ABCA1 Gene Research Articles

Identification of Side Chain Oxidized Sterols as Novel Liver X Receptor Agonists with Therapeutic Potential in the Treatment of Cardiovascular and Neurodegenerative Diseases.

The nuclear receptors-liver X receptors (LXR α and β) are potential therapeutic targets in cardiovascular and neurodegenerative diseases because of their key role in the regulation of lipid homeostasis and inflammatory processes. Specific oxy(phyto)sterols differentially modulate the transcriptional activity of LXRs providing opportunities to develop compounds with improved therapeutic characteristics. We isolated oxyphytosterols from Sargassum fusiforme and synthesized sidechain oxidized sterol derivatives. Five 24-oxidized sterols demonstrated a high potency for LXRα/β activation in luciferase reporter assays and induction of LXR-target genes APOE, ABCA1 and ABCG1 involved in cellular cholesterol turnover in cultured cells: methyl 3β-hydroxychol-5-en-24-oate (S1), methyl (3β)-3-aldehydeoxychol-5-en-24-oate (S2), 24-ketocholesterol (S6), (3β,22E)-3-hydroxycholesta-5,22-dien-24-one (N10) and fucosterol-24,28 epoxide (N12). These compounds induced SREBF1 but not SREBP1c-mediated lipogenic genes such as SCD1, ACACA and FASN in HepG2 cells or astrocytoma cells. Moreover, S2 and S6 enhanced cholesterol efflux from HepG2 cells. All five oxysterols induced production of the endogenous LXR agonists 24(S)-hydroxycholesterol by upregulating the CYP46A1, encoding the enzyme converting cholesterol into 24(S)-hydroxycholesterol; S1 and S6 may also act via the upregulation of desmosterol production. Thus, we identified five novel LXR-activating 24-oxidized sterols with a potential for therapeutic applications in neurodegenerative and cardiovascular diseases.

The effect of ox-LDL and platelets on macrophages, M2 macrophage polarization, and foam cell formation.

The accumulation of oxidized LDL (ox-LDL) in macrophages in association with platelet activity leads to the formation of foam cells, which play a key role in the pathophysiology of atherosclerosis and coronary artery diseases (CAD). Here, in this study, we aimed to investigate the simultaneous effect of ox-LDL and platelets on foam cell formation, as well as modification in cell markers. First, the U937, a human monocytic cell line, was cultured in RPMI-1640. Then, isolated platelets were co-cultured with the U937 and exposed to ox-LDL (80 µg/ml) to evaluate the impact of ox-LDL on foam cell formation using Oil red O (ORO) staining. Also, the expression of foam cells' surface markers and CD36, ABCA1, SR-B1, ACAT1, and LXRα genes, which are involved in macrophage metabolism and ox-LDL uptake, was measured by flow cytometry and real-time PCR, respectively. Our findings suggest that platelets promoted foam cell formation (ORO-positive cells), accompanied by a higher level of CD163+ M2 macrophages. Furthermore, the expression of CD36, ABCA1, SR-B1, ACAT1, and LXRα genes, which are implicated in cholesterol accumulation in macrophages, was significantly upregulated in the ox-LDL+ platelets group compared to the control (P < 0.05). Moreover, the up-regulation of CD36, ABCA1, and SR-B1 genes in the ox-LDL+ platelets group was more accentuated compared to the ox-LDL group (P < 0.05). Owing to the positive effector role of platelets in the formation of foam cells and CD163+ cells, it could be assumed that platelets play a dual role in the development of these cells.

Amyloid Beta Alters the Expression of microRNAs Regulating HMGCR and ABCA1 Genes in Astrocytes of C57BL/6J Mice.

Dysregulation of brain cholesterol homeostasis causes the accumulation of extracellular protein deposits called amyloid plaques in the hippocampus which eventually leads to neuronal death, memory and learning deficits. The aim of the present study was to investigate the effect of beta amyloid on miRNAs regulating HMGCR and ABCA1 as cholesterol synthesis and homeostasis genes. Primary astrocytes were isolated from C57BL/6J mice, and were treated with 0.5 μM amyloid beta (Aβ). Expression levels of genes and miRNAs were measured by real-time PCR. In comparison to control, Aβ treatment resulted in a significant decrease in miR-96-5p expression as a positive and negative regulator of HMGCR and ABCA1, respectively. There was no significant increase in miR-27a-3p expression as a negative regulator of HMGCR. miR- 106b- 5p and miR-143-3p expressions were also dramatically decreased as ABCA1 negative regulators. Amyloid beta can alter the expression of major genes in the cholesterol homeostasis pathway via their regulatory miRNAs.

Association of methylation status of ABCA1/G1 genes with the risk of coronary artery disease

BackgroundATP-binding cassette transporters A1/G1 (ABCA1/G1) is a main regulator of HDL (high-density lipoprotein) formation and reverse cholesterol transport. Impaired ABCA1/G1 genes function may seriously affect cholesterol homeostasis, leading to increased risk of cardiovascular disease. In the present study, the association of ABCA1/G1 genes methylation status with the risk of coronary artery disease (CAD), risk factors of CAD, and serum level of lipid parameters was investigated.This study was conducted on 70 CAD patients and 40 control subjects. All CAD subjects with diabetes mellitus were excluded. The promoter methylation status of ABCA1/G1 genes was determined by the methylation-specific polymerase chain reaction (MS-PCR) method and serum lipid parameters were assessed using commercial kits.ResultsABCA1 promoter methylation was higher in CAD group compared to the control participants (80% vs. 60%). Hypermethylation of the ABCA1 gene significantly increases the risk of CAD in the total population (OR 3.886, 95% CI (1.181–12.791), p = 0.026). ABCG1 methylation status showed no difference between CAD and control subjects. In addition, no significant association was noted between methylation status of ABCA1/G1 and serum level of lipid profile.ConclusionsAltogether, our study shows that ABCA1 gene promoter hypermethylation may increase the risk of CAD, which may help identify people at risk of developing CAD.

Identification of ABCA7 SNP‐by‐CpG interactions associated with cognition in older African Americans

AbstractBackgroundThe ABCA7 gene confers the largest genetic risk for Alzheimer’s Disease (AD) in African Americans (AA) after APOE ε4. However, the relationship between ABCA7 and cognitive function has not been thoroughly examined in AA without dementia. We investigated the effect of genetic variants and epigenetic markers in ABCA7, as well as their interaction, on cognition in older AA without dementia.MethodThe sample included 629 cognitively normal AA from the Genetic Epidemiology Network of Arteriopathy (GENOA). Methylation at 72 CpG sites located within 5kb of ABCA7 were measured using the Illumina EPIC array. General cognitive function (cognition) was measured by taking the first principal component of five cognitive tests. The association between SNPs and cognition was assessed using linear mixed models controlling for age, sex, education, population structure and relatedness. The association between CpGs and cognition was assessed using the same model with further adjustment for white blood cell proportions, batch effects and smoking. We also evaluated SNP‐by‐CpG interactions.ResultNo SNPs were associated with cognition at p&lt;0.05. A 1% change in methylation at three CpGs (cg22271697, cg11714200, cg12082025) was associated with a 0.02‐0.10 standard deviation (SD) increase in cognition (p&lt;0.05; no associations significant at FDR q&lt;0.1). Four SNP‐by‐CpG interactions were associated with cognition (FDR q&lt;0.1). Contrast tests show that methylation is associated with cognition in some genotype groups (p&lt;0.05): a 1% methylation increase at cg22271697 is associated with a 0.13 SD increase in cognition for those with the AA rs3764647 genotype, a 1% increase at cg06169110 is associated with a 0.35 SD decrease in cognition for those with the rs115550680 GG or AG genotype, and a 1% increase at cg00135882 is associated with a 1.19 SD decrease in cognition for those with a rs3764650 GG genotype.ConclusionWhile AD risk SNPs in ABCA7 are not associated with cognition in the full sample of older African Americans, some do interact with proximal methylation to influence cognition. This suggests that a complicated interplay between genetic and epigenetic factors in ABCA7 may influence cognition in cognitively normal AA. A similar mechanism may play a role in cognitive aging and decline.

