Association between type 1 diabetes age of onset and HLA among sibling pairs.

In this study, we report type 1 diabetes age-of-onset association with HLA class II (DRB1, DQB1, and DPB1) and class I (A) genes in 222 multiplex families from the Human Biological Data Interchange. Linear regression showed a small (R2 = 0.26) but significant correlation in the ages of onset among sib pairs. A strong association in age of onset between members of sib pairs was observed when the analysis was performed using contingency tables that split sibs into three age-at-onset ranges (0-10, 11-20, and 21-36 years). The association is strongest for sib pairs that share both haplotypes and is nonsignificant for sib pairs that do not share any DR-DQ haplotypes. A goodness-of-fit test revealed that DR-DQ haplotype sharing cannot account for all the association in age of onset among sib pairs. The age-of-onset distribution of DR-DQ haplotypes is affected by the DPB1 and A alleles present. The strongest associations were found with the A locus: DR3/DR4 genotype frequency decreases with age of onset in this data set only among A*0101- individuals, and A*2402 is strongly associated with younger age of onset in many DR-DQ haplotypes.     

Physical activity in the prevention of type 2 diabetes: the Finnish diabetes prevention study

Clinical trials have demonstrated that lifestyle changes can prevent type 2 diabetes, but the importance of leisure-time physical activity (LTPA) is still unclear. We carried out post hoc analyses on the role of LTPA in preventing type 2 diabetes in 487 men and women with impaired glucose tolerance who had completed 12-month LTPA questionnaires. The subjects were participants in the Finnish Diabetes Prevention Study, a randomized controlled trial of lifestyle changes including diet, weight loss, and LTPA. There were 107 new cases of diabetes during the 4.1-year follow-up period. Individuals who increased moderate-to-vigorous LTPA or strenuous, structured LTPA the most were 63-65% less likely to develop diabetes. Adjustment for changes in diet and body weight during the study attenuated the association somewhat (upper versus lower third: moderate-to-vigorous LTPA, relative risk 0.51, 95% CI 0.26-0.97; strenuous, structured LTPA, 0.63, 0.35-1.13). Low-intensity and lifestyle LTPA and walking also conferred benefits, consistent with the finding that the change in total LTPA (upper versus lower third: 0.34, 0.19-0.62) was the most strongly associated with incident diabetes. Thus increasing physical activity may substantially reduce the incidence of type 2 diabetes in high-risk individuals.     

Glycotoxin and autoantibodies are additive environmentally determined predictors of type 1 diabetes: a twin and population study

In type 1 diabetes, diabetes-associated autoantibodies, including islet cell antibodies (ICAs), reflect adaptive immunity, while increased serum N(ε)-carboxymethyl-lysine (CML), an advanced glycation end product, is associated with proinflammation. We assessed whether serum CML and autoantibodies predicted type 1 diabetes and to what extent they were determined by genetic or environmental factors. Of 7,287 unselected schoolchildren screened, 115 were ICA(+) and were tested for baseline CML and diabetes autoantibodies and followed (for median 7 years), whereas a random selection (n = 2,102) had CML tested. CML and diabetes autoantibodies were determined in a classic twin study of twin pairs discordant for type 1 diabetes (32 monozygotic, 32 dizygotic pairs). CML was determined by enzyme-linked immunosorbent assay, autoantibodies were determined by radioimmunoprecipitation, ICA was determined by indirect immunofluorescence, and HLA class II genotyping was determined by sequence-specific oligonucleotides. CML was increased in ICA(+) and prediabetic schoolchildren and in diabetic and nondiabetic twins (all P < 0.001). Elevated levels of CML in ICA(+) children were a persistent, independent predictor of diabetes progression, in addition to autoantibodies and HLA risk. In twins model fitting, familial environment explained 75% of CML variance, and nonshared environment explained all autoantibody variance. Serum CML, a glycotoxin, emerged as an environmentally determined diabetes risk factor, in addition to autoimmunity and HLA genetic risk, and a potential therapeutic target.     

