Publications

CONTEXT

High-mobility group A1 (HMGA1) protein is a key regulator of insulin receptor (INSR) gene expression. We previously identified a functional HMGA1 gene variant in 2 insulin-resistant patients with decreased INSR expression and type 2 diabetes mellitus (DM).

OBJECTIVE

To examine the association of HMGA1 gene variants with type 2 DM.

DESIGN, SETTINGS, AND PARTICIPANTS

Case-control study that analyzed the HMGA1 gene in patients with type 2 DM and controls from 3 populations of white European ancestry. Italian patients with type 2 DM (n = 3278) and 2 groups of controls (n = 3328) were attending the University of Catanzaro outpatient clinics and other health care sites in Calabria, Italy, during 2003-2009; US patients with type 2 DM (n = 970) were recruited in Northern California clinics between 1994 and 2005 and controls (n = 958) were senior athletes without DM collected in 2004 and 2009; and French patients with type 2 DM (n = 354) and healthy controls (n = 50) were enrolled at the University of Reims in 1992. Genomic DNA was either directly sequenced or analyzed for specific HMGA1 mutations. Messenger RNA and protein expression for HMGA1 and INSR were measured in both peripheral lymphomonocytes and cultured Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and controls.

MAIN OUTCOME MEASURES

The frequency of HMGA1 gene variants among cases and controls. Odds ratios (ORs) for type 2 DM were estimated by logistic regression analysis.

RESULTS

The most frequent functional HMGA1 variant, IVS5-13insC, was present in 7% to 8% of patients with type 2 DM in all 3 populations. The prevalence of IVS5-13insC variant was higher among patients with type 2 DM than among controls in the Italian population (7.23% vs 0.43% in one control group; OR, 15.77 [95% confidence interval {CI}, 8.57-29.03]; P < .001 and 7.23% vs 3.32% in the other control group; OR, 2.03 [95% CI, 1.51-3.43]; P < .001). In the US population, the prevalence of IVS5-13insC variant was 7.7% among patients with type 2 DM vs 4.7% among controls (OR, 1.64 [95% CI, 1.05-2.57]; P = .03). In the French population, the prevalence of IVS5-13insC variant was 7.6% among patients with type 2 DM and 0% among controls (P = .046). In the Italian population, 3 other functional variants were observed. When all 4 variants were analyzed, HMGA1 defects were present in 9.8% of Italian patients with type 2 DM and 0.6% of controls. In addition to the IVS5 C-insertion, the c.310G>T (p.E104X) variant was found in 14 patients and no controls (Bonferroni-adjusted P = .01); the c.*82G>A variant (rs2780219) was found in 46 patients and 5 controls (Bonferroni-adjusted P < .001); the c.*369del variant was found in 24 patients and no controls (Bonferroni-adjusted P < .001). In circulating monocytes and Epstein-Barr virus-transformed lymphoblasts from patients with type 2 DM and the IVS5-13insC variant, the messenger RNA levels and protein content of both HMGA1 and the INSR were decreased by 40% to 50%, and these defects were corrected by transfection with HMGA1 complementary DNA.

CONCLUSIONS

Compared with healthy controls, the presence of functional HMGA1 gene variants in individuals of white European ancestry was associated with type 2 DM.

Little is known about how genetic variations in enhancers influence drug response. In this study, we investigated whether nucleotide variations in enhancers that regulate drug transporters can alter their expression levels. Using comparative genomics and liver-specific transcription factor binding site (TFBS) analyses, we identified evolutionary conserved regions (ECRs) surrounding nine liver membrane transporters that interact with commonly used pharmaceuticals. The top 50 ECRs were screened for enhancer activity in vivo, of which five--located around ABCB11, SLC10A1, SLCO1B1, SLCO1A2, and SLC47A1--exhibited significant enhancer activity. Common variants identified in a large ethnically diverse cohort (n = 272) were assayed for differential enhancer activity, and three variants were found to have significant effects on reporter activity as compared with the reference allele. In addition, one variant was associated with reduced SLCO1A2 mRNA expression levels in human liver tissues, and another was associated with increased methotrexate (MTX) clearance in patients. This work provides a general model for the rapid characterization of liver enhancers and identifies associations between enhancer variants and drug response.

BACKGROUND

Although magnetic resonance imaging (MRI) is a useful imaging modality for invasive cancer, its role in preoperative surgical planning for ductal carcinoma in situ (DCIS) has not been established. We sought to determine whether preoperative MRI affects surgical treatment and outcomes in women with pure DCIS.

PATIENTS AND METHODS

We reviewed consecutive records of women diagnosed with pure DCIS on core biopsy between 2000 and 2007. Patient characteristics, surgical planning, and outcomes were compared between patients with and without preoperative MRI. Multivariable regression was performed to determine which covariates were independently associated with mastectomy or sentinel lymph node biopsy (SLNB).