The role of Abca7 in late‐onset Alzheimer’s disease animal models

AbstractBackgroundAlzheimer's disease (AD) and other neurodegenerative diseases are typified by a robust microglial‐mediated immune response. Genetic studies have demonstrated that variants in microglial genes are linked to risk for AD. Genome‐wide association studies (GWAS) originally identified ATP‐binding cassette, sub‐family A, member 7 (ABCA7), as a novel risk gene of Alzheimer's disease (AD). Since then, accumulating evidence from in vitro, in vivo, and human‐based studies has extended this association, promoting ABCA7 as one of the most important risk genes of late‐onset AD (LOAD), harboring both common and rare risk variants with relatively large effect on AD risk. Besides associations with disease status, genetic and epigenetic ABCA7 markers show significant correlations with AD endophenotypes; in particular amyloid deposition and brain morphology. In conclusion, human‐based ‐omics studies provide converging evidence of (partial) ABCA7 loss as an AD pathomechanism.MethodTo investigate the impact of Abca7 gene expression on microglia biology and disease pathology, we have generated Abca7A1527G mice on an APOE4.Trem2R47H (LOAD1) and APOE4.Trem2R47H.hAß (LOAD2) background. Cohorts of mice were established at JAX and IU and aged to either 4 and 12 months (LOAD1) or 4‐, 12‐, 18‐, and 24‐month. In vivo behavior and wellness assays included continuous activity monitoring, frailty assessment, open field, grip strength, spontaneous alternation, rotarod, delayed spatial novelty, episodic memory, and general health were completed as well as MRI and PET studies. Post‐mortem studies included blood chemistry, immunohistochemistry, and molecular studies. Studies of transcriptomics and proteomics were also completed on brain tissue.ResultCorrelation of transcriptional profiling with human AMP‐AD modules determined individual and synergistic effects with genetic risk factors. At 12 months of age, LOAD1.Abca7A1527G mice show similar correlations to LOAD in Consensus Cluster B (immune system), Consensus Cluster D (cell cycle), and Consensus Cluster E (organelle biogenesis). Neuropathology analysis in brain tissue is in progress, as are cytokine panels in brain homogenates and plasma of LOAD2. Abca7A1527G mice.ConclusionOur findings provide evidence that Abca7 plays an important role in LOAD and the addition of Abca7A1527G to a sensitized LOAD model (LOAD1 and LOAD2) more closely align phenotypes in the mouse to outcomes observed in human AD.

Evaluation of ABCA1 gene polymorphism as a prognostic index of fibrosis progression in NAFLD patients.

It had been evident that non-alcoholic fatty liver disease (NAFLD) is the new era epidemic. Despite emergence of many drugs on the pipeline that considered candidates to cure NAFLD/NASH, the critical need for defining the cohort liable to fibrosis progression is yet unmet. Evaluate ABCA1 (rs1800977) genotyping as a noninvasive predictor of liver fibrosis severity. This study included 118 liver biopsy-proven NAFLD-patients. According to Metavir-fibrosis-staging, cases were divided to early fibrosis (74 cases), and 44 cases with significant fibrosis (>F2), added to 49 healthy control subjects. All patients were subjected to liver function tests, lipids profile, triglyceride TG index, and hepatic steatosis index (HSI) and real-time PCR ABCA1 SNP (rs1800977). Significant differences in transaminases (p > .05), albumin (p < .009), cholesterol (p0.03), low density lipoproteins (LDL) (0.006), triglycerides (p < .001), HSI (p < .001), FIB4 (p < .001) and APRI (p < .001) were reported in those with significant than early fibrosis and control groups. CC was the most prevalent in significant (36.4%) than early fibrosis (13.5%) and control groups (8.2%), with prevalence of C allele in significant fibrosis (p ≤ .003). Univariate analysis revealed that DM (p ≤ .001), TG index (p ≤ .022), cholesterol (p ≤ .03), HSI (p ≤ .006), LDL (p ≤ .02), HDL (p ≤ .01), APRI (p ≤ .02) and CC genotype (p ≤ .005) were the main factors affecting fibrosis progression in NAFLD. However multivariate analysis proved only the role of HSI (p ≤ .005), LDL (p ≤ .02), HDL (p ≤ .003) and CC genotype (p ≤ .03) in predicting fibrosis severity. Dyslipidemias, hepatic steatosis index and ABCA1 (rs1800977) gene polymorphism CC genotype; were the only independent predictors of advanced fibrosis in NAFLD-patients.

