The incidence of childhood-onset type 1 diabetes, time trends and association with the population composition in Sweden: a 40 year follow-up.

AIMS/HYPOTHESIS: During the 1980s and 1990s, the incidence of childhood-onset type 1 diabetes more than doubled in Sweden, followed by a plateau. In the present 40 year follow-up, we investigated if the incidence remained stable and whether this could be explained by increased migration from countries reporting lower incidences. METHODS: We used 23,143 incident cases of childhood-onset type 1 diabetes reported between 1978 and 2019 to the nationwide, population-based Swedish Childhood Diabetes Registry and population data from Statistics Sweden. Generalised additive models and ANOVA were applied to analyse the effects of onset age, sex, time trends and parental country of birth and interaction effects between these factors. RESULTS: The flattening of the incidence increase seems to remain over the period 2005-2019. When comparing the incidence of type 1 diabetes for all children in Sweden with that for children with both parents born in Sweden, the trends were parallel but at a higher level for the latter. A comparison of the incidence trends between individuals with Swedish backgrounds (high diabetes trait) and Asian backgrounds (low diabetes trait) showed that the Asian subpopulation had a stable increase in incidence over time. CONCLUSIONS/INTERPRETATION: In Sweden, the increase in incidence of childhood-onset type 1 diabetes in the late 20th century has been approaching a more stable albeit high level over the last two decades. Increased immigration from countries with lower incidences of childhood-onset type 1 diabetes does not provide a complete explanation for the observed levelling off.

Risk of cancer in young and middle-aged adults with childhood-onset type 1 diabetes in Sweden-A prospective cohort study.

AIMS/HYPOTHESIS: In persons with type 1 diabetes, the risk of cancer remains controversial. We wanted to examine the excess risk of cancer in a large population-based cohort diagnosed with type 1 diabetes before 15 years of age. STUDY POPULATION AND METHODS: From 1 July 1977 to 31 December 2013, we prospectively and on a national scale included 18,724 persons (53% men) with childhood-onset type 1 diabetes. For each person with type 1 diabetes, we selected four referents, matched for the date at birth and municipality of living at the time when the case developed diabetes. Cases and referents were linked to national registers of cancer and of the cause of death. RESULTS: A total of 125 persons (61% women) with diabetes had 135 different cancers, all diagnosed after the diabetes diagnosis. The median duration from diabetes diagnosis to first cancer diagnosis was 19 years (interquartile range 10-26). The median age at cancer diagnosis in the diabetes group was 28 years (interquartile range 20-35). The overall standardized incidence ratio (95%), using the Swedish general population as referents for women with diabetes was 1.28 (1.02, 1.58) and when comparing women with diabetes with matched referents, we found a hazard ratio of 1.42 (1.10, 1.85). No elevated risk was seen for men. Cancers of the breast and testis were the most common types in women and men respectively. CONCLUSIONS: Women with childhood-onset type 1 diabetes had a small but significantly elevated risk of cancer. No such tendency was seen for men. The reason behind this is unclear.

Decreasing Cumulative Incidence of End-Stage Renal Disease in Young Patients With Type 1 Diabetes in Sweden: A 38-Year Prospective Nationwide Study.

OBJECTIVE: Diabetic nephropathy is a serious complication of type 1 diabetes. Recent studies indicate that end-stage renal disease (ESRD) incidence has decreased or that the onset of ESRD has been postponed; therefore, we wanted to analyze the incidence and time trends of ESRD in Sweden. RESEARCH DESIGN AND METHODS: In this study, patients with duration of type 1 diabetes >14 years and age at onset of diabetes 0-34 years were included. Three national diabetes registers were used: the Swedish Childhood Diabetes Register, the Diabetes Incidence Study in Sweden, and the National Diabetes Register. The Swedish Renal Registry, a national register on renal replacement therapy, was used to identify patients who developed ESRD. RESULTS: We found that the cumulative incidence of ESRD in Sweden was low after up to 38 years of diabetes duration (5.6%). The incidence of ESRD was lower in patients with type 1 diabetes onset in 1991-2001 compared with onset in 1977-1984 and 1985-1990, independent of diabetes duration. CONCLUSIONS: The risk of developing ESRD in Sweden in this population is still low and also seems to decrease with time.