RESULTS

Of 149 women diagnosed with DCIS, 38 underwent preoperative MRI. On univariate analysis, patients undergoing MRI were younger (50 years vs. 59 years; P < .001) and had larger DCIS size on final pathology (1.6 cm vs. 1.0 cm; P = .007) than those without MRI. Mastectomy and SLNB rates were significantly higher in the preoperative MRI group (45% vs. 14%, P < .001; and 47% vs. 23%, P = .004, respectively). However, there were no differences in number of re-excisions, margin status, and margin size between the two groups. On multivariate analysis, preoperative MRI and age were independently associated with mastectomy (OR, 3.16, P = .018; OR, 0.95, P = .031, respectively), while multifocality, size, and family history were not significant predictors.

CONCLUSION

We found a strong association between preoperative MRI and mastectomy in women undergoing treatment for DCIS. Additional studies are needed to examine the increased rates of mastectomy as a possible consequence of preoperative MRI for DCIS.

BACKGROUND

There has been marked expansion in the literature and practice of pediatric sleep medicine; however, no recent evidence-based practice parameters have been reported. These practice parameters are the first of 2 papers that assess indications for polysomnography in children. This paper addresses indications for polysomnography in children with suspected sleep related breathing disorders. These recommendations were reviewed and approved by the Board of Directors of the American Academy of Sleep Medicine.

METHODS

A systematic review of the literature was performed, and the American Academy of Neurology grading system was used to assess the quality of evidence. RECOMMENDATIONS FOR PSG USE: 1. Polysomnography in children should be performed and interpreted in accordance with the recommendations of the AASM Manual for the Scoring of Sleep and Associated Events. (Standard) 2. Polysomnography is indicated when the clinical assessment suggests the diagnosis of obstructive sleep apnea syndrome (OSAS) in children. (Standard) 3. Children with mild OSAS preoperatively should have clinical evaluation following adenotonsillectomy to assess for residual symptoms. If there are residual symptoms of OSAS, polysomnography should be performed. (Standard) 4. Polysomnography is indicated following adenotonsillectomy to assess for residual OSAS in children with preoperative evidence for moderate to severe OSAS, obesity, craniofacial anomalies that obstruct the upper airway, and neurologic disorders (e.g., Down syndrome, Prader-Willi syndrome, and myelomeningocele). (Standard) 5. Polysomnography is indicated for positive airway pressure (PAP) titration in children with obstructive sleep apnea syndrome. (Standard) 6. Polysomnography is indicated when the clinical assessment suggests the diagnosis of congenital central alveolar hypoventilation syndrome or sleep related hypoventilation due to neuromuscular disorders or chest wall deformities. It is indicated in selected cases of primary sleep apnea of infancy. (Guideline) 7. Polysomnography is indicated when there is clinical evidence of a sleep related breathing disorder in infants who have experienced an apparent life-threatening event (ALTE). (Guideline) 8. Polysomnography is indicated in children being considered for adenotonsillectomy to treat obstructive sleep apnea syndrome. (Guideline) 9. Follow-up PSG in children on chronic PAP support is indicated to determine whether pressure requirements have changed as a result of the child's growth and development, if symptoms recur while on PAP, or if additional or alternate treatment is instituted. (Guideline) 10. Polysomnography is indicated after treatment of children for OSAS with rapid maxillary expansion to assess for the level of residual disease and to determine whether additional treatment is necessary. (Option) 11. Children with OSAS treated with an oral appliance should have clinical follow-up and polysomnography to assess response to treatment. (Option) 12. Polysomnography is indicated for noninvasive positive pressure ventilation (NIPPV) titration in children with other sleep related breathing disorders. (Option) 13. Children treated with mechanical ventilation may benefit from periodic evaluation with polysomnography to adjust ventilator settings. (Option) 14. Children treated with tracheostomy for sleep related breathing disorders benefit from polysomnography as part of the evaluation prior to decannulation. These children should be followed clinically after decannulation to assess for recurrence of symptoms of sleep related breathing disorders. (Option) 15. Polysomnography is indicated in the following respiratory disorders only if there is a clinical suspicion for an accompanying sleep related breathing disorder: chronic asthma, cystic fibrosis, pulmonary hypertension, bronchopulmonary dysplasia, or chest wall abnormality such as kyphoscoliosis. (Option) RECOMMENDATIONS AGAINST PSG USE: 16. Nap (abbreviated) polysomnography is not recommended for the evaluation of obstructive sleep apnea syndrome in children. (Option) 17. Children considered for treatment with supplemental oxygen do not routinely require polysomnography for management of oxygen therapy. (Option)

CONCLUSIONS

Current evidence in the field of pediatric sleep medicine indicates that PSG has clinical utility in the diagnosis and management of sleep related breathing disorders. The accurate diagnosis of SRBD in the pediatric population is best accomplished by integration of polysomnographic findings with clinical evaluation.