Polymorphic Variants of AGT, ABCA1, and CYBA Genes Influence the Survival of Patients with Coronary Artery Disease: A Prospective Cohort Study.

Genetic factors can influence the risk of coronary artery disease (CAD) and the survival of patients. Our previous research led to the identification of genetic variants predisposing to CAD in the Polish population. Since many of them affect the clinical phenotype of the disease, the aim of this study was searching for genetic factors potentially influencing survival in patients with CAD. The study included 276 patients hospitalized due to coronary artery disease. The database of medical history and genotypic results of 29 polymorphisms were used. The endpoint was defined as death from cardiovascular causes. Survival was defined as the period from angiographic confirmation of CAD to death from cardiovascular causes. Three of all the analyzed genes were associated with survival. In the case of the AGT (rs699) and ABCA1 (rs2230806) genes polymorphisms, the risk of death was higher in GG homozygotes compared to the A allele carriers in the 10-year period. In the case of the CYBA (rs72811418) gene polymorphism, the effect on mortality was shown in both 5- and 10-year periods. The TA heterozygotes were predisposed to a higher risk of death than the TT homozygotes. Concluding, the AGT, ABCA1, and CYBA genes polymorphisms influence the risk of death in patients with CAD.

ODP149 Hypertriglyceridemia-Induced Acute Pancreatitis in Second Trimester of Pregnancy

Abstract Background Acute pancreatitis (AP) during pregnancy is a rare, potentially life-threatening disease, with an incidence of 1 case per 1,000-10,000. Hypertriglyceridemia (HTG)-induced pancreatitis accounts for only 5% of cases. Here we describe a rare case of HTG-induced AP during the second trimester of pregnancy, which was treated with concurrent insulin and plasmapheresis. Clinical Case A 35-year-old multigravida female was admitted for preterm premature rupture of membranes at 26 weeks gestation. Symptoms began on day 8 of admission and included severe epigastric pain radiating to the back. On exam, there was significant epigastric tenderness on palpation. There were no xanthelasmas or tendon xanthomas seen. She was afebrile but tachycardic. Laboratory evaluation noted a triglyceride (TG) level of &amp;gt;5,680 mg/dL (n&amp;lt;150), amylase 201 U/L (n&amp;lt;100) and lipase 277 U/L (n&amp;lt;60), consistent with AP. She was euglycemic. CT of the abdomen showed interstitial edematous pancreatitis with a peripancreatic collection. She was placed on NPO and started on intravenous (IV) fluid therapy, in combination with IV insulin and 10% dextrose. The patient also underwent one session of plasmapheresis. TG levels downtrended rapidly to 3,585 mg/dL within 24 hours. Once TG levels decreased below 1,000 mg/dL, insulin and dextrose infusions were stopped, and combination therapy of fenofibrate, omega-3 fatty acids, and low-fat low-carbohydrate diet was started. At 28 weeks and 5 days gestation, a cesarean section was performed due to suspected fetal distress. The patient was discharged on fenofibrate and Omega-3 fatty acids with a TG level of 456 mg/dL. Genetic testing revealed a heterozygous variant in the LPL gene mutation (c.644G&amp;gt;A; p. Gly215Glu) and a heterozygous variant of uncertain significance (VUS) in the ABCA1 gene (c.1765G&amp;gt;A; p. Val589Ile). She had no known family history of hyperlipidemia or cardiovascular disease. Conclusion Lipoprotein lipase (LPL) deficiency is an autosomal recessive disorder caused by biallelic pathogenic mutations in the LPL gene. The heterozygous c.644G&amp;gt;A variant has been previously described in several patients with LPL deficiency, however its impact on the function of the LPL protein has not yet been clearly defined. The ABCA1 gene is associated with Tangier disease, characterized by very low HDL levels and HTG. The ABCA1 gene variant detected in this case is classified as VUS as its effect on the gene function is not yet known. Further investigation is warranted to understand the role of these variants in familial dyslipidemia. Aside from the described patient, only one other case report of HCT-induced AP treated with concomitant plasmapheresis and IV insulin therapy has been reported in the literature. There are no published guidelines regarding the optimal treatment for HTG-induced AP in pregnancy. Combined treatment modality with plasmapheresis and IV insulin seems to be effective, however, its risks and benefits should be carefully assessed. Presentation: No date and time listed

ATP-Binding Cassette Transporter Family C Protein 10 Participates in the Synthesis and Efflux of Hexosylceramides in Liver Cells.

In addition to sphingomyelin and ceramide, sugar derivatives of ceramides, hexosylceramides (HexCer) are the major circulating sphingolipids. We have shown that silencing of ABCA1 transmembrane protein function for instance in cases of loss of function of ABCA1 gene results in low levels of HDL as well as a concomitant reduction in plasma HexCer levels. However, proteins involved in hepatic synthesis and egress of HexCer from cells is not well known although ABCA1 seems to be indirectly controlling the HexCer plasma levels by supporting HDL synthesis. In this study, we hypothesized that protein(s) other than ABCA1 are involved in the transport of HexCer to HDL. Using an unbiased knockdown approach, we found that ATP-binding cassette transporter protein C10 (ABCC10) participates in the synthesis of HexCer and thereby affects egress to HDL in human hepatoma Huh-7 cells. Furthermore, livers from ABCC10 deficient mice had significantly lower levels of HexCer compared to wild type livers. These studies suggest that ABCC10 partakes in modulating the synthesis and subsequent efflux of HexCer to HDL in liver cells.

Insulin Downregulates the Expression of ATP-binding Cassette Transporter A-I in Human Hepatoma Cell Line HepG2 in a FOXO1 and LXR Dependent Manner.

ATP-binding cassette transporter A-I (ABCA1) is an ubiquitously expressed protein whose main function is the transmembrane transport of cholesterol and phospholipids. Synthesis of ABCA1 protein in liver is necessary for high-density lipoprotein (HDL) formation in mammals. Thus, the mechanism of ABCA1 gene expression regulation in hepatocytes are of critical importance. Recently, we have found the insulin-dependent downregulation of other key player in the HDL formation-apolipoprotein A-I gene (J. Cell. Biochem., 2017, 118:382-396). Nothing is known about the role of insulin in the regulation of ABCA1 gene. Here we show for the first time that insulin decreases the mRNA and protein levels of ABCA1 in human hepatoma cell line HepG2. PI3K, p38, MEK1/2, JNK and mTORC1 signaling pathways are involved in the insulin-mediated downregulation of human ABCA1 gene. Transcription factors LXRα, LXRβ, FOXO1 and NF-κB are important contributors to this process, while FOXA2 does not regulate ABCA1 gene expression. Insulin causes the decrease in FOXO1, LXRα and LXRβ binding to ABCA1 promoter, which is likely the cause of the decrease in the gene expression. Interestingly, the murine ABCA1 gene seems to be not regulated by insulin in hepatocytes (in vitro and in vivo). We suggest that the reason for this discrepancy is the difference in the 5'-regulatory regions of human and murine ABCA1 genes.

