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==Natural History, Progression, Complications==
==Natural History, Progression, Complications==
*The age of symptom onset in patients with Apo A1 deficiency and the clinical presentation varies with different mutations.
*Few patients remain asymptomatic into adulthood and few individuals may present from adolescence with symptoms of blurred vision due to corneal opacities or cataract, tubero-eruptive, tendinous, palmar and/or planar xanthomas, xanthelasmas and premature CHD (e.g. myocardial infarction) and carotid atherosclerosis.
* Individuals with certain mutations present with neurosensory signs such as cerebellar ataxia, neurosensory hearing loss, proliferative retinopathy or manifestations of secondary amyloidosis such as hepatomegaly, nephropathy, cardiomyopathy.
*If left untreated the major complication is development of premature heart disease.
*Prognosis depends on occurrence of premature CHD and end-stage organ failure in individuals with amyloidosis.


==Pathogenesis==
==Pathogenesis==

Revision as of 21:26, 5 December 2016


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Synonyms and keywords: Familial hypoalphalipoproteinemia, FHA, familial HDL deficiency, FHD, high density lipoprotein deficiency, HDLD

Overview

Apolipoprotien deficiency is a rare monogenic metabolic disorder resulting in undetectable Apo A1 levels and HDL C less than 20mg/dl. APOA1 gene encodes for the ApoA1 protein which is the major component of HDL C. It is synthesized in the liver and released into the circulation as very small discoid pre beta HDL, which picks up free cholesterol from the cells and macrophages. Apo A1 also activates LCAT which esterifies free cholesterol on the surface of alpha 4 HDL resulting in the formation of cholesterol esters. These two initial steps in the reverse cholesterol are dependent on a functional ApoA1 which is affected in Apo A1 deficiency. Apo A1 synthesis is affected leading to very low HDL levels. Worldwide, 82 cases and a variety of mutations are reported. The biochemical phenotype is always low Apo A1 and low HDL C. Clinical phenotype varies with each mutation and is inconsistent. Symptomatic patients usually present with corneal opacities, xanthelasma and premature heart disease. Cardiovascular risk assessment and optimizing risk factors has an important role in the management.

Historical Perspective

  • In 1981, Vergani and Bettale described a familial syndrome with hypoalphalipoproteinemia.[1]
    • The proband and his relatives had low levels of HDL C, Apo-A1 with normal lipase and LCAT activity.
    • They reported a high prevalence of premature cardiac events without other established coronary risk factors present and a shortened life expectancy on longevity analysis.
    • Based on the biochemical data and the pedigree they have described to have an autosomal dominant inheritance.
  • In 1982, Breslow identified the gene sequence of human Apo A1.[2]
  • In 1982, Karathanasis isolated and described the characteristics of the human Apo A1 gene.[3]
  • In 1982, Daniel described cerebrovascular abnormalities and clinical status of eight children with history of familial lipoprotein disorders and evidence of thromboembolic cerebrovascular disease. Six of the eight children had low levels of plasma HDL C.[4]
    • They have speculated that the vascular events are due to lipoprotein-mediated endothelial damage and thrombus formation.
  • In 1983, Brewer reported that apoA-I mRNA codes for a precursor apolipoprotein, preproapoA-I by nucleic acid sequence analysis.[5]
  • In 1986, Borecki described the possibility of genetic heterogeneity and provided clear evidence of a major gene involved in hypolipoproteinemia after studying 64 individuals in 14 nuclear families.[6]
  • In 1986, Jose described a polymorphic site on the 3' end of the Apo-A1 gene and reported that the patients with this finding had lower HDL C levels. They have also suggested the polymorphism as a useful marker for the risk of premature coronary artery disease and familial hypoalphalipoproteinemia.[7]
  • In 1988, LiWH speculated that the gene coding for apo A-1 is a member of apolipoprotien multigene superfamily, which include genes encoding for Apo AI, Apo-A-II, Apo-C and Apo-E.[8]
  • In 1998, Gillotte described the mechanism apolipoprotein mediated cellular lipid efflux.[9]
  • In 2006, crystal structure of Apo A1 and the description of the electrostatic features of Apo A1 which are crucial in understanding the interactions of Apo A1 with ABCA1 and SR-B1 were described by Ajees.[10]

Classification

  • Apolipoprotein A1 deficiency can be classified based on the type of mutation and the genes affected as follows:
    • Familial apolipoprotein A-I/C-III/A-IV deficiency
    • ApoA1/C-III deficiency
    • Isolated Apo A1 deficiency
    • Apo A1 Variants

Familial apolipoprotein A-I/C-III/A-IV deficiency

  • In 1982, Schaefer and colleagues reported a 45 year old female proband with marked HDL deficiency, undetectable plasma ApoA-I, low-TG, normal LDL-C, corneal arcus, planar xanthomas and premature CVD. The patient had severe CVD with no other known CVD risk factors and died during coronary artery bypass surgery at age 43 years.[11]
  • Her plasma LCAT activity was normal.
  • Defect was a homozygous deletion of the entire APOA1/C3/A4 gene complex.
  • Heterozygotes had plasma HDL-C, Apo AI, Apo AIV, and Apo C-III levels that were about 50% of normal in the kindred.[12]

ApoA1/ApoC-III Deficiency

  • In 1982, Norum and colleagues described two sisters with marked HDL deficiency, undetectable plasma Apo AI, Apo C-III, planar xanthomas, and premature CVD requiring bypass surgery at ages 29 and 30 years.[13]
  • These patients had low TG, normal LDL-C and had enhanced clearance of VLDL Apo B.[14]
  • The defect was a homozygous DNA re-arrangement affecting the APOA1 and APO CIII genes.

Apo A1 Deficiency

  • In 1991, Matsunaga and colleagues described a 56-year-old Japanese woman with premature CVD, planar xanthomas, normal TG, LDL-C, marked HDL C deficiency and undetectable plasma apoA-I levels. The defect was a homozygous APOAI codon 84 nonsense mutation, resulting in a lack of normal Apo AI production.[15]
  • In 1994, Ng and colleagues reported a Canadian kindred with a isolated mutation in the apolipoprotein A1 gene. The proband was a 34-year presented with bilateral retinopathy, bilateral cataracts, spinocerebellar ataxia, and tendon xanthomata.[16]
    • HDL-C was very low and Apo AI was undetectable. Genomic DNA sequencing of the proband's Apo AI gene identified a nonsense mutation at codon [-2], which was designated as Q[-2]X.
    • Genotyping of the kindred showed four homozygotes, four heterozygotes and two unaffected subjects.
    • Heterozygotes had 50% of normal HDL C and Apo-A1.
  • In 2008, Santos reported a kindred with the similar mutation that was identified in the Canadian kindred in two homozygous brothers presenting with tubo-eruptive, planar xanthomas, corneal arcus, mild corneal opacification, HDL C <5 mg/dL, normal LDL-C and TG levels. They had no detectable Apo AI containing HDL. Multiple heterozygotes in this kindred had HDL C 50% of normal levels.[17]
  • In 2009, Wada and colleagues reported a Apo A1 mutation (apoA-I Tomioka) in a 64year old with corneal opacities and prior history of myocardial infarction. He had marked plasma HDL C (4 mg/dl) and Apo AI (5mg/dl) deficiency. Genomic sequencing revealed a homozygous deletion of successive adenine residues in codon 138 in Apo A1 gene, resulting in a frameshift mutation.[18]
  • In 2010, Al-Sarraf and colleagues reported an Iraqi kindred with two probands in 2010 with complete Apo AI deficiency, marked HDL C deficiency, normal LDL C and TG levels caused by a homozygous nonsense mutation with a stop codon at Arg10. One proband was a 35 year old woman with xanthelasma and xanthomas with no CVD, while her 37 year old brother had planar xanthomas and sustained a myocardial infarction (MI) at age 35 years.[19]

Apo A1 Variants

  • ApoA-I variants are heterozygous premature terminations, frameshift mutation or amino acid substitutions in the 243 amino acid Apo AI sequence.
  • These patients may have HDL C levels that are low or normal, plasma LCAT activity that is normal or reduced, may develop premature CVD or amyloidosis.
  • Six Heterozygous Apo A1 missense mutations with low HDL C and decreased LCAT activity are reported. They are not at increased risk of developing premature heart disease.[20][21][22]
  • Few mutations resulting in low HDL C with normal LCAT function have an increased risk of coronary artery disease at a young age.[23][24]
  • Few mutations in Apo A1 are associated with familial visceral amyloidosis.[25][26]
  • Below is a list of few selected Apo A1 variants which support the inconsistency in the biochemical and clinical phenotype:
    • In 1980, Franceschini reported significant hypertriglyceridemia and marked decrease of HDL C (7-14 mg/dl) with no signs of coronary atherosclerosis in the father, son, and daughter of an Italian family. They had normal lipoprotein lipase, LCAT activity and a reduced Apo A1 on 2D gel electrophoresis. He suggested the finding was probably due to a change in the amino acid composition and it was designated as Apo A1Milano.[27]
    • In 1991, Funke and colleagues reported a 42-year-old German patient with corneal opacification, marked HDL deficiency, apoA-I deficiency, decreased plasma LCAT activity, increased non- HDL-C and TG, and lack of CVD. Sequencing of LCAT gene was normal, but the patient was found to be homozygous for an apoA-I frameshift mutation resulting in a truncated 229 amino acid protein instead of full length apoA-I.[28]
    • In 1995, Takata and colleagues reported a 39-year-old Japanese man with corneal opacification, HDL-C of 6 mg/dL, Apo AI level of <3.0 mg/dL, increased LDL-C, with normal levels of plasma TG, phospholipid, Apo B, Apo C-III, and ApoE levels and no coronary artery lumen narrowing on angiography. LCAT activity was about 50% of normal. The patient was homozygous for a codon 8 nonsense mutation in exon 3 of the Apo AI gene. Heterozygotes in the family had normal HDL-C values.[29]
    • In 2013, reported a 61-year-old male with significant coronary heart disease from the age of 42, corneal arcus, combined hyperlipidemia, HDL C of 1 mg/dL, Apo AI of 23 mg/dL, normal LCAT acticity and only preβ-1 and α-2 HDL particles present in his HDL particles. He had a novel heterozygous inframe insertion mutation with a duplication of nucleotides.(Apo AI Nashua).[23]
    • In 2014, Anthanont and colleagues reported a Apo A1 mutation in a 68-year-old male and two other family members with premature heart disease, corneal arcus, HDL-C 14 mg/dL, Apo AI 57 mg/dL, normal TG, LDL C levels and a lack of very large α-1 HDL. Genotypic sequencing revealed a heterozygous nonsense mutation (Gln216termination) resulting in a truncated Apo AI containing only 215 amino acids. This mutation is designated as Apo AIMytilene. Kinetic studies showed proband Apo A1 production to be 40% of normal, cellular cholesterol efflux capacity 65% of normal, and normal LCAT activity.[30]
    • In 2015, Anthanont and colleagues reported a mutation in a 68-year female and her two sons with severe HDL deficiency, mild hypertriglyceridemia, and detectable large alpha-1 and alpha-2 HDL particles by 2-dimensional gel electrophoresis. Sequencing revealed a a heterozygous missense mutation of Apo A1, designated as Apo AIBoston. They had decreased LCAT function and cholesterol efflux.[22]

Demographics, Epidemiology

  • Worldwide, 82 Apo AI mutations have been reported in human subjects.[22]
  • The prevalence of Apo A1 deficiency is estimated to be less than 1/1,000,000 population.[31]
  • Apo A1 deficiency accounts for 6% of Japanese population with low HDL C.[32]
  • Genomic sequencing of ApoA1 gene in 10,330 population based participants in the Copenhagen City Heart study revealed[24]:
    • In the study, only 0.27% of the individuals in the general population were heterozygous for non-synonymous variants which were associated with significant reductions in Apo A1 and HDL C.
    • In the study, only 0.41% of the population was heterozygous for variants predisposing to amyloidosis.

