Human molecular genetics
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Human molecular genetics · Jan 2017
Mendelian randomization estimates of alanine aminotransferase with cardiovascular disease: Guangzhou Biobank Cohort study.
Observational studies of the association of alanine aminotransferase (ALT) levels with ischaemic heart disease (IHD) and cardiovascular disease (CVD) risk factors are inconsistent, probably because of confounding and reverse causality. Mendelian randomization (MR) provides less confounded results. We used MR analysis to assess the associations of ALT (U/L) with IHD, diabetes and other CVD risk factors. ⋯ In the MR study, using a credible genetic instrument (F-statistic = 23) for ALT, ALT levels were negatively associated with IHD (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.87 to 0.97) and triglycerides (β - 0.08, 95% CI - 0.13 to - 0.03), but were not associated with other CVD risk factors. Our results using Mendelian randomization suggest that ALT reduces the risk of IHD, probably through reducing triglyceride levels. The underlying mechanisms deserve further investigation.
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Human molecular genetics · Dec 2016
Meta AnalysisProtective coding variants in CFH and PELI3 and a variant near CTRB1 are associated with age-related macular degeneration†.
Although numerous common age-related macular degeneration (AMD) alleles have been discovered using genome-wide association studies, substantial disease heritability remains unexplained. We sought to identify additional common and rare variants associated with advanced AMD. A total of 4,332 cases and 25,268 controls of European ancestry from three different populations were genotyped using the Illumina Infinium HumanExome BeadChip. ⋯ Suggestive protective loci were identified in the COL4A3 and APOH genes. Our results support the involvement of common and low-frequency protective variants in this vision-threatening condition. This study expands the roles of the innate immune pathway as well as the extracellular matrix and high-density lipoprotein pathways in the aetiology of AMD.
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Human molecular genetics · Nov 2016
Knockout of Tmem70 alters biogenesis of ATP synthase and leads to embryonal lethality in mice.
TMEM70, a 21-kDa protein localized in the inner mitochondrial membrane, has been shown to facilitate the biogenesis of mammalian F1Fo ATP synthase. Mutations of the TMEM70 gene represent the most frequent cause of isolated ATP synthase deficiency resulting in a severe mitochondrial disease presenting as neonatal encephalo-cardiomyopathy (OMIM 604273). To better understand the biological role of this factor, we generated Tmem70-deficient mice and found that the homozygous Tmem70-/- knockouts exhibited profound growth retardation and embryonic lethality at ∼9.5 days post coitum. ⋯ Nevertheless, they presented with mild deterioration of heart function. Our results demonstrated that Tmem70 knockout in the mouse results in embryonic lethality due to the lack of ATP synthase and impairment of mitochondrial energy provision. This is analogous to TMEM70 dysfunction in humans and verifies the crucial role of this factor in the biosynthesis and assembly of mammalian ATP synthase.
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Human molecular genetics · May 2016
Comparative StudyGenome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis.
Thrombotic diseases are among the leading causes of morbidity and mortality in the world. To add insights into the genetic regulation of thrombotic disease, we conducted a genome-wide association study (GWAS) of 6135 self-reported blood clots events and 252 827 controls of European ancestry belonging to the 23andMe cohort of research participants. Eight loci exceeded genome-wide significance. ⋯ In addition, we present data showing that this locus also acts as a novel risk factor for stroke and coronary artery disease (CAD). In conclusion, our study reveals novel common genetic risk factors for VTE, stroke and CAD and provides evidence that self-reported data on blood clots used in a GWAS yield results that are comparable with those obtained using clinically diagnosed VTE. This observation opens up the potential for larger meta-analyses, which will enable elucidation of the genetics of thrombotic diseases, and serves as an example for the genetic study of other diseases.
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Human molecular genetics · Dec 2015
APP overexpression in the absence of NPC1 exacerbates metabolism of amyloidogenic proteins of Alzheimer's disease.
Amyloid-β (Aβ) peptides originating from β-amyloid precursor protein (APP) are critical in Alzheimer's disease (AD). Cellular cholesterol levels/distribution can regulate production and clearance of Aβ peptides, albeit with contradictory outcomes. To better understand the relationship between cholesterol homeostasis and APP/Aβ metabolism, we have recently generated a bigenic ANPC mouse line overexpressing mutant human APP in the absence of Niemann-Pick type C-1 protein required for intracellular cholesterol transport. ⋯ Cholesterol sequestration impaired endocytic-autophagic-lysosomal, but not proteasomal, clearance of APP-CTFs/Aβ peptides. Moreover, markers of oxidative stress were increased in vulnerable brain regions of ANPC mice and enhanced β-CTF/Aβ levels increased susceptibility of N2a-ANPC cells to H2O2-induced toxicity. Collectively, our results show that cellular cholesterol sequestration plays a key role in APP/Aβ metabolism and increasing neuronal vulnerability to oxidative stress in AD-related pathology.