Cholesterol homeostasis is essential in normal physiology of all cells One of several proteins involved in cholesterol homeostasis is the ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein widely expressed in many tissues One of its main functions is the efflux of intracellular free cholesterol and phospholipids across the plasma membrane to combine with apolipoproteins, mainly apolipoprotein A-I (Apo A-I), forming nascent high-density lipoprotein-cholesterol (HDL-C) particles, the first step of reverse cholesterol transport (RCT) In addition, ABCA1 regulates cholesterol and phospholipid content in the plasma membrane affecting lipid rafts, microparticle (MP) formation and cell signaling Thus, it is not surprising that impaired ABCA1 function and altered cholesterol homeostasis may affect many different organs and is involved in the pathophysiology of a broad array of diseases This review describes evidence obtained from animal models, human studies and genetic variation explaining how ABCA1 is involved in dyslipidemia, coronary heart disease (CHD), type 2 diabetes (T2D), thrombosis, neurological disorders, age-related macular degeneration (AMD), glaucoma, viral infections and in cancer progression

https://www.mdpi.com/1422-0067/22/4/1593/pdf

The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease

It is estimated that approximately 15% of diabetic people world-wide will at some stage develop diabetic foot ulceration. The prevalence of active foot ulceration varies from approx‐ imately 1% in certain European and North American studies to more than 11% in reports from some African countries (table 1). Although there have been many developments in recent years which encourage optimism for future improvement in diabetic foot care, there is still much to be done; the recent data from the Netherlands show that with a concerted team approach, it is possible to increase the numbers of foot clinics with the provision of podiatry services by more than 100%. However, many countries still lack proper podiatry and specialist nursing provision and there remains much to be done in the next millennium to improve the lot of the diabetic patient with foot problems. [2,3] In general, in diabetic patients, the incidence of foot ulcers ranges from 1.0% to 4.1%, and the incidence of lower-extremity amputations ranges from 2.1 to 13.7 per 1000. [4-6]

Diabetic Foot Ulcer

OBJECTIVE To compare the accuracies of MRI and leukocyte scanning in diagnosing clinically unsuspected osteomyelitis in diabetic foot ulcers. RESEARCH DESIGN AND METHODS A prospective study of 16 diabetic foot ulcers in 12 patients, including both ambulatory and hospitalized patients, was performed at a university medical center. Pedal images were obtained by leukocyte scanning with [111In]oxyquinoline and MRI. Definitive diagnosis of osteomyelitis then was determined by bone biopsy for culture and histology. RESULTS Biopsy-proven osteomyelitis was present in 7 (44%) of the 16 foot ulcers. The diagnosis was suspected clinically in 0%. Leukocyte scanning was 100% sensitive, whereas MRI was only 29% sensitive in diagnosing osteomyelitis in diabetic foot ulcers. Specificities were 67 and 78%, respectively. The positive and negative predictive values (70 and 100%, respectively) for the leukocyte scan also were > those of MRI (50 and 58%, respectively). CONCLUSIONS Leukocyte scanning is superior to MRI in detecting clinically unsuspected osteomyelitis in diabetic foot ulcers.

Leukocyte Scanning With 111In Is Superior to Magnetic Resonance Imaging in Diagnosis of Clinically Unsuspected Osteomyelitis in Diabetic Foot Ulcers

Background A few genes have previously been identified in which very rare variants can have major effects on lipid levels. Methods Weighted burden analysis of rare variants was applied to exome sequenced UK Biobank subjects with hyperlipidaemia as the phenotype, of whom 44 054 were designated cases and 156 578 controls, with the strength of association characterised by the signed log 10 p value (SLP). Results With principal components included as covariates there was a tendency for genes on the X chromosome to produce strongly negative SLPs, and this was found to be due to the fact that rare X chromosome variants were identified less frequently in men than women. The test performed well when both principal components and sex were included as covariates and strongly implicated LDLR (SLP=50.08) and PCSK9 (SLP=−10.42) while also highlighting other genes previously found to be associated with lipid levels. Variants classified by SIFT as deleterious have on average a twofold effect and their cumulative frequency is such that they are present in approximately 1.5% of the population. Conclusion These analyses shed further light on the way that genetic variation contributes to risk of hyperlipidaemia and in particular that there are very many protein-altering variants which have on average moderate effects and whose effects can be detected when large samples of exome-sequenced subjects are available. This research has been conducted using the UK Biobank Resource.

