diabetes research and training center
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Publication
Journal: Journal of the American Society of Nephrology : JASN
June/15/2011
Abstract
Identification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.
Publication
Journal: Journal of Biological Chemistry
October/23/2014
Abstract
Thyroid hormones (TH) are critical for development, growth, and metabolism. Circulating TH levels are tightly regulated by thyroid-stimulating hormone (TSH) secretion within the hypothalamic-pituitary-thyroid axis. Although circadian TSH secretion has been well documented, the mechanism of this observation remains unclear. Recently, the nuclear corepressor, NCOR1, has been postulated to regulate TSH expression, presumably by interacting with thyroid hormone receptors (THRs) bound to TSH subunit genes. We report herein the first in vitro study of NCOR1 regulation of TSH in a physiologically relevant cell system, the TαT1.1 mouse thyrotroph cell line. Knockdown of NCOR1 by shRNA adenovirus increased baseline Tshb mRNA levels compared with scrambled control, but surprisingly had no affect on the T3-mediated repression of this gene. Using ChIP, we show that NCOR1 enriches on the Tshb promoter at sites different from THR previously identified by our group. Furthermore, NCOR1 enrichment on Tshb is unaffected by T3 treatment. Given that NCOR1 does not target THR on Tshb, we hypothesized that NCOR1 targeted Rev-Erbα (NR1D1), an orphan nuclear receptor that is a potent repressor of gene transcription and regulator of metabolism and circadian rhythms. Using a serum shock technique, we synchronized TαT1.1 cells to study circadian gene expression. Post-synchronization, Tshb and Nr1d1 mRNA levels displayed oscillations that inversely correlated with each other. Furthermore, NR1D1 was enriched at the same locus as NCOR1 on Tshb. Therefore, we propose a model for Tshb regulation whereby NR1D1 and NCOR1 interact to regulate circadian expression of Tshb independent of TH negative regulation.
Publication
Journal: Obesity (Silver Spring, Md.)
November/2/2014
Abstract
OBJECTIVE
To compare body-mass index (BMI)-related mortality risk in U.S. Blacks vs. Whites as the relationship appears to differ across race/ethnicity groups.
METHODS
Cross-sectional surveys of nationally representative samples of 11,934 Blacks and 59,741 Whites aged 35-75 in the National Health Interview Survey from 1997 to 2002 with no history of cardiovascular disease (CVD) or cancer were pooled. Mortality follow-up was available through 2006. BMI was calculated from self-reported height and weight. We used adjusted Cox regression analysis to adjust for potential confounders.
RESULTS
Over 9 years of follow-up, there were 4303 deaths (1205 among never smokers). Age-adjusted mortality rates were higher in Blacks compared to Whites at BMI < 25 kg/m2 and showed no increase at higher levels of BMI. In men, adjusted hazard ratios for all-cause death rose in a similar fashion across upper BMI quintiles in Blacks and Whites; in women, however, BMI was positively associated with mortality risk in Whites, but inversely associated in Blacks (P interaction = 0.01). Racial disparities were amplified in subsidiary analyses that introduced a 12-month lag for mortality or focused on CVD mortality.
CONCLUSIONS
The relationship of elevated BMI to mortality appeared weaker in US Blacks than in Whites, especially among women.
Publication
Journal: BMC Research Notes
March/29/2015
Abstract
BACKGROUND
SOCS7 is a member of the suppressor of cytokine signaling family of proteins and is expressed in skeletal muscle and islets. SOCS7 deficient mice develop islet hyperplasia in the setting of increased insulin sensitivity and normal glucose tolerance. The objective of this study was to determine if variants in SOCS7 play a role in variation of glucose and insulin levels and the development of type 2 diabetes (T2DM).
RESULTS
Five SOCS7 tagging SNPs were genotyped in diabetic and nondiabetic Old Order Amish. A case-control study was performed in T2DM (n = 145) and normal glucose tolerant (n = 358) subjects. Nominal associations were observed with T2DM and the minor alleles for rs8068600 (P = 0.01) and rs8074124 (P = 0.04); however, only rs8068600 remained significant after Bonferroni adjustment for multiple comparisons (P = 0.01). Among nondiabetic Amish (n = 765), no significant associations with glucose or insulin traits including fasting or 2 hour glucose and insulin from the oral glucose tolerance test, insulin or glucose area under the curve, Matsuda Index or HOMA-IR were found for any of the SNPs.
CONCLUSIONS
In conclusion, genetic variants in the SOCS7 gene do not impact variation in glucose homeostasis traits and only minimally impact risk of T2DM in the Old Order Amish. Our study was not able to address whether rare variants that potentially impact gene function might influence T2DM risk.