Gender-specific association of vitamin D receptor polymorphism combinations with type 1 diabetes mellitus

OBJECTIVE: Recent data have indicated the significance of vitamin D receptor (VDR) polymorphisms in type 1 diabetes mellitus (T1DM). We have studied the association of five known restriction enzyme polymorphisms of the VDR gene in patients with T1DM. DESIGN AND METHODS: One hundred and seven children with T1DM (T1DM for 5 Years; age, 1-14 Years; boys/girls, 57/50; body mass index, 17.0+/-2.3 kg/m(2); haemoglobin A(Ic) (HbA(Ic)), 7.87+/-1.05) and 103 healthy subjects were enrolled. The VDR polymorphisms ApaI, BsmI, FokI, TaqI and Tru9I ("a", "b", "f", "t" and "u" alleles respectively) were investigated. RESULTS: The "t" and "T" alleles miss the Hardy-Weinberg equilibrium (P<0.01) in control and diabetic populations; we therefore excluded this polymorphism from further analysis. We did not find a difference in the allele prevalence in T1DM patients and controls of any of the five polymorphisms. However, when the "b", "a" and "u" alleles were simultaneously compared in girls, there was a significantly higher prevalence in patients with diabetes compared with controls ("b"+"a"+"u" present/absent: healthy, 0/53; diabetic, 13/37; P<0.005). In boys the prevalence of "b"+"a"+"u" genotype was similar in T1DM and controls. CONCLUSIONS: The impact of the "t" allele cannot be investigated in this study population. Not a single VDR polymorphism increases the susceptibility to T1DM. The common presence of the "b", "a" and "u" alleles greatly increases the probability of T1DM in girls.     

Evidence of increased islet cell proliferation in patients with recent-onset type 1 diabetes

Aims/hypothesis  

In adults, the rate of beta cell replication is normally very low, but recent evidence suggests that it may increase during insulitis. We therefore studied tissue from donors with recent-onset type 1 diabetes to establish whether islet cell proliferation is increased during the disease process.     

肝细胞癌患者外周血NK细胞频率及受体表达

目的检测肝细胞癌(hepatocellular carcinoma,HCC)患者外周血NK细胞频率、功能及受体表达的变化,并分析其在HCC患者中表达特点。方法用流式细胞术检测36例HCC患者、34例乙型肝炎肝硬化(liver cirrhosis,LC)患者的外周血NK细胞频率及其受体CD158a、CD158b、NKG2D、NKP30、NKP44、NKP46的表达情况,用IL-12刺激外周血单个核细胞(peripheral blood mononuclear cell,PBMC)、流式细胞术检测NK细胞分泌IFN-γ、TNF-α的能力,并用流式细胞毒性分析法检测NK细胞对K562细胞的杀伤效率,对2组NK细胞频率、受体及功能进行分析和比较。结果 2组患者NK细胞的频率差异无统计学意义(P0.05)。CD56dimNK细胞的活化性受体NKG2D、NKP30表达在HCC组高于LC组(P0.05)。在IL-12刺激下HCC组CD56brightNK细胞IFN-γ、TNF-α表达率、CD56dimNK细胞IFN-γ表达率均低于LC组(P0.05)。HCC组NK细胞对K562的杀伤比例高于LC组(P0.05)。结论 HCC组NK细胞分泌细胞因子能力低于LC组,但杀伤功能强于LC组,可能与其表面活化性受体高表达有关。     

