
T-type Ca
channel Ca
3.1 promotes microvessel contraction ex vivo. It was hypothesized that in vivo, functional deletion of Ca
3.1, but not Ca
3.2, protects mice against angiotensin II (ANG ...II)-induced hypertension. Mean arterial blood pressure (MAP) and heart rate were measured continuously with chronically indwelling catheters during infusion of ANG II (30 ng·kg
·min
, 7 days) in wild-type (WT), Ca
3.1
, and Ca
3.2
mice. Plasma aldosterone and renin concentrations were measured by radioimmunoassays. In a separate series, WT mice were infused with ANG II (100 ng·kg
·min
) with and without the mineralocorticoid receptor blocker canrenoate. Ca
3.1
and Ca
3.2
mice exhibited no baseline difference in MAP compared with WT mice, but day-night variation was blunted in both Ca
3.1 and Ca
3.2
mice. ANG II increased significantly MAP in WT, Ca
3.1
, and Ca
3.2
mice with no differences between genotypes. Heart rate was significantly lower in Ca
3.1
and Ca
3.2
mice compared with control mice. After ANG II infusion, plasma aldosterone concentration was significantly lower in Ca
3.1
compared with Ca
3.2
mice. In response to ANG II, fibrosis was observed in heart sections from both WT and Ca
3.1
mice and while cardiac atrial natriuretic peptide mRNA was similar, the brain natriuretic peptide mRNA increase was mitigated in Ca
3.1
mice ANG II at 100 ng/kg yielded elevated pressure and an increased heart weight-to-body weight ratio in WT mice. Cardiac hypertrophy, but not hypertension, was prevented by the mineralocorticoid receptor blocker canrenoate. In conclusion, T-type channels Ca
3.1and Ca
3.2 do not contribute to baseline blood pressure levels and ANG II-induced hypertension. Ca
3.1, but not Ca
3.2, contributes to aldosterone secretion. Aldosterone promotes cardiac hypertrophy during hypertension.
Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses ...of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency MAF = 3.3%, p = 2 × 10−10 for hemoglobin HGB) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10−8 for hematocrit HCT and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10−11) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10−9). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10−7). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.
Heterogeneity in type 2 diabetes presentation and progression suggests that precision medicine interventions could improve clinical outcomes. We undertook a systematic review to determine whether ...strategies to subclassify type 2 diabetes were associated with high quality evidence, reproducible results and improved outcomes for patients.
We searched PubMed and Embase for publications that used 'simple subclassification' approaches using simple categorisation of clinical characteristics, or 'complex subclassification' approaches which used machine learning or 'omics approaches in people with established type 2 diabetes. We excluded other diabetes subtypes and those predicting incident type 2 diabetes. We assessed quality, reproducibility and clinical relevance of extracted full-text articles and qualitatively synthesised a summary of subclassification approaches.
Here we show data from 51 studies that demonstrate many simple stratification approaches, but none have been replicated and many are not associated with meaningful clinical outcomes. Complex stratification was reviewed in 62 studies and produced reproducible subtypes of type 2 diabetes that are associated with outcomes. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into clinically meaningful subtypes.
Critical next steps toward clinical implementation are to test whether subtypes exist in more diverse ancestries and whether tailoring interventions to subtypes will improve outcomes.
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