Natural History, Progression, Complications

  • The age of symptom onset in patients with Apo A1 deficiency and the clinical presentation varies with different mutations.
  • Few patients remain asymptomatic into adulthood and few individuals may present from adolescence with symptoms of blurred vision due to corneal opacities or cataract, tubero-eruptive, tendinous, palmar and/or planar xanthomas, xanthelasmas and premature CHD (e.g. myocardial infarction) and carotid atherosclerosis.
  • Individuals with certain mutations present with neurosensory signs such as cerebellar ataxia, neurosensory hearing loss, proliferative retinopathy or manifestations of secondary amyloidosis such as hepatomegaly, nephropathy, cardiomyopathy.
  • If left untreated the major complication is development of premature heart disease.
  • Prognosis depends on occurrence of premature CHD and end-stage organ failure in individuals with amyloidosis.

Pathogenesis

Pathophysiology

  • HDL C is synthesized and secreted from the liver and intestine as nascent very small discoid pre-β-1 HDL, conformed predominantly by apolipoprotein A-I.
  • Apo-A1 is a predominant lipoprotein of HDL and plays an important role in maturation of HDL and reverse cholesterol transport by[33]:
    • Apo-AI is important for mediating the efflux of cholesterol from peripheral tissues.[34]
    • ApoA-I interacts with ABCA1 and accepts free cholesterol.[35][36]
    • Apo-A1 is a potent activator of LCAT, enzyme helpful in the formation of cholesterol esters.[37]
    • Delivery of cholesterol esters to the liver mediated by scavenger receptor class B type I (SR-B1).[38]
  • Genetic factors regulate the circulating levels of HDL and its functionality, mutations in the Apo A1 gene affect the total plasma levels of Apo A1 leading to low undetectable HDL C.[39]
  • Majority of clinical and epidemiological studies like the Framingham Heart Study, Emerging Risk Factor Collaboration, Munster Heart Study, INTERHEART Study have proved an inverse relationship between HDL-C concentration and cardiovascular risk.[40][41][42][43]
  • The atheroprotective function of HDL C is determined by measuring the cholesterol efflux from the cells and its anti-oxidative ability.[44]

Reverse Cholesterol Transport[45]

 
 
 
Very small discoidal pre beta-1 HDL picks up free cholesterol from cells via ABCA1 transporter[46] to become small discoidal alpha-4 HDL, this intitial step is disrupted in Tangier disease resulting in only pre beta HDL on 2D electrophoresis.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discoidal HDL particles are converted to medium spherical α-3 HDL and larger particles by the esterification of free cholesterol via the enzyme lecithin:cholesterol acyltransferase (LCAT) and the addition of apoA-II.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
These particles are further converted to large and very large spherical α-2 and α-1 HDL by the actions of cholesteryl ester transfer protein (CETP). CETP transfers cholesteryl ester from HDL to triglyceride-rich lipoproteins in exchange for triglyceride
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Very large α-1 HDL particles are donors of cholesterol to the liver, and the constituents of these particles can recycle back to form very small discoidal particles and can re-enter the HDL cycle, or be catabolized directly by the kidney or liver
 
 
 
  • In Apo A1 deficiency there is complete absence of Apo A1 and HDL C in homozygotes and less than 50% normal in heterozygotes, this disrupts the reverse cholesterol transport by :
    • Change of chemical compositon in sub-populations of HDL C.[45]
    • Decrease in the cholesterol efflux.
    • Failure of cholesterol ester formation as LCAT function is compromised in few mutations.
  • The changes in the reverse cholesterol transport predispose the patients to premature heart disease.

Genetics

  • Apolipoprotein deficiency is caused by mutation in the Apo A1 gene (11q23-q24) which codes for the apolipoprotein A1.
  • Mutations in the gene can lead to decreased production, impaired function or increased Apo A1 catabolism.
  • Clinical phenotype varies with individual mutation and the type.
  • Frameshift mutations, nonsense mutations, genomic rearrangements, deletions are more commonly associated with premature heart disease and undetectable ApoA1 levels.
  • Patients with mis-sense mutations usually have detectable plasma Apo A1 and low HDL C can present with cardiovascular symptoms, amyloidosis or are healthy patients with no signs of atherosclerosis.