Marginal structural model to evaluate the joint effect of socioeconomic exposures on the risk of developing end-stage renal disease in patients with type 1 diabetes: a longitudinal study based on data from the Swedish Childhood Diabetes Study Group.

PURPOSE: Diabetic nephropathy is a severe complication of type 1 diabetes (T1D) that may lead to renal failure and end-stage renal disease (ESRD) demanding dialysis and transplantation. The etiology of diabetic nephropathy is multifactorial and both genes and environmental and life style-related factors are involved. In this study, we investigate the effect of the socioeconomic exposures, unemployment and receiving income support, on the development of ESRD in T1D patients, using a marginal structural model (MSM) in comparison with standard logistic regression models. METHODS: The study is based on the Swedish Childhood Diabetes Register which in 1977 started to register patients developing T1D before 15 years of age. In the analyses, we include patients born between 1965 and 1979, developing diabetes between 1977 and 1994, and followed until 2013 (n = 4034). A MSM was fitted to adjust for both baseline and time-varying confounders. RESULTS: The main results of the analysis indicate that being unemployed for more than 1 year and receiving income support are risk factors for the development of ESRD. Multiple exposures over time to these risk factors increase the risk associated with the disease. CONCLUSIONS: Using a MSM is an advanced method well suited to investigate the effect of exposures on the risk of complications of a chronic disease with longitudinal data. The results show that socioeconomic disadvantage increases the risk of developing ESRD in patients with T1D.

Impact of parental socioeconomic status on excess mortality in a population-based cohort of subjects with childhood-onset type 1 diabetes.

OBJECTIVE: The aim of this study was to analyze the possible impact of parental and individual socioeconomic status (SES) on all-cause mortality in a population-based cohort of patients with childhood-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: Subjects recorded in the Swedish Childhood Diabetes Registry (SCDR) from 1 January 1978 to 31 December 2008 were included (n = 14,647). The SCDR was linked to the Swedish Cause of Death Registry (CDR) and the Longitudinal Integration Database for Health Insurance and Labour Market Studies (LISA). RESULTS: At a mean follow-up of 23.9 years (maximum 46.5 years), 238 deaths occurred in a total of 349,762 person-years at risk. In crude analyses, low maternal education predicted mortality for male patients only (P = 0.046), whereas parental income support predicted mortality in both sexes (P < 0.001 for both). In Cox models stratified by age-at-death group and adjusted for age at onset and sex, parental income support predicted mortality among young adults (≥18 years of age) but not for children. Including the adult patient's own SES in a Cox model showed that individual income support to the patient predicted mortality occurring at ≥24 years of age when adjusting for age at onset, sex, and parental SES. CONCLUSIONS: Exposure to low SES, mirrored by the need for income support, increases mortality risk in patients with childhood-onset type 1 diabetes who died after the age of 18 years.

Five-region study finds no evidence of undiagnosed type 2 diabetes in Swedish 11- to 13-year-olds.

AIM: Childhood obesity is now an established public health problem in most developed countries, and there is concern about a parallel increase of type 2 diabetes. The aim of this study was to estimate the prevalence of undiagnosed type 2 diabetes in overweight Swedish school children from 11 to 13 years of age. METHODS: Body mass index (BMI) was measured in 5528 schoolchildren in the 6th grade, from 11 to 13 years of age, in five different regions in Sweden. Overweight was defined by international age- and sex-specific BMI cut-offs, corresponding to adult BMI cut-offs of 25 kg/m(2) at 18 years of age (ISO-BMI ≥25, n = 1275). Haemoglobin A1c (HbA1c) was measured in 1126 children with ISO-BMI ≥25. Children with a Diabetes Control and Complications Trial aligned HbA1c ≥6.1% on two occasions underwent an oral glucose tolerance test (OGTT) to establish the diabetes diagnosis. RESULTS: Of 1126 children with ISO-BMI ≥25, 24 (2.1%) had at least one HbA1c value ≥6.1%. Three of them had HbA1c ≥6.1% on two occasions, and all of them had a normal OGTT. CONCLUSION: In this cross-sectional, population-based screening study of a high-risk group of 11- to 13-year-old Swedish school children, we found no indication of undiagnosed diabetes or impaired glucose tolerance.

Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes.

AIMS/HYPOTHESIS: An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes. METHODS: The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10(-4) were followed up in 3,750 additional patients with type 1 diabetes from seven studies. RESULTS: The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p < 5 × 10(-8)). In the replication group, a nominally significant association (p = 0.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic association observed at the common variants in GLRA3. The strongest replication (p = 0.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes. CONCLUSIONS/INTERPRETATION: This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.

Renal replacement therapy due to type 1 diabetes; time trends during 1995-2010--a Swedish population based register study.

BACKGROUND: End stage renal disease (ESRD), is the most severe complication of diabetes mellitus. This population-based study analysed time trends for start of renal replacement therapy (RRT) due to type 1 diabetes compared to type 2 diabetes and other diagnoses. MATERIAL AND METHODS: We used data on patients who were registered 1995-2010 in the Swedish Renal Registry, a nationwide register covering 95 % of all patients with uraemia. The patients were analysed according to their original kidney disease. The incidence was analysed by calendar year, age at start of RRT and gender. RESULTS: Of 17389 patients who were registered, 1833 had type 1 diabetes; 65% were men. The mean age at onset of RRT for patients with type 1 diabetes was 52.8 years which increased by more than 3 years over the studied period. The number of patients in need of RRT due to type 1 diabetes decreased, while RRT due to type 2 diabetes increased during the period studied. CONCLUSIONS: The overall incidence of RRT in Sweden is rather constant over the years but the need for RRT in type 1 diabetes patients decreased and patients with type 1 diabetes tend to become older at onset of RRT.

IGF2BP2 and IGF2 genetic effects in diabetes and diabetic nephropathy.

OBJECTIVE: The IGF2BP2 gene is located on chromosome 3q27.2 within a region linked to type 1 diabetes (T1D), type 2 diabetes (T2D) and diabetic nephropathy (DN). Its protein functionally binds to 5'-UTR of the imprinting IGF2 gene. The present study aims to evaluate the IGF2BP2-IGF2 genetic effects in diabetes and DN. MATERIALS AND METHODS: Three cohorts including T1D with and without DN (n=1139) of European descents from the GoKinD study, Swedish T1D with and without DN (n=303) and Czech control subjects without diabetes, T1D, T2D with and without DN (n=1418) were enrolled in TaqMan genotyping experiments for IGF2BP2 rs4402960 and IGF2 rs10770125. Igf2bp2 gene expression in kidney tissues of db/db and control mice at the ages of 5 and 26 weeks was examined with real time RT-PCR and Western blot. RESULTS: An association of IGF2BP2 rs4402960 with T2D in the Czech population was replicated. This IGF2BP2 polymorphism (P=0.037, OR=0.69 95% CI 0.49-0.98) was found to be associated with DN in male not in female patients with T1D selected from the GoKinD study. In the analyses of combined the GoKinD, Czech and Swedish populations, the association between IGF2BP2 polymorphism and DN in male patients with T1D was still significant (P=0.030, OR=0.73, 95% CI 0.54-0.97). IGF2 rs10770125 was also associated with DN in male T1D patients of the GoKinD population (P=0.038, OR=0.67 95% CI 0.46-0.98). There might be a genetic interaction between IGF2BP2 and IGF2 (P=0.05). The Igf2bp2 gene expression levels were increased in the kidneys of db/db mice compared to controls at the age of 5weeks but not at 26 weeks. CONCLUSIONS: The present study has replicated the association of IGF2BP2 rs4402960 with T2D in the Czech population and provided data suggesting that IGF2BP2 may have genetic interaction with IGF2 with a protective effect against DN in male patients with T1D.

A polymorphism in the angiotensin II type 1 receptor gene has different effects on the risk of diabetic nephropathy in men and women.