Hip strength in adults with type 1 diabetes is associated with age at onset of diabetes

We investigated the association of age at onset of type 1 diabetes with areal bone mineral density (aBMD), estimates of bone strength, and outer diameter. Using dual-energy X-ray absorptiometry (DXA), aBMD, axial strength (cross-sectional area [CSA]), bending strength (section modulus [SM]), and outer diameter at the narrow neck, intertrochanter, and shaft of the proximal femur were determined for 60 adults. Analysis of covariance (ANCOVA) was used to determine if the DXA-based measures of bone were related to age at onset and if this relationship differed by gender. Age at onset, gender, and the interaction of age at onset by gender were included in the ANCOVA models along with current age, duration, height, lean soft tissue mass, and hemoglobin A1c as covariates. In the adjusted models with CSA, SM, or outer diameter as the dependent variable, age at onset (p<0.01) and gender (p<0.0001) were significant with no interaction. For shaft aBMD, there was a significant age at onset by gender interaction (p=0.0285), where an earlier onset was associated with lower aBMD in the femoral shaft of females but not males. The findings suggest that an earlier onset of type 1 diabetes is associated with lower measures of bone strength and outer diameter.     

Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes

Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.     

Effects of duration and age at onset of type 1 diabetes on preclinical manifestations of nephropathy

Several studies have reported that the effect of type 1 diabetes disease duration on nephropathy may be greater during or after puberty than an equivalent number of years before puberty. The International Diabetic Nephropathy Study examined the effects of disease duration and age at onset on glomerular morphometry obtained from kidney biopsy in 243 young type 1 diabetic subjects with albumin excretion rates <100 micro g/min: 184 with prepubertal onset, 35 with pubertal onset, and 24 with postpuberty onset. Outcomes included the volume fraction of the glomerulus occupied by the mesangium [Vv(Mes/glom)], glomerular basement membrane (GBM) width, and the surface density of peripheral glomerular capillary basement membrane per glomerulus Sv(PGBM/glom). Vv(Mes/glom) progressed slowly in the first 14 or 15 years after disease onset but more rapidly thereafter. GBM width increased, while Sv(PGBM/glom) decreased with increasing disease duration. No statistically significant differences in the effect of duration were observed among the three age-at-onset subgroups, even with multivariate adjustment for sex, center, baseline HbA(1c) concentration, diastolic blood pressure, height, and BMI. Our results may explain the conflicting results of previous studies regarding the effects of pre-versus postpuberty disease duration.     

Genetic and gender influences on nocturnal bladder control--a study of 2900 3-year-old twin pairs

OBJECTIVE: The present study of over 2900 twin pairs born in England and Wales in 1994 examines the influences of genetics and gender on nocturnal bladder control at 3 years of age. MATERIALS AND METHOD: Parent report data was analysed in terms of means and components of variance, using a sex-limitation model to explore genetic and environmental variation within and between the sexes. RESULTS: Both genetics and gender are seen to influence acquisition: bladder control at 3 years is moderately heritable (24%), and girls show on average slightly increased acquisition compared with boys, even within opposite-sex pairs. The sex-limitation modelling showed an interaction between genetic influence and gender whereby nocturnal bladder control was significantly more heritable in boys (33%) than girls (10%). CONCLUSIONS: Both genetics and gender are important and interacting factors in the aetiology of nocturnal bladder control.     

Reproductive disturbances among Saudi adolescent girls and young women with type 1 diabetes mellitus

AIM To identify reproductive disturbances among adolescent girls and young women with type 1 diabetes mellitus(T1 DM) in Saudi Arabia.METHODS This cross sectional study was conducted among 102 female with T1 DM,(aged 13-29 years) who attended the Diabetes Clinic at Diabetes Treatment Center, Prince Sultan Military Medical City, Saudi Arabia between April 2015 to March 2016. Clinical history, anthropometric characteristics and reproductive disturbance were collected through a questionnaire.RESULTS Of 102 patients included in this analysis, 26.5%(27/102) were reported that they experienced an irregular menses. Of these patients, when compared to whose diabetes was diagnosed before menarche(35.4%, 17/48), patients diagnosed with diabetes after menarche(18.5%, 10/54) showed significantly less irregular menses(difference 16.9%, P = 0.04). Similarly, compared to patients diagnosed with diabetes prior to menarche(mean age 12.9 years; n = 48), patients diagnosed with diabetes after menarche(meanage 12.26 years; n = 54) were found to have 0.64 years delay in the age of menarche(P = 0.04). Among the studied patients, 15.7%(16/102) had polycystic ovary syndrome(PCOS). Of these PCOS patients, 37.5%(6/16) had irregular menses, 6.3%(1/16) had Celiac disease, 37.5%(6/16) had Hashimoto thyroiditis and 18.7%(3/16) had acne.CONCLUSION More than one fourth of the study population with T1 DM experiencing an irregular menses. Adolescent girls and young women diagnosed with diabetes prior to menarche showed higher menstrual irregularity and a delay in the age of menarche.     