Prevalence and characteristics of early-onset type 2 diabetes in Mexico

OBJECTIVE: To investigate the prevalence and characteristics of patients with type 2 diabetes diagnosed before the age of 40 years (early-onset disease) in a nationwide, population-based study. METHODS: Using a multistage sampling procedure, we enrolled a representative sample of Mexican urban adults aged 20 to 69 years. Weight, height, blood pressure, and plasma levels of glucose, insulin, and other metabolic parameters were measured in all subjects. RESULTS: We identified 993 subjects with type 2 diabetes, including 143 subjects aged 20 to 39 years (14% of those with diabetes). Subjects with early-onset diabetes had a greater prevalence of obesity and higher plasma insulin and lipid levels than did age-matched controls, and a greater prevalence of high-density lipoprotein cholesterol levels <35 mg/dL and severe hypertriglyceridemia than did older subjects with diabetes. Those (n = 32) with a normal body mass index (20 to 25 kg/m(2)) tended to have insulin deficiency as the main abnormality, whereas the "metabolic syndrome" characterized the remaining 111 subjects with early-onset diabetes. CONCLUSION: Most patients with early-onset type 2 diabetes in Mexico are obese or overweight, suggesting that obesity treatment and prevention programs may be effective in reducing the prevalence of this disease.     

Maternal-child blood group incompatibility and other perinatal events increase the risk for early-onset type 1 (insulin-dependent) diabetes mellitus

Summary The nationwide Swedish Childhood Diabetes Registry, which ascertains 99% of recent-onset Type 1 (insulin-dependent) diabetic children (0–14 years) in Sweden, was linked with the Swedish Medical Birth Registry. A matched case-control study was carried out analysing about 20 perinatal variables concerning mother and child. A total of 2757 infants who became diabetic during the period 1978–1988 were analysed. For each case infant three control children were randomly selected from among all infants born in the same year and at the same delivery unit as the case infant. The following statistically significant risk factors were identified for Type 1 diabetes with an onset before 15 years of age: maternal diabetes (OR=3.90), maternal age above 35 (OR=1.36), maternal non-smoking (OR=1.54), pre-ec-lamptic toxaemia (OR=1.19), caesarian section (OR=1.32), and maternal-child blood group incompatibility (OR=1.61). When the analysis was restricted to Type 1 diabetes with an onset before the age of 5 years, most odds ratios were increased — for blood group incompatibility OR=3.86 (95% confidence interval 1.54–9.65). Icterus without blood group incompatibility was not a significant risk factor. When each risk factor was analysed after standardization for all other risk factors, the odds ratios remained significantly increased. Scrutiny of medical records for cases and control children with a diagnosis of blood group incompatibility verified the diagnosis in close to 90% of children. The more severe cases needing phototherapy and/or blood transfusion were found to have a greater risk than milder cases. In conclusion, an early immunological event due to maternal-child blood group incompatibility, known to be associated with neonatal Beta-cell dysfunction, represents an increased risk for Type 1 diabetes in young children. Other stressful perinatal events may also be risk factors for Type 1 diabetes.     

HLA-C and killer cell immunoglobulin-like receptor genes in idiopathic bronchiectasis

RATIONALE: In idiopathic bronchiectasis, lung inflammation and chronic bacterial infection lead to progressive lung damage. A possible role for natural killer (NK) cells is suggested by the observation that familial bronchiectasis occurs in a rare group of individuals with impaired HLA class I expression and consequent NK cell dysfunction. OBJECTIVE: Because the HLA-C locus and killer cell immunoglobulin-like receptors (KIRs) are of key importance for NK cell recognition, we analyzed HLA-C/KIR combinations by genotyping patients with idiopathic bronchiectasis. METHODS: Genomic DNA from 96 individuals with idiopathic bronchiectasis and 101 control subjects was analyzed by polymerase chain reaction with sequence-specific primers. High-resolution HLA-C genotyping was performed in addition to KIR analysis. RESULTS: HLA-Cw*03 alleles and, in particular, HLA-C group 1 homozygosity are associated with the presence of bronchiectasis. Analysis of the relationship between HLA-C and KIR genes suggests a shift to activatory NK cell function. CONCLUSION: This is the first demonstration of genetic susceptibility in idiopathic bronchiectasis. The association with HLA-C group 1 homozygosity, and the interplay between HLA-C and KIR genes, argue for a role for NK cells in the progressive lung damage seen in this disease. This will require further investigation using functional studies.     