Relationship of hypertension with interactions among ABCA1 gene, AGT gene, and occupational stress

Relationship of hypertension with interactions among ABCA1 gene, AGT gene, and occupational stress

Comparative Transcriptomic Analyses Revealed the Effects of Poly (I:C) on the Liver and Spleen of Argyrosomus japonicus.

Poly (I:C) can work as an immunostimulant and a viral vaccine; however, its functional mechanism in aquatic animals needs to be further investigated. In this study, comparative transcriptomic analyses were performed to investigate the effects of poly (I:C) on Argyrosomus japonicus at 12 h and 48 h postinjection. A total of 194 and 294 differentially expressed genes were obtained in the liver and spleen, respectively. At 12 h, poly (I:C) injection could significantly influence the function of the metabolism-related pathways and immune-related pathways in the liver through the upregulation of the genes GST, LPIN, FOXO1, CYP24A1, ECM1, and SGK1, and the downregulation of the genes IL-1β, CXC19, TNFAIP3, and IRF1. At 48 h, poly (I:C) could enhance the liver energy metabolism by upregulating the genes TXNRD and ECM1, while it also induced some injury in the cells with the downregulation of the genes HBA and CYP24A1. In the spleen, poly (I:C) could regulate the fish immunity and inflammatory response by upregulating the genes DDIT4, C3, EFNA, and MNK, and by downregulating the genes ABCA1, SORT1, TNF, TLR2, IL8, and MHCII at 12 h, and at 48 h, the poly (I:C) had a similar influence as that in the liver. Intersection analyses demonstrated that CYP24A1 and ECM1 were the main functional genes that contributed to the health of the liver. Ten and four genes participated in maintaining the health of the two tissues after 12 h and 48 h, respectively. In summary, our results provided a new insight into ploy (I:C) application in A. japonicus, and it also helped us to better understand the fish response mechanism to the viral vaccine injection.

ATP-binding cassette protein ABCA7 deficiency impairs sphingomyelin synthesis, cognitive discrimination, and synaptic plasticity in the entorhinal cortex

Sphingomyelin (SM) is an abundant plasma membrane and plasma lipoprotein sphingolipid. We previously reported that ATP-binding cassette family A protein 1 (ABCA1) deficiency in humans and mice decreases plasma SM levels. However, overexpression, induction, downregulation, inhibition, and knockdown of ABCA1 in human hepatoma Huh7 cells did not decrease SM efflux. Using unbiased siRNA screening, here, we identified that ABCA7 plays a role in the biosynthesis and efflux of SM without affecting cellular uptake and metabolism. Since loss of function mutations in the ABCA7 gene exhibit strong associations with late-onset Alzheimer’s disease across racial groups, we also studied the effects of ABCA7 deficiency in the mouse brain. Brains of ABCA7-deficient (KO) mice, compared with WT, had significantly lower levels of several SM species with long chain fatty acids. In addition, we observed that older KO mice exhibited behavioral deficits in cognitive discrimination in the active place avoidance task. Next, we performed synaptic transmission studies in brain slices obtained from older mice. We found anomalies in synaptic plasticity at the intracortical synapse in layer II/III of the lateral entorhinal cortex but not in the hippocampal CA3-CA1 synapses in KO mice. These synaptic abnormalities in KO brain slices were rescued with extracellular SM supplementation but not by supplementation with phosphatidylcholine. Taken together, these studies identify a role of ABCA7 in brain SM metabolism and the importance of SM in synaptic plasticity and cognition, as well as provide a possible explanation for the association between ABCA7 and late-onset Alzheimer’s disease.