History, Symptoms

  • Age of of symptom onset and age of clinical presentation varies as many patients can remain asymptomatic into adulthood. Many patients are diagnosed for the first time with a cardiovascular event at a young age.
  • Patients who are symptomatic usually present with:
    • Blurry vision due to corneal opacities
    • Yellowish orange lumps in the skin, palms and feet
  • Coronary heart disease - History of angina or MI when younger than 60 years, history of premature heart disease in siblings and first-degree relatives.
  • Less common findings in Apo A1 deficiency include:
    • Ataxia
    • Hearing loss
    • Manifestions of amyloidosis:
      • Nephropathy presents with hematuria, generalized body swelling, shortness of breath on exertion.
      • Cardiomyopathy can present with chest pain, shortness of breath on exertion, syncope, pedal edema.

Physical Examination

  • Corneal opacities, corneal arcus
  • Tubero-eruptive, palmar or planar xanthomas
  • Cerebellar ataxia
  • Neuro-sensory hearing loss
  • Hepatomegaly

Diagnosis

  • Apo A1 deficiency is diagnosed by combination undectectable Apo A1 and HDL C levels.

Lipid Analysis

  • Laboratory features consistent with the diagnosis of Apo A1 deficiency include:
    • Undetectable Apo A1
    • HDL C less than 10mg/dl
    • Normal or elevated triglyceride
    • Normal or elevated LDL C

2D Electrophoresis

  • 2D gel electrophoresis with anti-apo A1 immunoblotting is very useful in differentiating the diseases with low HDL C. It is based on the distribution of Apo A1 in different sub-populations of HDL C.
  • The normal values and distribution of Apo A1 in HDL C are as follows:
    • Normal Plasma Apo A1 is 140mg/dl
    • 10% is found in small discoidal pre beta HDL and alpha-1 HDL C.
    • 90% is found in alpha-2 and alpha-3 HDL C.
  • In Apo A1 deficiency, a total absence of Apo A1 containing HDL C is demonstrated on 2D electrophoresis.

Molecular Gene Sequencing

  • The gold standard for diagnosis of Apo A1 deficiency is molecular gene sequencing for identification of the mutation.

Differential Diagnosis

Familial LCAT

Deficiency

Fish Eye

Disease

Homozygous Tangier

Disease

Heterozygous Tangier

Disease

Apo A1 Deficiency
Gene Defect LCAT LCAT ABCA1 ABCA1 Apo A1
Inheritance Autosomal Recessive Autosomal Recessive Autosomal Recessive Autosomal Recessive Autosomal Dominant
Pathogenesis
  • Loss of alpha and beta LCAT function
  • Failure of cholesterol ester formation.
 Loss of alpha function only

Pre beta-1 HDL fails to picks up free cholesterol from cells due to mutation in ABCA1 transporter.

Similar to homozygous Defective synthesis of Apo A1 resulting in failure of maturation of HDL and defective reverse cholesterol transport.
Clinical Features
  • Annular corneal opacity
  • Anaemia
  • Progressive renal disease with proteinuria
  • Corneal opacities only
  • Normal renal function
  • Large yellow-orange tonsils
  • Dense central corneal opacity
  • Relapsing and remitting course of neuropathy
 Asymptomatic
  • Corneal Opacities
  • Tuboeruptive, Planar and palmar Xanthomas
  • Premature Heart Disease
Lipid Panel
  • Elevated Free cholesterol
  • HDL-C < 10 mg/dL
  • Low Apo A1 and Apo AII
  • Elevated Apo E and Triglycerides
  • Low LDL C
  • Elevated free cholesterol
  • HDL C < 27 mg/dL
  • Apo A1＜30mg/dl and low Apo A2
  • Elevated Apo E and Triglycerides
  • Normal LDL and VLDL
  • HDL < 5% of normal
  • Apo A1 < 1% of normal
  • LDL < 40% of normal
  • HDL C, Apo A1 and LDL 50% less than normal.
  • Undetectable Apo A1
  • HDL C less than 10mg/dl
  • Normal or low Apo AII
  • LDL C normal
  • Triglyceride normal or elevated
2D Gel Electrophoresis Pre β-1 and α-4 HDL, LDL with β mobility due to Lipoprotien-X Pre β-1and α-4 HDL with normal pre-β LDL. Only preβ-1 HDL present
  • Lack of large α-1 and α-2 HDL particles
  • Normal preβ-1 HDL
 Lack of Apo A1 containing HDL particles.
Distinguishing features of homozygous patients with very low or undetectable HDL C and Apo A1[47]:
Apo A/CIII/A-IV Deficiency ApoA/CIII Deficiency Apo A Deficiency
Planar Xanthomas Absent Present Present
Tubo-Eruptive Xanthomas Absent Absent Present
Premature Heart Disease Present Present Present
Triglyceride Decreased due to the absence