免疫干预联合骨髓干细胞移植治疗早发1型糖尿病的前景

1型糖尿病是由于胰岛β细胞进行性自身免疫性破坏所引起的,其治疗需要自身免疫件反应的逆转、胰岛β细胞的再牛和功能恢复.适度的免疫抑制剂治疗早发1型糖尿病可阻止胰岛β细胞进一步损失、减少胰岛素的使用,但不能阻止并发症的恶化.最近许多研究报道,免疫干预联合骨髓干细胞移植可维持较长的胰岛素非依赖时间,然而其能有效治疗早发1型槠尿病的机制尚未清楚.     

2型糖尿病患者外周血淋巴细胞G蛋白偶联受体激酶2基因表达升高

目的探讨糖尿病对G蛋白偶联受体激酶2（GRK-2）基因的影响及其机制。方法56例40-65岁非高血压2型糖尿病（T2DM）患者为T2DM组,以年龄、性别相匹配的高血压糖尿病患者46例（HT-DM组）和体检健康者29例（NC组）为对照组,提取外周血淋巴细胞RNA,通过RT-PCR半定量检测GRK-2 mRNA表达。结果与HT-DM组相似,T2DM组外周血淋巴细胞GRK-2 mRNA表达水平较NC组明显增加（P〈0.05）。Pearson线性相关分析提示T2DM组患者GRK-2基因表达水平升高与PG、HbA1c、糖尿病病程、年龄、TC水平正相关（P〈0.05）。结论T2DM患者外周血淋巴细胞GRK-2基因表达升高,血糖升高可能是其重要原因。     

Demonstration of increased toll-like receptor 2 and toll-like receptor 4 expression in monocytes of type 1 diabetes mellitus patients with microvascular complications

Type 1 diabetes mellitus (T1DM) is associated with increased microvascular complications and is a proinflammatory state. The toll-like receptors (TLRs) are pattern recognition receptors on monocytes and important in atherosclerosis. We have shown increased TLR2 and TLR4 expression on monocytes of T1DM compared with controls. In this report, we tested the surface expression of TLR2 and TLR4 on monocytes of T1DM patients with microvascular complications (T1DM-MV) compared with those without (T1DM) and healthy controls. The study was performed at the University of California Davis. Healthy controls (n = 31), T1DM patients (n = 31), and T1DM-MV patients (n = 34) were included. The TLR2 and TLR4 surface expression was significantly increased in T1DM-MV monocytes compared with T1DM and controls (P < .01). In addition, nuclear factor κB activity and interleukin-1β release were significantly increased in monocytes from T1DM-MV compared with T1DM (P < .005). Thus, we make the novel observation that TLR2 and TLR4 expression and signaling are increased in T1DM-MV compared with T1DM and may contribute to the accentuated proinflammatory state and complications of T1DM.     

Time-course changes in clinical features of early-onset Japanese type 1 and type 2 diabetes: TWMU hospital-based study

Using a database of patients with type 1 (n=1675) and type 2 (n=2259) diabetes diagnosed before the age of 30 years at the Diabetes Center, Tokyo Women's Medical University (TWMU), in which such Japanese patients have been registered at the time of first visit since the 1960s, we performed a hospital-based study over the last 40 years to clarify time-course changes in clinical features of type 1 and type 2 diabetes diagnosed before the age of 30 years. Type 2 diabetes had a male dominancy, while there has been a female dominancy in patients with type 1 diabetes as in previous reports of Japanese childhood-onset type 1 diabetes. Such dominances had been continued over the last 40 years. The number of patients with type 2 diabetes and with a past history of obesity increased with time. The age at which type 2 diabetes was diagnosed was suggested to have been getting lower with time, whereas that of type 1 diabetes has been higher with time. There was no marked difference in family history of diabetes in the first-degree relatives of patients with type 2 diabetes, regardless of the presence or absence of a past history of obesity. More female patients with type 2 diabetes diagnosed before the age of 15 years had mothers with type 2 diabetes compared to corresponding male patients.     