BACKGROUND: The etiology of diabetic nephropathy depends partly on genetic factors. Elevated systemic and intraglomerular blood pressure and glomerular filtration rate, partly regulated by the renin-angiotensin system, increase the risk of diabetic nephropathy. METHODS: The present case-control study investigated the association of the rs5186 polymorphism, in the angiotensin II type 1 receptor gene (AGTR1), with diabetic nephropathy. The study included 3561 patients with type 1 diabetes from Denmark, Finland, France and Sweden. Microalbuminuria was defined as albumin excretion rate (AER) ≥20 to <200 µg/min or albumin concentration ≥30 to <300 mg/l (n=707), macroalbuminuria was defined as AER≥200 µg/min or ≥300 mg/l (n=1546), and patients with renal replacement therapy were also included in this group. The controls had >15 years diabetes duration, AER <20 µg/min or <30 mg/l, and no antihypertensive treatment (n=1308). RESULTS: AA genotype of the rs5186 polymorphism significantly increased the risk of diabetic nephropathy in male patients, OR=1.27 (95% CI=1.02-1.58), P=0.03, adjusted for age at diabetes onset, HbA1c, diabetes duration, smoking and country of origin. Among the women, there were no significant associations between rs5186 and diabetic nephropathy, OR=0.89 (0.71-1.11), P=0.30. CONCLUSION: We conclude that the AGTR1 gene may be associated with increased risk of diabetic nephropathy in men with type 1 diabetes.

Thirty years of prospective nationwide incidence of childhood type 1 diabetes: the accelerating increase by time tends to level off in Sweden.

OBJECTIVE: During the past few decades, a rapidly increasing incidence of childhood type 1 diabetes (T1D) has been reported from many parts of the world. The change over time has been partly explained by changes in lifestyle causing rapid early growth and weight development. The current study models and analyzes the time trend by age, sex, and birth cohort in an exceptionally large study group. RESEARCH DESIGN AND METHODS: The present analysis involved 14,721 incident cases of T1D with an onset of 0-14.9 years that were recorded in the nationwide Swedish Childhood Diabetes Registry from 1978 to 2007. Data were analyzed using generalized additive models. RESULTS: Age- and sex-specific incidence rates varied from 21.6 (95% CI 19.4-23.9) during 1978-1980 to 43.9 (95% CI 40.7-47.3) during 2005-2007. Cumulative incidence by birth cohort shifted to a younger age at onset during the first 22 years, but from the birth year 2000 a statistically significant reversed trend (P < 0.01) was seen. CONCLUSIONS: Childhood T1D increased dramatically and shifted to a younger age at onset the first 22 years of the study period. We report a reversed trend, starting in 2000, indicating a change in nongenetic risk factors affecting specifically young children.

Tamm-Horsfall protein gene is associated with distal tubular dysfunction in patients with type 1 diabetes.

OBJECTIVE: The first changes in the diabetic kidney are glycogen deposits in the epithelial cells of the thick ascending limb of Henle, which leads to decreased production of Tamm-Horsfall protein (THP). The production of THP is also influenced by nitric oxide (NO). The aims of this study were to investigate whether low excretion of THP, a sign of distal tubular dysfunction, in patients with type 1 diabetes was associated with polymorphisms in the THP gene and the endothelial NO synthase (eNOS) gene. MATERIAL AND METHODS: Urine was collected from 301 patients with type 1 diabetes, 164 with normoalbuminuria, 91 with microalbuminuria and 46 with macroalbuminuria. Urinary THP concentration below median (3.12 mg/l) was defined as tubular dysfunction. Representative polymorphisms were analysed in the THP and eNOS genes. RESULTS: Patients with tubular dysfunction had longer diabetes duration and higher blood pressure than patients without tubular dysfunction. Tubular dysfunction was common in patients with macroalbuminuria (70% of patients) and it was associated with the AA+AT genotypes of rs12444268 in the THP gene [odds ratio (OR) 1.8, 95% confidence interval (CI) 1.1-2.8], and the GG genotype of rs1799983 in the eNOS gene (OR 1.6, 95% CI 1.03-2.6). When adjusting for other associated factors, diabetes duration, glycosylated haemoglobin (HbA(1c)), mean arterial pressure and albuminuria, the THP rs12444268 and macroalbuminuria were independently associated with tubular dysfunction. CONCLUSION: Distal tubular dysfunction was associated with the THP gene and macroalbuminuria in patients with type 1 diabetes.

