Whole-exome sequencing study identifies four novel gene loci associated with diabetic kidney disease.

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease and diabetes. Our two-stage WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies (stage 1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine participants (stage 2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single-variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds [95% confidence interval (CI): 33.6, 1105] of DKD compared with noncarriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% CI: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.

Comparison between F-18-FDG positron emission tomography and histology for the assessment of tumor necrosis rates in primary osteosarcoma.

BACKGROUND: The purpose of this prospective study was to identify if F-18-fluorodeoxy-D-glucose positron emission tomography (F-18-FDG PET) was a reliable noninvasive surrogate of histologic response in determining the efficacy of neoadjuvant chemotherapy before surgical resection in primary osteosarcoma. METHODS: Between January 2003 and December 2003, 10 patients with primary osteosarcomas were examined using F-18-FDG PET before neoadjuvant chemotherapy and surgery. The mean age at the time of first intervention was 19 years (range, 4-47 years). Positive prognostic significance was defined as more than 90% tumor necrosis response following neoadjuvant chemotherapy. The parameters of FDG uptake were correlated with histologic findings. The intraclass correlation coefficient was used to validate the tumor necrosis rates determined by PET and histology. RESULTS: The tumor necrosis rate determined by PET was comparable with that determined histologically. The mean standardized uptake value before and following neoadjuvant chemotherapy were 8.2 and 4.4, respectively. The average tumor necrosis rate determined by PET was 22%. However, the mean tumor necrosis rate determined histologically was 54.5%. According to the intraclass correlation coefficient models, the intraclass correlation coefficient equaled O. The relationship of tumor necrosis rates determined by F-18-FDG PET and histology seems to be statistically insignificant. CONCLUSION: In this preliminary study, FDG PET did not seem to be a promising tool for evaluating the response of primary osteosarcoma to neoadjuvant chemotherapy.