/pdf/analysis-of-200-000-exome-sequenced-uk-biobank-subjects-597muxp57z.pdf

Analysis of 200 000 exome-sequenced UK Biobank subjects illustrates the contribution of rare genetic variants to hyperlipidaemia.

Conflicting evidence was found about the relationship between lipid profiles and R219K polymorphism in adenosine triphosphate-binding cassette exporter A1 (ABCA1) gene. In this study, four meta-analyses were conducted to assess the effect of R219K on lipid levels, including high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol, total cholesterol, and triglycerides (TG). A total of 125 samples of 87 studies (about 60,262 subjects) were included. The effect of each study was expressed using the standard mean difference (SMD) and 95% confidence interval (95% CI) and pooled by meta-analysis in the random-effects model. Subgroup and meta-regression analyses were conducted to explore potential heterogeneity sources. The overall pooled effect showed the following results. (1) The R219K was significantly associated with HDLC level (SMD = − 0.25 mmol/L, 95%CI − 0.32 to − 0.18, z = − 6.96, P < 0.01, recessive genetic model). People with different genotypes had significantly different HDLC levels under the recessive, codominant and dominant genetic models (all Ps < 0.01). (2) A weak and indeterminate relationship between R219K and TG level was observed (SMD = 0.18 mmol/L, 95%CI 0.06–0.30, z = 3.01, P < 0.01, recessive genetic model). These findings suggested that R219K was associated with HDLC and TG levels, which might implicate a promising clinical application for lipid-related disorders, though the influences of race, health status, BMI, and other heterogeneity sources should be considered when interpreting current findings. The protocol was registered at PROSPERO (registration number: CRD42021231178).

Association between the ABCA1 (R219K) polymorphism and lipid profiles: a meta-analysis.

Objective To explore the possible effects of the microRNA(miR)-143/145 polymorphisms on cardiovascular risk factors and the severity of coronary heart disease(CHD) in Chinese Han people. Methods Polymerase chain reaction-restriction fragment length polymorphism analysis was employed to identify the genotypes of the rs353292 and rs4705343 polymorphisms for 380 patients with CHD and 163 CHD-free controls. The physiological and biochemical parameters between the genotypes were compared in the CHD patients and in controls,and the incidence of myocardial infarction(MI) was also compared between the genotypes in the CHD patients. Results The subjects with the rs353292 TT genotype had higher serum levels of triglycerides(F=3.00,P=0.05) and glucose(F=9.91,P<0.001) than the C carriers,and the subjects with the rs4705343 TT genotype had significantly higher prevalence of hypertension(Χ2=6.35,P=0.04) than the C carriers in the control group. The patients with the rs353292 TT genotype had significantly higher serum levels of hypersensitive C-reactive protein(hs-CRP)(F=8.43,P<0.001) than the C carriers in the CHD group,and the frequency of MI was significantly higher in the patients with the rs353292 TT genotype than that in the C carrier patients(Χ2=5.29,P=0.02). Conclusion The T allele of the rs353292 polymorphism is associated with serum hs-CRP levels in CHD patients,and it may affect the occurrence and development of MI by up-regulation of CRP gene through miR-143/145. The rs4705343 polymorphism is not related to the risk and severity of CHD.

[Associations of the MicroRNA-143/145 Polymorphisms with Cardiovascular Risk Factors and the Severity of Coronary Heart Disease].

Associations of the ABCA1 gene polymorphisms with plasma lipid levels: A meta-analysis.

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[Associations of the MicroRNA-143/145 Polymorphisms with Cardiovascular Risk Factors and the Severity of Coronary Heart Disease].

Associations of the ABCA1 gene polymorphisms with plasma lipid levels: A meta-analysis.