The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance (P<5 × 10−8): KANK4 rs79742895, LAMC1 rs3768617 and LINC00970/ATP1B1 rs1200114. We also observe an overwhelming effect of the established TCF4 locus. Interestingly, we detect differential sex-specific association at LAMC1, with greater risk in women, and TCF4, with greater risk in men. Combining GWAS results with biological evidence we expand the knowledge of common FECD loci from one to four, and provide a deeper understanding of the underlying pathogenic basis of FECD.
Quality of dementia care improves with a personalized approach to aged care, and knowledge of the disease process and unique care needs of residents with dementia. A personalized model of care can have a significant impact on the overall organizational culture in aged care homes. However, the dimensions of personalized aged care relating to dementia often remain under-managed. We aim to explore the factors that shape the dimensions of personalized dementia care in rural nursing homes using qualitative data of a mixed-method 'Harmony in the Bush' dementia study. The study participants included clinical managers, registered nurses, enrolled nurses and care workers from five rural aged care homes in Queensland and South Australia. One hundred and four staff participated in 65 semi-structured interviews and 20 focus groups at three phases: post-intervention, one-month followup and three-months follow-up. A multidimensional model of nursing home care quality developed by Rantz et al. (1998) was used in data coding and analysis of the factors. Three key themes including seven dimensions emerged from the findings: resident and family [resident and family centeredness, and assessment and care planning]; staff [staff education and training, staff-resident interaction and work-life balance]; and organization [leadership and organizational culture, and physical environment and safety]. A lack of consideration of family members views by management and staff, together with poorly integrated, holistic care plan, limited resources and absence of ongoing education for staff, resulted in an ineffective implementation of personalized dementia care. Understanding the dimensions and associated factors may assist in interpreting the multidimensional aspects of personalized approach in dementia care. Staff training on person-centered approach, assessment and plan, and building relationships among and between staff and residents are essential to improve the quality of care residents receive.
Fuchs' endothelial dystrophy (FED) is a disease affecting the corneal endothelium. Recent studies reported significant association of polymorphisms in the TCF4 (transcription factor 4) gene, and a borderline association of PTPRG (protein tyrosine phosphatase, receptor type, G) variants with late-onset FED in Caucasians from the United States. Association of TCF4 has also been reported in the Chinese population. We aimed to determine association of the reported polymorphisms in TCF4 and PTPRG, and association of polymorphisms in the candidate genes ZEB1 (zinc-finger E-box binding homoebox 1), COL8A2 (collagen, type VIII, alpha 2), TGFBI (transforming growth factor, b-induced) and CLU (clusterin) in Australian cases. We also compared the expression of TGFBI and CLU proteins between FED and normal whole corneas. In all, 30 single-nucleotide polymorphisms (SNPs) from the candidate genes were genotyped in 103 cases and 275 controls. Each SNP and haplotype was assessed for association with the disease. SNP analysis identified an association of TCF4 (rs613872 (P¼5.25Â10 À15 , OR¼4.05), rs9954153 (P¼3.37Â10 À7 , OR¼2.58), rs2286812 (P¼4.23Â10 À6 , OR¼2.55) and rs17595731 (P¼3.57Â10 À5 , OR¼3.79)), CLU (rs17466684; P¼0.003, OR¼1.85) and one haplotype of TGFBI SNPs (P¼0.011, OR¼2.29) with FED in Caucasian Australians. No evidence for genetic association of PTPRG, ZEB1 and COL8A2 was found. Immunohistochemistry showed differential expression of CLU and TGFBI proteins in FED-affected compared with normal corneas. In conclusion, variation in TCF4, CLU and TGFBI, but not PTPRG, ZEB1 and COL8A2 genes are associated with FED in Caucasian Australian cases. Differential expression of CLU and TGFBI proteins in FED-affected corneas provides novel insights into the disease mechanism.
BackgroundAsymmetric dimethylarginine (ADMA), present in human serum, is an endogenous inhibitor of nitric oxide synthase and contributes to vascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) is an ADMA degrading enzyme that has two isoforms: DDAHI and DDAHII. We sought to determine whether serum ADMA levels in type 2 diabetes are influenced by common polymorphisms in the DDAH1 and DDAH2 genes.Methodology/Principal FindingsRelevant clinical parameters were measured and peripheral whole blood obtained for serum and genetic analysis on 343 participants with type 2 diabetes. Serum ADMA concentrations were determined by mass spectroscopy. Twenty six tag SNPs in the DDAH1 and 10 in the DDAH2 gene were genotyped in all subjects and tested for association with serum ADMA levels. Several SNPs and haplotypes in the DDAH genes were strongly associated with ADMA levels. Most significantly in the DDAH1 gene, rs669173 (p = 2.96×10−7), rs7521189 (p = 6.40×10−7), rs2474123 (p = 0.00082) and rs13373844 (p = 0.00027), and in the DDAH2 gene, rs3131383 (p = 0.0029) and the TGCCCAGGAG haplotype (p = 0.0012) were significantly associated with ADMA levels. Sub-analysis by diabetic retinopathy (DR) status revealed these variants were associated with ADMA levels predominantly in participants without DR. Combined analysis of the most strongly associated SNPs in DDAH1 (rs669173) and DDAH2 (rs3131383) revealed an additive effect (p = 1.37×10−8) on ADMA levels.Conclusions/SignificanceGenetic variation in the DDAH1 and 2 genes is significantly associated with serum ADMA levels. Further studies are required to determine the pathophysiological significance of elevated serum ADMA in type 2 diabetes and to better understand how DDAH gene variation influences ADMA levels.
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