Cumulative risk, age at onset, and sex-specific differences for developing end-stage renal disease in young patients with type 1 diabetes: a nationwide population-based cohort study.

OBJECTIVE: This study aimed to estimate the current cumulative risk of end-stage renal disease (ESRD) due to diabetic nephropathy in a large, nationwide, population-based prospective type 1 diabetes cohort and specifically study the effects of sex and age at onset. RESEARCH DESIGN AND METHODS: In Sweden, all incident cases of type 1 diabetes aged 0-14 years and 15-34 years are recorded in validated research registers since 1977 and 1983, respectively. These registers were linked to the Swedish Renal Registry, which, since 1991, collects data on patients who receive active uremia treatment. Patients with > or =13 years duration of type 1 diabetes were included (n = 11,681). RESULTS: During a median time of follow-up of 20 years, 127 patients had developed ESRD due to diabetic nephropathy. The cumulative incidence at 30 years of type 1 diabetes duration was low, with a male predominance (4.1% [95% CI 3.1-5.3] vs. 2.5% [1.7-3.5]). In both male and female subjects, onset of type 1 diabetes before 10 years of age was associated with the lowest risk of developing ESRD. The highest risk of ESRD was found in male subjects diagnosed at age 20-34 years (hazard ratio 3.0 [95% CI 1.5-5.7]). In female subjects with onset at age 20-34 years, the risk was similar to patients' diagnosed before age 10 years. CONCLUSIONS: The cumulative incidence of ESRD is exceptionally low in young type 1 diabetic patients in Sweden. There is a striking difference in risk for male compared with female patients. The different patterns of risk by age at onset and sex suggest a role for puberty and sex hormones.

The endothelial nitric oxide synthase gene and risk of diabetic nephropathy and development of cardiovascular disease in type 1 diabetes.

Nitric oxide (NO) is important in the maintenance of vascular tone and regulation of blood pressure. NO may also play a role in the development of both nephropathy and cardiovascular disease (CVD) in patients with diabetes. The susceptibility to nephropathy and CVD depends to some extent on genetic factors, therefore polymorphisms in the gene coding for endothelial NO-synthase, NOS3, can affect the risk of developing these diseases. Type 1 diabetes patients attending the Steno Diabetes Center, Denmark, between 1993 and 2001 were enrolled in this study. A total of 458 cases with diabetic nephropathy (albumin excretion >300 mg/24h) and 319 controls with persistent normoalbuminuria (<30 mg/24h), despite > or =20 years of diabetes duration at follow-up were identified. Patients were followed until death or end of the study. Associations between seven NOS3-gene polymorphisms and nephropathy, progression of nephropathy and CVD were studied. There was significant association between the rs743507 TT-genotype and diabetic nephropathy. When including age at diabetes onset, diabetes duration at follow-up, baseline Hb(A1c), sex and ever smoking in the analysis the OR was 1.43 (95% CI=1.03-2.00), P=0.035. In analyses of CVD development using Cox-regression the rs1799983 GG-genotype was a significant protective factor in normoalbuminuric patients, HR=0.32 (0.12-0.82), P=0.018, but not in patients with macroalbuminuria (covariates were; age at follow-up, baseline Hb(A1c), baseline systolic blood pressure, baseline cholesterol, sex and ever smoking). Our conclusion is that the NOS3-gene may be involved in the development of diabetic nephropathy in patients with type 1 diabetes and can be predictive of CVD during follow-up.

Genetic polymorphisms in the renin-angiotensin system confer increased risk of stroke independently of blood pressure: a nested case-control study.