of Apo C III- a lipolysis inhibitor

Decreased Normal
LDL C Normal Normal Normal
HDL C Less than 5mg/dl Less than 5mg/dl Less than 5mg/dl
Apo A1 Undetectable Undetectable Undetectable
Apo C III Undetectable Undetectable Normal
Apo A IV Undetectable Normal Normal

Approch to a patient with low HDL C[48]

 
 
 
 
 
HDL <20mg/dl in the absence of severe hypertriglyceridemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rule out secondary causes of low HDL C
Paraproteinemia from multiple myeloma
Anabolic steriod use
Fibrate use
Thiazolidinedione use
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consider Monogenic primary disorders
Order ApoA1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
>5mg/dl
 
 
 
 
Undetectable or <5mg/dl
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Familial LCAT deficiency
High plasma FC:CE ratio
2D electrophoresis: Prebeta and Alpha-4, Beta mobility of LDL
 
 
 
 
Do 2D Gel Electrophoresis with Apo A1 Immunoassay
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete absence of Apo A1 containing HDL C
 
 
Only Pre-Beta HDL C
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Apo A1 Deficiency
(Confirm with gene sequencing)
 
 
Homozygous Tangier Disease
(Confirm with gene sequencing)

Treatment

Medical Therapy

The mainstay of therapy for Apo A1 deficiency include:

  • Patients with low HDL C and Apo A1 should be treated with statins for reduction of LDL C.
  • Patients with Apo A1 variants do not develop clinical sequelae generally to need specific treatment.
  • Apo A1 infusion therapy is the future of treatment, which helps in improving the cholesterol efflux and reduce the plaque burden in patients who undergo interventions like PCI.[49]

Surgical Therapy

  • Patients presenting with myocardial infarction should undergo PCI with stent of the blocked vessel.

Primary Prevention

  • Assessment of cardiovascular risk in patients diagnosed with Apo A1 deficiency and Apo A1 variants.
  • The goal of LDL C should be targeted below 70mg/dl according to the ATP III guidelines with high intensity statin therapy.
  • All the traditional risk factors of CVD should be identified and addressed.
  • Sub-clinical atherosclerosis can be identified by imaging with coronary artery calcium or carotid media thickness assessment which helps in guiding the lipid lowering therapy and assess the cardiovascular risk.