Study of factors influencing susceptibility and age at onset of type 1 diabetes: A review of data from Continental Italy and Sardinia

AIM:To investigate the role of protein tyrosin phosphatase 22(PTPN22),maternal age at conception and sex on susceptibility and age at onset of type 1 diabetes(T1D)in Continental Italy and Sardinian populations.METHODS:Three hundred seventy six subjects admitted consecutively to the hospital for T1D and 1032healthy subjects as controls were studied in Continental Italy and 284 subjects admitted consecutively to the hospital for T1D and 5460 healthy newborns were studied in Sardinia.PTPN22 genotype was determined by DNA analysis.Maternal age at conception and age at onset of disease were obtained from clinical records.χ2 test of independence,student t test for differences between means and odds ratio analysis were carried out by SPSS programs.Three way contingency table analysis was carried out according to Sokal and Rohlf.RESULTS:The pattern of association between PTPN22and T1D is similar in Continental Italy and Sardinia:the proportion of*T allele carriers is 13.6%in T1D vs6.7%in controls in Continental Italy while in Sardinia is 7.3%in T1D vs 4.4%in controls.The association between T1D and maternal age at conception is much stronger in Sardinia than in Italy:the proportion of newborn from mother aging more than 32 years is89.3%in T1D vs 32.7%in consecutive newborn in Sardinia(P10-6)while in Continental Italy is 32.2%in T1D vs 19.1%in consecutive newborns(P=0.005).This points to an important role of ethnicity.A slight prevalence of T1D males on T1D females is observed both in Continental Italy and Sardinia.PTPN22 genotype does not exert significant effect on the age at onset neither in Continental Italy nor and Sardinia.Maternal age does not influence significantly age at onset in Italy(8.2 years in T1D infants from mothers aging32 years or less vs 7.89 years in T1D infants from mothers aging more than 32 years:P=0.824)while in Sardinia a border line effect is observed(5.75 years in T1D infants from mothers aging 32 years or less vs7.54 years in T1D infants from mothers aging more than 32 years:P=0.062).No effect of sex on age at onset is observed in Continental Italy while in Sardinia female show a lower age at onset of T1D as compared to males(8.07 years in males vs 6.3 years in females:P=0.002).CONCLUSION:The present data confirm the importance of ethnicity on susceptibility and on the age at onset of T1D.     

Three-yr follow-up of a type 1 diabetes mellitus patient with an islet xenotransplant

In order to alleviate the shortage of human donors, the use of porcine islets of Langerhans for xenotransplantation in diabetic patients has been proposed as a solution. To overcome rejection, we have developed a procedure for protecting the islets by combining them with Sertoli cells and placing them in a novel subcutaneous device, that generates an autologous collagen covering. A type 1 diabetic woman was closely monitored for 10 months, and then transplanted in two devices with two months of difference and a third time after 22 months. Here we present a three-yr follow-up. The close monitoring induced a rapid decrease in exogenous insulin requirements, which stabilized between 19 and 28 IU/d for nine months. After transplantation, the requirements reduced further to below 6 IU/d and for some weeks she was insulin free. Glycosylated hemoglobin levels decreased concomitantly. Porcine insulin could be detected in the serum after a glucose challenge and insulin positive cells inside a removed device after two yr. No complications have arisen and no porcine endogenous retrovirus infection has been detected through PCR and RT-PCR. This case demonstrates the feasibility of using the xenotransplantation of porcine cells to alleviate metabolic complications and insulin requirements in type 1 diabetic patients.     

Peroxisome proliferator-activated receptor alpha gene variation influences age of onset and progression of type 2 diabetes

Dysregulation of fatty acid metabolism is important in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor (PPAR)alpha is a master regulator of fatty acid catabolism, and PPARalpha activators delay the onset of type 2 diabetes. We examined association between three PPARalpha gene polymorphisms (an A-->C variant in intron 1, the L162V variant, and the intron 7 G-->C variant) and age at diagnosis of type 2 diabetes in 912 Caucasian type 2 diabetic subjects. Individually, PPARalpha gene variants did not influence age at diagnosis, but in combination, the rare alleles of both the intron 1 A-->C (P < 0.001) and intron 7 G-->C (P = 0.025) variants synergistically lowered age at diagnosis (interaction P < 0.001). Overall, the PPARalpha haplotype signficantly influenced age at diagnosis (P = 0.027), with the C-L-C and C-V-C haplotypes (intron 1-L162V-intron 7) accelerating onset of diabetes by 5.9 (P = 0.02) and 10 (P = 0.03) years, respectively, as compared with the common A-L-G haplotype, and was associated with an odds ratio for early-onset diabetes (age at diagnosis 相似文献   

Genetic determinants of bone mineral content at the spine and radius: a twin study

The possible role of genetic and/or environmental factors in determining bone mass has been investigated in 30 pairs of twins (16 monozygotic and 14 dizygotic) divided in two age groups (below and above 25 years of age). Bone mineral content was evaluated by single- and dual photon absorptiometry at the distol third of the radius for peripheral cortical bone and in the lumbar spine for the axial bone. The "within pair" variance has been used as an index of genetic influence. A significant (p less than 0.01) genetic determinant was found for the bone mass of the radius in adults and for the spinal bone mass in the age group younger than 25 years. The heritability index h2 was 0.75 for cortical BMC and 0.88 for axial BMC. Such a genetic determinant could not conclusively be demonstrated in adult twins for the spine and in youngsters for the cortical bone, suggesting that environmental factors may play a more dominant role in growth of cortical bone during adolescence and diminution of axial bone during adult life.     

Heritability of BMD of femoral neck and lumbar spine: a multivariate twin study of Finnish men.

Of the 80% variation in BMD among male twins that is caused by genetics, part was explained by genetic influences on lifting strength and lean body mass/height. Lifting strength was significant in both the femoral and spine BMD and body weight only for lumbar BMD. INTRODUCTION: The dominant role of heritability in BMD has been shown in twin studies among women. However, the mechanisms of genetic influences are poorly understood. BMD is associated with lean body mass and muscle strength, which both have a genetic component, but the relative effects of muscle strength and lean body mass/height on the total genetic and environmental variations influencing BMD of men are unclear. MATERIALS AND METHODS: Measurements of BMD from a DXA scanner on a representative sample of 147 monozygotic and 153 dizygotic male twin pairs (age, 35-70 yr) were related to a variety of anthropometric and behavioral covariates and interview data. Data were analyzed with univariate modeling of genetic characteristics, bivariate modeling of covariates that were significant in univariate models, and multivariate modeling of the simultaneous effects of significant covariates from the bivariate models. RESULTS: Heritability influences were estimated to account for 75% of the variance in femoral BMD and 83% in lumbar BMD. Univariate and bivariate modeling showed that, of the factors studied, only lifting force and lean body mass/height had statistically significant influences. Of the total genetic variation in femoral BMD, lifting force explained 9%, and lean body mass/height 18%; the proportions for lumbar BMD were 9% and 11%, respectively. Of the total environmental variation, the correlation with isokinetic lifting force explained 9% for femoral BMD and 10% for lumbar BMD. The genetic correlations between lifting force and femoral and lumbar BMD were approximately 0.3, as were the environmental correlations of isokinetic lifting force and femoral and lumbar BMD and of lean body mass/height and femoral BMD. The environmental correlation of lean body mass/height and femoral BMD was not significant. CONCLUSIONS: Lifting force had effects on both femoral and lumbar BMD. Body weight was important, but only for lumbar BMD. Muscle strength may have the best potential for modification among behavioral factors to increase both femoral and lumbar BMD.     

Genetic influence on the progression of radiographic knee osteoarthritis: a longitudinal twin study

OBJECTIVE: Genetic influences on rates of osteoarthritis (OA) progression are unknown. Our aim was to estimate the heritability of progression of radiographic knee OA using a longitudinal twin study. METHODS: Unselected monozygotic (MZ) and dizygotic (DZ) twin pairs from the TwinsUK registry were utilized. Anteroposterior radiographs were performed on both knees at baseline and follow-up using the same protocol. Radiographic features of knee OA including osteophyte and joint space narrowing (JSN) were assessed on a four-point scale using a standard atlas. Progression of knee osteophyte and JSN was defined as the difference in the corresponding score between follow-up and baseline > or =1. Liability threshold modelling using logistic regression was utilized for heritability estimation. RESULTS: A total of 114 MZ pairs and 195 DZ pairs were studied. The average follow-up time was 7.2 years. Medial progression of osteophyte and JSN was more common than lateral progression. Prevalence of progression was generally higher in the MZs than the DZs. Similarly, concordances and tetrachoric correlations for both osteophyte and JSN were higher in the MZs than the DZs although only significant for overall and medial JSN and osteophyte. The heritability estimates were 69% [95% confidence interval (CI) 42-97%] and 80% (95% CI 50-100%) for medial osteophyte and JSN, respectively. The estimates were reduced by 7-15% after adjustment for age, body mass index (BMI), and the severity of osteophyte/JSN at baseline. CONCLUSION: Our data documented a substantial genetic influence on the progression of knee OA--as seen in the medial compartment, providing a solid basis to search for genes involved in this highly relevant clinical trait.