OBJECTIVE: The renin-angiotensin system has a pathophysiological role in cardiovascular disease through a variety of processes. Polymorphisms in involved genes have been described and implicated in stroke. The aim of this study was to investigate two polymorphisms in two genes in the renin-angiotensin system and the risk of stroke. DESIGN: A nested case-control study using baseline data obtained from population-based surveys in northern Sweden was performed. There were 275 individuals without major concomitant disease who suffered a first ever stroke during follow-up and 549 controls matched for age, sex and domicile. METHODS: Blood samples obtained at baseline were analyzed for potential risk factors including the A1166C polymorphism of the angiotensin II type I receptor (AT1R) gene and the functional insertion/deletion polymorphism of the angiotensin-converting enzyme gene. RESULTS: Individuals with the AA genotype of the AT1R gene were at increased risk of ischemic stroke (odds ratio = 1.60; P = 0.005) compared with those with the AC and CC genotypes. The D allele of the angiotensin-converting enzyme insertion/deletion polymorphism was associated with a higher risk of stroke (odds ratio = 1.58; P = 0.014). CONCLUSION: In this prospective study, there was an association between A1166C polymorphism in the angiotensin II receptor gene and ischemic stroke. We also replicated previous observations that the D allele of the angiotensin-converting enzyme insertion/deletion polymorphism was associated with increased risk of stroke. The observed elevated stroke risks conferred by these two polymorphisms are independent of each other and common risk factors such as blood pressure, diabetes, smoking and high cholesterol levels.

The effect of polymorphisms in the renin-angiotensin-aldosterone system on diabetic nephropathy risk.

OBJECTIVES: The risk of diabetic nephropathy (DN) can be increased by elevated intraglomerular pressure and glomerular filtration rate, leading to glomerular damage. This can be controlled by the renin-angiotensin-aldosterone (RAA) system, which has an important function regulating both systemic and intrarenal blood pressure. Smoking increases the risk of DN, but not all diabetic patients who smoke develop DN. There is a possibility that smoking has different effects depending on the different genotypes of the individual. We investigated the association of DN with seven polymorphisms in the RAA system and their possible interaction with smoking. SUBJECTS AND METHODS: In the present case-control study, type 1 diabetic patients with diabetes duration > or =20 years, without albuminuria and without antihypertensive treatment (n=197), were included as controls. An albumin excretion rate (AER) of 20-200 microg/min (n=73) was considered as incipient DN, and an AER >200 microg/min was considered as overt DN (n=48). Smoking habits were obtained from questionnaires. RESULTS: Homozygosity for the A allele, of the angiotensin II type 1 receptor (AGTR1) A1166C polymorphism, was associated with increased risk of overt DN (OR=3.04; 99% CI=1.02-9.06), independently of the other associated variables: age, duration of diabetes, ever smoking, HbA1c, and sex. The effect of the AA genotype was enhanced to a four times risk increase among ever-smoking patients. Two alleles of the microsatellite marker adjacent to the angiotensinogen gene were less common among nephropathy cases than among controls, but this was not significant when controlling for the same variables as above. CONCLUSIONS: The risk of having overt DN was increased in patients homozygous for the A1166 allele, and smoking seemed to enhance the effect of the AGTR1 genotype.

Distribution of neuropeptide Y Leu7Pro polymorphism in patients with type 1 diabetes and diabetic nephropathy among Swedish and American populations.

OBJECTIVE: The distribution of Leu7Pro polymorphism in the neuropeptide Y gene shows a geographical north to south gradient of decreasing frequency, suggesting that it may be a population-specific causal variant. This polymorphism is found to be associated with diabetic nephropathy (DN) and coronary heart disease in Finnish women with type 1 diabetes (T1D). The present study aims to evaluate the susceptibility of this polymorphism to the development of DN in two different populations. DESIGN: One sample set consists of 174 (females 98 and males 76) Swedish T1D patients with DN and 249 (females 132 and males 117) patients without DN. Another sample set includes 597 (females 356 and males 241) American T1D patients without DN and 577 (females 264 and males 313) patients with DN, who were descents of European Caucasians and were from the Genetics of Kidneys in Diabetes (GoKinD) Study. METHODS: Genotyping of Leu7Pro polymorphism was performed by dynamic allele-specific hybridization. RESULTS: The C allele frequencies of Leu7Pro polymorphism in T1D patients between Swedish and American GoKinD populations were significantly different (6.3 vs 4.0%; P=0.006). Particularly, the C allele frequency in Swedish female T1D patients with DN was significantly higher in comparison with T1D patients without DN (10.2 vs 4.2%; P=0.011, OR=2.614, 95% confidence intervals: 1.249-5.467). No significant association of this polymorphism with DN was observed in Swedish male T1D patients and the patients from GoKinD. CONCLUSIONS: The present study provides further evidence that Leu7Pro polymorphism confers the susceptibility to the development of DN in Swedish female T1D patients.

