Genetic association analyses of non-synonymous single nucleotide polymorphisms in diabetic nephropathy

Aims/hypothesis: Diabetic nephropathy, characterised by persistent proteinuria, hypertension and progressive kidney failure, affects a subset of susceptible individuals with diabetes. It is also a leading cause of end-stage renal disease (ESRD). Non-synonymous (ns) single nucleotide polymorphisms (SNPs) have been reported to contribute to genetic susceptibility in both monogenic disorders and common complex diseases. The objective of this study was to investigate whether nsSNPs are involved in susceptibility to diabetic nephropathy using a case-control design.

Methods: White type 1 diabetic patients with (cases) and without (controls) nephropathy from eight centres in the UK and Ireland were genotyped for a selected subset of nsSNPs using Illumina's GoldenGate BeadArray assay. A ? 2 test for trend, stratified by centre, was used to assess differences in genotype distribution between cases and controls. Genomic control was used to adjust for possible inflation of test statistics, and the False Discovery Rate method was used to account for multiple testing.

Results: We assessed 1,111 nsSNPs for association with diabetic nephropathy in 1,711 individuals with type 1 diabetes (894 cases, 817 controls). A number of SNPs demonstrated a significant difference in genotype distribution between groups before but not after correction for multiple testing. Furthermore, neither subgroup analysis (diabetic nephropathy with ESRD or diabetic nephropathy without ESRD) nor stratification by duration of diabetes revealed any significant differences between groups.

Conclusions/interpretation: The nsSNPs investigated in this study do not appear to contribute significantly to the development of diabetic nephropathy in patients with type 1 diabetes.

Collaborative artistic laboratories. Transfrontier spaces of cultural production

The appearance of the open code paradigm and the demands of social movements have permeated the ways in which today’s cultural institutions are organized. This article analyzes the birth of a new critical and cooperative spatiality and how it is transforming current modes of cultural research and production. It centers on the potential for establishing the new means of cooperation that are being tested in what are defined as collaborative artistic laboratories. These are hybrid spaces of research and creation based on networked and cooperative structures producing a new societal-technical body that forces us to reconsider the traditional organic conditions of the productive scenarios of knowledge and artistic practice.

Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR - 1.10, 95% CI: 1.03-1.18, P - 0.006 and HR - 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P 7 = 10 x (11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42%

Delineation of a recognisable phenotype of interstitial deletion 3 (q22.3q25.1) in a case with previously unreported truncus arteriosus

Interstitial deletions of chromosome 3q22.3e25.1 are very rare with only five previous reports of deletions in this region [1,2,4,7,9]. We describe a case of a female infant with a de novo deletion. Dysmorphic features and congenital heart disease led to a clinical genetics assessment on day 1 of life. Chromosomal analysis showed an interstitial deletion with a female karyotype 46,XX,del (3)(q23q25.1) dn. Subsequent array CGH demonstrated the breakpoints as 3q22.3q25.1. This is the first documented association with a truncus arteriosus. We identify an emerging clinical phenotype of microphthalmia, microcephaly, congenital heart disease, slow feeding, skeletal abnormalities, with an abnormal facies and developmental delay. Array CGH demonstrated that the FOXL2 gene responsible for BPES was not deleted in this patient. (C) 2010 Elsevier Masson SAS. All rights reserved.

Advances in the Genetics of Familial Renal Cancer

We discuss recent advances in the diagnosis and management of renal cell cancer (RCC) given the enhanced molecular genetics knowledge in this area. A number of hereditary renal cancer syndromes have been described, including von Hippel-Lindau disease, Birt-Hogg-Dube syndrome, hereditary leiomyomatosis/RCC syndrome, and hereditary papillary renal cancer. Early molecular diagnosis now facilitates the management and prevention of RCC in families. Recommendations for screening in families are discussed. The Oncologist 2010;15:532-538

Identification of a Second Kindred with Familial Hypocalciuric Hypercalcemia Type 3 (FHH3) Narrows Localization to a

Context: Familial hypocalciuric hypercalcemia (FHH) is a genetically heterogenous disorder that consists of three defined types, FHH1, FHH2, and FHH3 whose chromosomal locations are 3q21.1, 19p, and 19q13, respectively. FHH1, caused by mutations of the calcium-sensing receptor (CASR), occurs in more than 65% of patients, whereas the abnormalities underlying FHH2 and FHH3, which have each been described in single North American kindreds, are unknown.

Tumor Risks and Genotype-Phenotype-Proteotype Analysis in 358 Patients With Germline Mutations in SDHB and SDHD

Succinate dehydrogenase B (SDHB) and D (SDHD) subunit gene mutations predispose to adrenal and extraadrenal pheochromocytomas, head and neck paragangliomas (HNPGL), and other tumor types. We report tumor risks in 358 patients with SDHB (n = 295) and SDHD (n = 63) mutations. Risks of HNPGL and pheochromocytoma in SDHB mutation carriers were 29% and 52%, respectively, at age 60 years and 71% and 29%, respectively, in SDHD mutation carriers. Risks of malignant pheochromocytoma and renal tumors (14% at age 70 years) were higher in SDHB mutation carriers; 55 different mutations (including a novel recurrent exon 1 deletion) were identified. No clear genotype-phenotype correlations were detected for SDHB mutations. However, SDHD mutations predicted to result in loss of expression or a truncated or unstable protein were associated with a significantly increased risk of pheochromocytoma compared to missense mutations that were not predicted to impair protein stability (most such cases had the common p.Pro81Leu mutation). Analysis of the largest cohort of SDHB/D mutation carriers has enhanced estimates of penetrance and tumor risk and supports in silicon protein structure prediction analysis for functional assessment of mutations. The differing effect of the SDHD p.Pro81Leu on HNPGL and pheochromocytoma, risks suggests differing mechanisms of tumorigenesis in SDH-associated HNPGL and pheochromocytoma. Hum Mutat 31:41-51, 2010. (C) 2009 Wiley-Liss, Inc.

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)

BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron I of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers.