These findings suggest that UGT1A1*6 and UGT1A9*22 genotypes may be important for SN-38 glucuronidation and associate with irinotecan-related severe toxicity. Specifically, UGT1A1*6 might be useful for predicting tumor response and survival outcome of Korean patients with NSCLC treated with irinotecan-based chemotherapy.
Singleton-Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, psoriasis, and other conditions. Despite an apparent autosomal-dominant pattern of inheritance, the genetic background of SMS and information about its phenotypic heterogeneity remain unknown. Recently, we found a family affected by glaucoma, aortic calcification, and skeletal abnormalities. Unlike subjects with classic SMS, affected individuals showed normal dentition, suggesting atypical SMS. To identify genetic causes of the disease, we performed exome sequencing in this family and identified a variant (c.1118A>C [p.Glu373Ala]) of DDX58, whose protein product is also known as RIG-I. Further analysis of DDX58 in 100 individuals with congenital glaucoma identified another variant (c.803G>T [p.Cys268Phe]) in a family who harbored neither dental anomalies nor aortic calcification but who suffered from glaucoma and skeletal abnormalities. Cys268 and Glu373 residues of DDX58 belong to ATP-binding motifs I and II, respectively, and these residues are predicted to be located closer to the ADP and RNA molecules than other nonpathogenic missense variants by protein structure analysis. Functional assays revealed that DDX58 alterations confer constitutive activation and thus lead to increased interferon (IFN) activity and IFN-stimulated gene expression. In addition, when we transduced primary human trabecular meshwork cells with c.803G>T (p.Cys268Phe) and c.1118A>C (p.Glu373Ala) mutants, cytopathic effects and a significant decrease in cell number were observed. Taken together, our results demonstrate that DDX58 mutations cause atypical SMS manifesting with variable expression of glaucoma, aortic calcification, and skeletal abnormalities without dental anomalies.
We introduce the design and implementation of a new array, the Korea Biobank Array (referred to as KoreanChip), optimized for the Korean population and demonstrate findings from GWAS of blood biochemical traits. KoreanChip comprised >833,000 markers including >247,000 rare-frequency or functional variants estimated from >2,500 sequencing data in Koreans. Of the 833 K markers, 208 K functional markers were directly genotyped. Particularly, >89 K markers were presented in East Asians. KoreanChip achieved higher imputation performance owing to the excellent genomic coverage of 95.38% for common and 73.65% for low-frequency variants. From GWAS (Genome-wide association study) using 6,949 individuals, 28 associations were successfully recapitulated. Moreover, 9 missense variants were newly identified, of which we identified new associations between a common population-specific missense variant, rs671 (p.Glu457Lys) of ALDH2, and two traits including aspartate aminotransferase (P = 5.20 × 10−13) and alanine aminotransferase (P = 4.98 × 10−8). Furthermore, two novel missense variants of GPT with rare frequency in East Asians but extreme rarity in other populations were associated with alanine aminotransferase (rs200088103; p.Arg133Trp, P = 2.02 × 10−9 and rs748547625; p.Arg143Cys, P = 1.41 × 10−6). These variants were successfully replicated in 6,000 individuals (P = 5.30 × 10−8 and P = 1.24 × 10−6). GWAS results suggest the promising utility of KoreanChip with a substantial number of damaging variants to identify new population-specific disease-associated rare/functional variants.
Glomerular visceral epithelial cells, namely podocytes, are highly specialized cells and give rise to primary processes, secondary processes, and finally foot processes. The foot processes of neighboring podocytes interdigitate, leaving between them filtration slits. These are bridged by an extracellular substance, known as the slit diaphragm, which plays a major role in establishing size-selective barrier to protein loss. Furthermore, podocytes are known to synthesize matrix molecules to the glomerular basement membrane (GBM), including type IV collagen, laminin, entactin, and agrin. Because diabetic nephropathy is clinically characterized by proteinuria and pathologically by glomerular hypertrophy and GBM thickening with foot process effacement, podocytes have been the focus in the field of research on diabetic nephropathy. As a result, many investigations have demonstrated that the diabetic milieu per se, hemodynamic changes, and local growth factors such as transforming growth factor-beta and angiotensin II, which are considered mediators in the pathogenesis of diabetic nephropathy, induce directly and/or indirectly hypertrophy, apoptosis, and structural changes, and increase type IV collagen synthesis in podocytes. This review explores some of the structural and functional changes of podocytes under diabetic conditions and their role in the development and progression of diabetic nephropathy.
The data listed in two parts of this article were inaccurate. The following are the results sections of the abstract and the main article, respectively.Results: Among 8 polymorphisms, 3435TT and 2677TT were associated with AUC SN-38G and CL . When haplotypes are assigned, 2677TT/3435TT carriers showed significantly lower AUC SN-38G (P ¼ .006), whereas, 2677GG/3435CC carriers showed significantly higher AUC (P ¼.039). These findings suggest that 2677TT and 3435TT variants are associated with higher efflux activity. In toxicity, the 2677G/T or A was associated with grade 4 neutropenia. The 2677GG carriers showed significantly lower absolute neutrophil count during the 1st cycle (P ¼ .012) as well as entire course of chemotherapy (P ¼ .042). The 3435TT was associated with higher frequency of grade 3 diarrhea (P ¼ .047). In tumor response, ABCC2 À24TT and 3972TT genotypes were associated with higher response rates (P ¼ .031 and P ¼ .048, respectively) and longer progression-free survival (P ¼ .010 and P ¼ .019, respectively), which was sustained in haplotype analysis.Of the 107 patients enrolled, 103 were assessable for response and 48 [36 (44%) in 80 mg/m 2 group v 12 (46%) in 65 mg/m 2 group, P ¼ 1.0\patients achieved partial responses (PR). 27 By genotypes, patients with ABCC2 À24T and 3972T genotypes showed a significantly higher tumor response rate (P ¼ .031 and P ¼ .048, respectively, Table 6). We also examined the effect of haplotypes on the tumor response to IP chemotherapy. Only patients with À24C/3972C or À24T/3972T were associated with tumor response rates. Patients with À24T/3972T were associated with higher tumor response rates than absence of this haplotype [24/38 (63%) v 24/65 (36%), P ¼ .014], whereas, those with homozygous À24C/3972C were associated with lower tumor response rates than heterozygous or absence of this haplotype [12/38 (31%) v 36/65 (55%), P ¼ .025].Likewise the association of genotypes with tumor response rates, the ABCC2 À24C>T and 3972C>T were associated with progression-free survival (PFS). Patients with À24TT or 3972TT showed significantly longer progression-free survival (P ¼ .010 and P¼.019, respectively, Fig. 2). When haplotypes were analyzed, patients with homozygous À24T/3972T showed significantly longer PFS than heterozygous or absence of this haplotype (P ¼ .036). Whereas, patients with at least one À24C/3972C showed significantly shorter PFS than those without this haplotype (P ¼ .03).The authors regret this error.
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