早发2型糖尿病的临床特点分析

目的比较早发和迟发2型糖尿病（T2DM）患者的临床特点。方法将304例诊断为T2DM的患者按诊断年龄不同分为早发组和迟发组，比较两组在体质指数（BMI）、血糖、血压、血脂、空腹C肽、家族史、微血管病变等方面的差异。结果与迟发组患者相比，早发组有高BMI、HbA-C、空腹C肽和甘油三酯，低高密度脂蛋白胆固醇，高视网膜病变和肾功能损害比例，更显著的家族聚集倾向。结论（1）早发T2DM患者有显著的家族聚集倾向和更严重的代谢紊乱。（2）早发T2DM患者患糖尿病肾病及视网膜病变的危险性较高。     

Metabolic decompensation in children with type 1 diabetes mellitus associated with increased serum levels of the soluble leptin receptor

OBJECTIVE: Type 1 diabetes mellitus (T1DM) leads to increased serum levels of the soluble leptin receptor (sOB-R) by an as yet unknown cellular mechanism. The aim of our study was to investigate potential metabolic factors that may be associated with the induction of the sOB-R release from its membrane receptor. MATERIALS AND METHODS: Twenty-five children (aged between 1.5 and 17.0 years) were studied at the onset of T1DM. Blood samples were collected before (n = 25), during the first 18 h (mean +/- S.D. 11.1 +/- 4.3 h, n = 16) and 92 h (47.5 +/- 22.5 h; n = 14) after beginning insulin therapy. Serum sOB-R and leptin levels were determined by in-house immunoassays. RESULTS: The sOBR-level and the molar sOB-R/leptin ratio were significantly higher before than after starting insulin treatment (P < 0.05). In contrast, leptin levels were significantly lower (P < 0.05) before insulin therapy. The correlation between sOB-R and blood glucose (r = 0.49; P < 0.05), as well as sOB-R with parameters of ketoacidosis, such as pH (r = -0.72), base excess (r = -0.70), and bicarbonate (r = -0.69) (P < 0.0001) at diagnosis of T1DM remained significant during the first 18 h of insulin treatment. Multiple regression analysis revealed that base excess predicted 41.0% (P < 0.001), age 16.4% (P < 0.05), and height SDS 13.9% (P < 0.01) of the sOB-R variance. CONCLUSIONS: Metabolic decompensation in children with new onset T1DM is associated with dramatic changes of the leptin axis; serum levels of sOB-R are elevated and of leptin are reduced. The molar excess of sOB-R over leptin (median 11.3) in this condition may contribute to leptin insensitivity. Upregulation of the soluble leptin receptor appears to be a basic mechanism to compensate for intracellular substrate deficiency and energy-deprivation state.     

Disease-association of different killer cell immunoglobulin-like receptors (KIR) and HLA-C gene combinations in reactive arthritis

Abstract

Background: Reactive arthritis (ReA) is sterile arthritis triggered by bacterial gastrointestinal or urogenital infections. Although the pathogenesis of ReA remains unclear, genetic factors seem to play an important role. Different killer cell immunoglobulin-like receptors (KIRs) and their corresponding specific histocompatibility leukocyte antigen-C (HLA-C) ligand genotypes have been implicated in susceptibility and resistance to infections and autoimmune diseases but have, thus far, not been investigated in ReA.

Methods: This study was conducted in 138 ReA patients (65 females, 73 males); aged 18–69 years (mean, 37 years) and 151 randomly selected healthy control individuals matched for ethnicity, age and sex. These subjects were genotyped for KIR genes and HLA-C alleles by polymerase chain reaction with sequence-specific primers.