GENETIC STUDY OF PATIENT WITH THE DIAGNOSIS OF NIEMANNPICK LYSOSOMAL STORAGE DISEASE

For the first time in Azerbaijan Republic, a patient with Niemann-Pick diagnosis has been studied by means of modern molecular-genetic method complex. Patient H.D. (2006), has been examined by doctor-pediatrician, doctor-neurologist and doctor-geneticist, and during consultation they considered him suspicious of lysosome storage disease. Acidic sphingomyelinase activity, value of biomarker lyso-SM-509were identified with liquid chromotography mass spectroscopy method. Gene analysis was carried out with NGS (next generation sequencing) method. Deficiency of acidic sphingomyelinase enzyme, value of biomarker lyso-SM-509 higher than norm was the evidence that patient had got Niemann-Pick metabolic disease. SMPD1 gene analysis identified substitution of Adenine nucleotide with Guanine nucleotide in the position c.1556 and showed homozygous state (c.1556A&gt;G: p.Tyr519Cys). Alongside with Niemann-Pick A/B types the patient had got CYP21A2 gene homozygous, ALAS2 gene hemizygous inheritance types, ABCA1 and LPL genes showed heterozygous carriage. The patient’s parents being in their reproductive age we advised to undergo fetus prenatal diagnostics in the next pregnancy course.

Genetic landscape of early-onset dementia in Hungary

IntroductionEarly-onset dementias (EOD) are predominantly genetically determined, but the underlying disease-causing alterations are often unknown. The most frequent forms of EODs are early-onset Alzheimer’s disease (EOAD) and frontotemporal dementia (FTD).PatientsThis study included 120 Hungarian patients with EOD (48 familial and 72 sporadic) which had a diagnosis of EOAD (n = 49), FTD (n = 49), or atypical dementia (n = 22).ResultsMonogenic dementia was detected in 15.8% of the patients. A pathogenic hexanucleotide repeat expansion in the C9ORF72 gene was present in 6.7% of cases and disease-causing variants were detected in other known AD or FTD genes in 6.7% of cases (APP, PSEN1, PSEN2, GRN). A compound heterozygous alteration of the TREM2 gene was identified in one patient and heterozygous damaging variants in the CSF1R and PRNP genes were detected in two other cases. In two patients, the coexistence of several heterozygous damaging rare variants associated with neurodegeneration was detected (1.7%). The APOE genotype had a high odds ratio for both the APOE ɛ4/3 and the ɛ4/4 genotype (OR = 2.7 (95%CI = 1.3–5.9) and OR = 6.5 (95%CI = 1.4–29.2), respectively). In TREM2, SORL1, and ABCA7 genes, 5 different rare damaging variants were detected as genetic risk factors. These alterations were not present in the control group.ConclusionBased on our observations, a comprehensive, targeted panel of next-generation sequencing (NGS) testing investigating several neurodegeneration-associated genes may accelerate the path to achieve the proper genetic diagnosis since phenotypes are present on a spectrum. This can also reveal hidden correlations and overlaps in neurodegenerative diseases that would remain concealed in separated genetic testing.

A novel homozygous frameshift mutation in the APOA1 gene associated with marked high-density lipoprotein deficiency

The proband was a 53-year-old Japanese woman. Despite having no atherosclerotic vascular lesions on a physiological examination, markedly decreased levels of high-density lipoprotein (HDL) were always noted at her annual medical checkup. She also had corneal opacities but neither xanthoma nor tonsillar hypertrophy. A biochemical examination showed decreased levels of both apolipoprotein A-I (apoA-I) (<5 mg/dL) and lecithin-cholesterol acyltransferase (LCAT) activity. Her brother and son also had low concentrations of HDL-cholesterol, suggesting the presence of a genetic abnormality. Therefore, a sequence analysis of the genes for ABCA1, LCAT and apoA-I proteins was performed in the proband. The analysis of the APOA1 gene revealed a novel homozygous two-nucleotide deletion in exon 4 (c.614_615delTC), which causes a frameshift after residue 205 of the apoA-I protein (p.Leu205fs). Since no mutation has been found in the ABCA1 or LCAT gene, functional abnormalities of the carboxyl-terminal region of the apoA-I protein in lipid binding might have caused the low HDL-cholesterol levels and decreased LCAT activity, possibly associated with corneal opacities but not premature CAD, in the patient.