Genetic association analysis of the adiponectin polymorphisms in type 1 diabetes with and without diabetic nephropathy.

OBJECTIVE: Adiponectin [adipocyte C1q and collagen domain containing (ACDC)] is the most abundant adipose-specific protein. It is beneficial in that it improves insulin sensitivity and mitigates vascular damage, in addition to the possibility of it having anti-inflammatory properties. Clinical evidences demonstrate that serum adiponectin concentrations are increased in patients with type 1 diabetes (T1D) as well as in patients with microvascular complications. However, the genetic influence of the ACDC gene in T1D and diabetic microvascular complications is still unclear. The present study aims to evaluate the association of the ACDC genetic variation in T1D and diabetic nephropathy (DN). MATERIALS AND METHODS: Ten single nucleotide polymorphisms (SNPs) of the ACDC gene were genotyped in 432 T1D patients (of which, 196 had DN) and 187 nondiabetic control subjects, who were all Swedish Caucasians, by using dynamic allele specific hybridization. RESULTS: Single-marker association analysis demonstrated that SNPs +45G15G(T/G) and +276(G/T) were strongly associated with T1D [P=.002, OR=1.855 (1.266-2.717) and P=.001, OR=1.694 (1.337-2.147)]. Further analysis for haplotypes of these two SNPs indicated that one of the common haplotype (T_G) was strongly associated with T1D [P<.001, OR=1.769 (1.430-2.188)]. However, there was no significant difference in the allele frequencies of these two SNPs between the groups of T1D patients with nephropathy and the patients without nephropathy. CONCLUSIONS: The present study thus suggests that SNPs +45G15G(T/G) and +276(G/T) in the ACDC gene are associated with T1D but not with DN among Swedish Caucasians.

A functional polymorphism in the manganese superoxide dismutase gene and diabetic nephropathy.

Oxidative stress has been suggested to contribute to the development of diabetic nephropathy. Manganese superoxide dismutase (MnSOD) protects the cells from oxidative damage by scavenging free radicals. The demand for antioxidants is increased by smoking, which could disturb the balance between antioxidants and radicals. The present study aimed to determine whether a valine/alanine polymorphism in MnSOD (V16A, rs4880), alone or in combination with smoking, can contribute to development of diabetic nephropathy in 1,510 Finnish and Swedish patients with type 1 diabetes. Overt diabetic nephropathy (n = 619) was defined as having an albumin excretion rate (AER) >200 microg/min or renal replacement therapy; incipient diabetic nephropathy was defined as having an AER of 20-200 microg/min (n = 336). The control subjects had diabetes duration of >or=20 years, without albuminuria (AER <20 microg/min) and without antihypertensive treatment (n = 555). In addition to male sex and elevated A1C, smoking was significantly associated with diabetic nephropathy (overt plus incipient), odds ratio (OR) 2.00 (95% CI 1.60-2.50). When controlling for age at onset, diabetes duration, A1C, smoking, and sex, the Val/Val genotype was associated with an increase in risk of diabetic nephropathy (1.32 [1.00-1.74], P = 0.049). When evaluating the combined effect of genotype and smoking, we used logistic regression with stratification according to smoking status and genotype. The high-risk group (ever smoking plus Val/Val genotype) had 2.52 times increased risk of diabetic nephropathy (95% CI 1.73-3.69) compared with the low-risk group, but no departure from additivity was found. Our results indicate that smoking and homozygosity for the MnSOD Val allele is associated with an increased risk of diabetic nephropathy, which supports the hypothesis that oxidative stress contributes to the development of diabetic nephropathy.