Results: The frequencies of inhibitory KIR2DL2 and KIR2DL5 were significantly lower in the ReA patients than in the controls (p?=?.005 and p?=?.033, respectively). The presence of more than seven inhibitory KIR genes was protective (p?=?.016). Moreover, we found that activating KIR2DS1 alone or in combination with the HLA-C1C1 genotype (which indicates the absence of the HLA ligands for their homologous inhibitory receptor KIR2DL1) is associated with susceptibility to ReA (p?=?.039 and p?=?.011, respectively), whereas KIR2DL2 in combination with the HLA-C1 ligand is associated with protection against ReA (p?=?.039).

Conclusion: These observations indicate that high levels of activating and low levels of inhibitory KIR signals may affect the functions of NK cells and T cells. This imbalance enables the innate and adaptive immune responses of the host to be easily triggered by pathogens, resulting in the overproduction of local and systemic cytokines that contribute to the pathogenesis of ReA.     

糖尿病家系先证者同胞的患病危险性分析

目的通过计算早发2型糖尿病（T2DM）家系先证者同胞中糖尿病患病危险性（λs值）来评价早发2型糖尿病家系糖尿病的遗传强度。方法：采用在1997-2004年间收集的有完整资料的北京地区227个同胞对糖尿病家系,分为早发糖尿病家系（患病同胞的诊断年龄均≤45岁）122家,晚发糖尿病家系（患病同胞的诊断年龄均〉45岁）76家。采用问卷调查的方法收集家系成员有关糖尿病信息,计算λs值。结果总家系中λs=10.33,早发糖尿病家系λs值高于晚发糖尿病家系（P=0.000）。早发糖尿病家系中糖尿病家族史比例显著高于晚发糖尿病家系（P=0.000）。母系家族史比例显著高于父系家族史比例（P=0.01）,但母系遗传和父系遗传家系的λs间差异无统计学意义。结论采用患病同胞策略所收集的糖尿病家系均具有较强遗传倾向,但早发糖尿病患者同胞具有更高的糖尿病风险,早发糖尿病家系具有更强遗传倾向,选择早发糖尿病家系可能更适于寻找新的糖尿病易感基因。     

A type 1 diabetes genetic risk score can discriminate monogenic autoimmunity with diabetes from early-onset clustering of polygenic autoimmunity with diabetes

Aims/hypothesis

Identifying individuals suitable for monogenic autoimmunity testing and gene discovery studies is challenging: early-onset type 1 diabetes mellitus can cluster with additional autoimmune diseases due to shared polygenic risk and islet- and other organ-specific autoantibodies are present in both monogenic and polygenic aetiologies. We aimed to assess whether a type 1 diabetes genetic risk score (GRS) could identify monogenic autoimmune diabetes and be useful to prioritise individuals for gene discovery studies.

Methods

We studied 79 individuals with diabetes and at least one additional autoimmune disease diagnosed before the age of 5 years. We screened all participants for the seven genes known to cause monogenic autoimmunity that can include diabetes (AIRE, IL2RA, FOXP3, LRBA, STAT1, STAT3, STAT5B). We genotyped the top ten risk alleles for type 1 diabetes, including HLA and non-HLA loci, to generate a type 1 diabetes GRS.

Results

Of the 79 individuals studied, 37 (47%) had mutations in the monogenic autoimmunity genes. The type 1 diabetes GRS was lower in these individuals than in those without mutations in these genes (median 9th vs 49th centile of type 1 diabetes controls, p?<?0.0001). Age of diabetes diagnosis and type 1 diabetes GRS combined to be highly discriminatory of monogenic autoimmunity (receiver operating characteristic AUC: 0.88). Most individuals without a mutation in a known gene had a high type 1 diabetes GRS, suggesting that they have polygenic clustering of type 1 diabetes and additional autoimmunity and should not be included in gene discovery studies.

Conclusions/interpretation

We have shown that the type 1 diabetes GRS can identify individuals likely to have monogenic autoimmunity, helping both diagnostic testing and novel monogenic autoimmunity gene discovery. Individuals with monogenic autoimmunity have a different clinical course to those with polygenic type 1 diabetes and can respond well to therapies targeting the underlying genetic defect.