Association between ABCA7 gene polymorphisms and Parkinson’s disease susceptibility in a northern Chinese Han population

ObjectiveAs a typical member of the ABC transporter superfamily, ABCA7 has been shown to play an important role in stalling the pathogenesis of neurodegenerative disorders through maintaining the normal microglial function, regulating cellular responses to inflammation and ER stress, and modulating lipid metabolism. Variants in the ABCA7 locus have been hypothesized to be correlated with the genetic predisposition of several neurodegenerative disorders. The goal of this study was to examine whether there is a link between three specific single nucleotide polymorphisms in the ABCA7 gene, namely, rs3764650, rs4147929, and rs3752246, with the risk of developing Parkinson’s disease (PD) in a northern Chinese Han community. MethodsIn this case-control study, we recruited 821 participants, including 411 patients with sporadic PD and 410 independent, healthy controls. A Polymerase Chain Reaction-Restriction Fragment Length Polymorphism genotyping assay was used to identify polymorphisms of the three selected single nucleotide polymorphisms (rs3764650, rs4147929, and rs3752246) of the ABCA7 gene. Sanger sequencing was further applied to identify the accuracy of the genotyping results. The chi-square test was used to compare the frequencies of alleles and genotypes in patients and controls. Odds ratios and 95% confidence intervals were calculated using logistic regression. ResultsWe found significant between-group differences in the alleles (A vs. G, nominal P = 0.014) and dominant models (AA + GA vs. GG, nominal P = 0.015) of rs4147929. Subgroup analysis showed that the frequency of the rs4147929 A allele in male patients with PD was significantly higher than that in male controls (nominal P = 0.036). For the rs3752246 polymorphism, the frequency of the G allele was significantly higher in patients with PD than in controls, and the dominant model fit the data best when considering the nominal P-values (nominal P = 0.019, nominal P = 0.033, respectively). Differences in G allele and genotypes frequencies between patients and controls remained significant in women (nominal P = 0.032 for allele, nominal P = 0.015 for genotype), as well as in individuals aged more than 50 years (nominal P = 0.044, nominal P = 0.020, respectively). No significant differences were observed in allele or genotype frequencies between patients with PD and healthy controls for rs3764650. The frequency of the TCG (rs3764650–rs3752246–rs4147929) haplotype was significantly lower in the PD group than in the healthy control group (odds ratio = 0.772; 95% confidence interval = 0.634–0.940; P = 0.011). ConclusionThe rs4147929 polymorphism was significantly associated with PD susceptibility in the northern Chinese Han population. The A allele of rs4147929 was a risk factor for developing PD. The TCG haplotype presented a protective role in the pathogenesis of PD. Further studies using larger sample sizes, considering different clinical and biochemical parameters such as the cognitive status of subjects at the same time, are warranted to better clarify the effects of these common variants on the pathogenesis and development of PD.

The Genetics of Type 2 Diabetes in Youth: Where We Are and the Road Ahead

The Genetics of Type 2 Diabetes in Youth: Where We Are and the Road Ahead

THE ATP-BINDING CASSETTE TRANSPORTER A1 GENE POLYMORPHISMS AND TYPE 2 DIABETES MELLITUS

Insulin resistance (IR), secretion of insulin, and abnormalities of lipid metabolism are all markers of type 2 diabetes (T2DM), which is a progressive and complex metabolic disorder. Major risk factors for the development of T2DM were identified as genetic, environmental, and lifestyle factors. Several studies found that many genes contribute to T2DM susceptibility after glucose tolerance. Adenosine Binding Cassette Transporter Proteins 1 is a member of the ABC gene superfamily that is involved in cholesterol transport and HDL cholesterol (HDL-C) biosynthesis. Abnormal cholesterol metabolism, particularly high-density lipoprotein, has been related to genetic variations in the ABCA1 gene (HDL-C). Previous research suggested that ABCA1 gene polymorphisms may a hereditary risk factor for type 2 diabetes, along with lower HDLlevels in various populations.