A Genome-Wide Association Study Identifies a Novel Major Locus for Glycemic Control in Type 1 Diabetes, as Measured by Both A1C and Glucose

OBJECTIVE

Glycemia is a major risk factor for the development of long-term complications in type 1 diabetes; however, no specific genetic loci have been identified for glycemic control in individuals with type 1 diabetes. To identify such loci in type 1 diabetes, we analyzed longitudinal repeated measures of A1C from the Diabetes Control and Complications Trial.

RESEARCH DESIGN AND METHODS

We performed a genome-wide association study using the mean of quarterly A1C values measured over 6.5 years, separately in the conventional (n = 667) and intensive (n = 637) treatment groups of the DCCT. At loci of interest, linear mixed models were used to take advantage of all the repeated measures. We then assessed the association of these loci with capillary glucose and repeated measures of multiple complications of diabetes.

RESULTS

We identified a major locus for A1C levels in the conventional treatment group near SORCS1 (10q25.1, P = 7 × 10⁻¹⁰), which was also associated with mean glucose (P = 2 × 10⁻⁵). This was confirmed using A1C in the intensive treatment group (P = 0.01). Other loci achieved evidence close to genome-wide significance: 14q32.13 (GSC) and 9p22 (BNC2) in the combined treatment groups and 15q21.3 (WDR72) in the intensive group. Further, these loci gave evidence for association with diabetic complications, specifically SORCS1 with hypoglycemia and BNC2 with renal and retinal complications. We replicated the SORCS1 association in Genetics of Diabetes in Kidneys (GoKinD) study control subjects (P = 0.01) and the BNC2 association with A1C in nondiabetic individuals.

CONCLUSIONS

A major locus for A1C and glucose in individuals with diabetes is near SORCS1. This may influence the design and analysis of genetic studies attempting to identify risk factors for long-term diabetic complications.Elevation in plasma glucose, as measured by A1C, is a major risk factor for long-term diabetic complications (1–13). Twin and family studies have shown that A1C levels are heritable in nondiabetic individuals (14–16). In addition, significant correlation in A1C between monozygotic twins both concordant and discordant for type 1 diabetes (14,17), as well as in siblings with type 1 diabetes (18,55), suggests that some genetic factors influence A1C in both diabetic and nondiabetic individuals. However, no study of dizygous twins has been performed. These observations have motivated genome-wide linkage studies of measures of glycemia (typically single fasting plasma glucose or A1C), predominantly in nondiabetic individuals, but have not led to the identification of novel genes possibly because of small effect sizes of individual loci and underpowered studies (15,19,20). More recently, association studies of fasting glucose in nondiabetic individuals have identified multiple loci that meet genome-wide significance criteria (P < 5 × 10⁻⁸, supplementary Table 1, available in an online appendix at http://diabetes.diabetesjournals.org/cgi/content/full/db09-0653/DC1) (20–29).In individuals with type 1 diabetes, there is considerable variability in glycemic control both between and within individuals. Intra-individual variation is likely caused by changes in diabetes management (e.g., pump versus multiple daily injections [30]), diet, activity, weight control, and insulin dosing in response to glucose and A1C measures. Other factors that may influence A1C are erythrocyte turnover, hemoglobinopathies, defects of glucose transport into erythrocytes, mechanisms of glycation and de-glycation, and alterations in intracellular glucose metabolism. Specifically, in the conventional treatment arm of the Diabetes Control and Complications Trial (DCCT), the intra-class correlation between consecutive quarterly A1C values was 0.79, falling to 0.42 for values measured 3 years apart. In the face of such high variability over time, analyzing longitudinally repeated measures via mixed models can increase power to identify risk factors. Alternatively, taking the mean of the values over time may be sufficient to initially screen for important genetic effects. We hypothesized that common genetic variants associated with glycemic control in subjects with type 1 diabetes could be identified using repeated measures of A1C from subjects in the DCCT. Because glycemic control was the major intervention in DCCT, we performed genetic analysis separately in each treatment group, with the expectation that genetic effects may be larger in the conventional treatment group in which there was no attempt to alter A1C (apart from preventing very high values [i.e., >13.11%]).     

Fidelity and Recovery-Orientation in Assertive Community Treatment

There has been increasing commentary about the degree to which Assertive Community Treatment (ACT) teams provide recovery-oriented services, often centered around the question of the use of coercion. The present study was designed to contribute to this discussion through an examination of recovery-oriented service provision and ACT fidelity among 67 teams in the province of Ontario, Canada. The findings indicated a moderate to high degree of recovery orientation in service provision, with no significant relationship between ACT fidelity and consumer and family/key support ratings of recovery orientation. A significant relationship was found, however, between the ‘nature of services’ domain of the Dartmouth Assertive Community Treatment Scale (DACTS) and ratings of recovery orientation provided by staff and ACT coordinators. These findings extend the existing dialogue regarding the evaluation of ACT intervention process factors and indicate that current measures of fidelity may not be adequately addressing dimensions of recovery-oriented service provision.     

A randomized study of laparoscopic chromopertubation with lipiodol versus saline in infertile women

Eighty-eight infertile patients undergoing laparoscopy were randomized to undergo chromopertubation with lipiodol or with normal saline. The cumulative probability of conception at 1, 3, and 6 months following laparoscopy was not statistically different between the lipiodol group (21%, 31% , and 43%, respectively) and the saline group (18%, 21%, and 33%, respectively).     

Cell cycle and molecular targets: CDK inhibition

Protein phosphorylation is a fundamental post-translational modification. It regulates a large number of critical cellular processes (differentiation, division, proliferation, apoptosis). Cell division is a process including a series of phases by which a parent cell divides into two daughter cells. The cells enter these stages then progress within the cell division under an accurate control by many proteins. These proteins are activated by phosphorylation. Cyclin-dependent kinases are responsible for this phosphorylation and therefore represent potential therapeutic targets especially in oncology.     

Lung injury induced by trichloroethylene

Trichloroethylene (TCE) produced bronchiolar damage when administered to mice. Administration of 2000 mg/kg caused injury in Clara cells of the bronchiolar epithelium, which was observed at 24 h following TCE treatment; increase of the dosage to 2500 mg/kg induced additionally, alterations in alveolar Type II cells of the parenchyma. Specifically, lamellar bodies were reduced in number and microvilli displayed distorted protrusions. The increase in severity of cellular injury with higher dosages of TCE coincided with increased accumulation of pulmonary calcium and lengthened anesthesia recovery times following TCE-induced anesthesia. Time-course studies conducted with 2000 mg/kg demonstrated rapid and marked reduction in pulmonary microsomal cytochrome P-450 content and aryl hydrocarbon hydroxylase activity. Significant decreases were observed as early as 1 h, and the levels were still depressed at 24 h following TCE treatment. Hepatic necrosis was relatively mild at the dosages of TCE examined. These results demonstrate that TCE is pneumotoxic and affects Clara and alveolar Type II cells.