References

  1. ↑ Vergani C, Bettale G (1981). "Familial hypo-alpha-lipoproteinemia". Clin Chim Acta. 114 (1): 45–52. PMID 7249374.
  2. ↑ Breslow JL, Ross D, McPherson J, Williams H, Kurnit D, Nussbaum AL; et al. (1982). "Isolation and characterization of cDNA clones for human apolipoprotein A-I". Proc Natl Acad Sci U S A. 79 (22): 6861–5. PMC 347233. PMID 6294659.
  3. ↑ Karathanasis SK, Zannis VI, Breslow JL (1983). "Isolation and characterization of the human apolipoprotein A-I gene". Proc Natl Acad Sci U S A. 80 (20): 6147–51. PMC 390160. PMID 6413973.
  4. ↑ Daniels SR, Bates S, Lukin RR, Benton C, Third J, Glueck CJ (1982). "Cerebrovascular arteriopathy (arteriosclerosis) and ischemic childhood stroke". Stroke. 13 (3): 360–5. PMID 7080131.
  5. ↑ Law SW, Gray G, Brewer HB (1983). "cDNA cloning of human apoA-I: amino acid sequence of preproapoA-I". Biochem Biophys Res Commun. 112 (1): 257–64. PMID 6404278.
  6. ↑ Borecki IB, Rao DC, Third JL, Laskarzewski PM, Glueck CJ (1986). "A major gene for primary hypoalphalipoproteinemia". Am J Hum Genet. 38 (3): 373–81. PMC 1684774. PMID 3953576.
  7. ↑ Ordovas JM, Schaefer EJ, Salem D, Ward RH, Glueck CJ, Vergani C; et al. (1986). "Apolipoprotein A-I gene polymorphism associated with premature coronary artery disease and familial hypoalphalipoproteinemia". N Engl J Med. 314 (11): 671–7. doi:10.1056/NEJM198603133141102. PMID 3081805.
  8. ↑ Li WH, Tanimura M, Luo CC, Datta S, Chan L (1988). "The apolipoprotein multigene family: biosynthesis, structure, structure-function relationships, and evolution". J Lipid Res. 29 (3): 245–71. PMID 3288703.
  9. ↑ Gillotte KL, Zaiou M, Lund-Katz S, Anantharamaiah GM, Holvoet P, Dhoest A; et al. (1999). "Apolipoprotein-mediated plasma membrane microsolubilization. Role of lipid affinity and membrane penetration in the efflux of cellular cholesterol and phospholipid". J Biol Chem. 274 (4): 2021–8. PMID 9890960.
  10. ↑ Ajees AA, Anantharamaiah GM, Mishra VK, Hussain MM, Murthy HM (2006). "Crystal structure of human apolipoprotein A-I: insights into its protective effect against cardiovascular diseases". Proc Natl Acad Sci U S A. 103 (7): 2126–31. doi:10.1073/pnas.0506877103. PMC 1413691. PMID 16452169.
  11. ↑ Schaefer EJ, Heaton WH, Wetzel MG, Brewer HB (1982). "Plasma apolipoprotein A-1 absence associated with a marked reduction of high density lipoproteins and premature coronary artery disease". Arteriosclerosis. 2 (1): 16–26. PMID 6800349.
  12. ↑ Schaefer EJ (1984). "Clinical, biochemical, and genetic features in familial disorders of high density lipoprotein deficiency". Arteriosclerosis. 4 (4): 303–22. PMID 6431953.
  13. ↑ Norum RA, Lakier JB, Goldstein S, Angel A, Goldberg RB, Block WD; et al. (1982). "Familial deficiency of apolipoproteins A-I and C-III and precocious coronary-artery disease". N Engl J Med. 306 (25): 1513–9. doi:10.1056/NEJM198206243062503. PMID 7078608.
  14. ↑ Forte TM, Nichols AV, Krauss RM, Norum RA (1984). "Familial apolipoprotein AI and apolipoprotein CIII deficiency. Subclass distribution, composition, and morphology of lipoproteins in a disorder associated with premature atherosclerosis". J Clin Invest. 74 (5): 1601–13. doi:10.1172/JCI111576. PMC 425337. PMID 6501564.
  15. ↑ Matsunaga T, Hiasa Y, Yanagi H, Maeda T, Hattori N, Yamakawa K; et al. (1991). "Apolipoprotein A-I deficiency due to a codon 84 nonsense mutation of the apolipoprotein A-I gene". Proc Natl Acad Sci U S A. 88 (7): 2793–7. PMC 51325. PMID 1901417.
  16. ↑ Ng DS, Leiter LA, Vezina C, Connelly PW, Hegele RA (1994). "Apolipoprotein A-I Q[-2]X causing isolated apolipoprotein A-I deficiency in a family with analphalipoproteinemia". J Clin Invest. 93 (1): 223–9. doi:10.1172/JCI116949. PMC 293756. PMID 8282791.
  17. ↑ Santos RD, Schaefer EJ, Asztalos BF, Polisecki E, Wang J, Hegele RA; et al. (2008). "Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency". J Lipid Res. 49 (2): 349–57. doi:10.1194/jlr.M700362-JLR200. PMID 17991756.
  18. ↑ Wada M, Iso T, Asztalos BF, Takama N, Nakajima T, Seta Y; et al. (2009). "Marked high density lipoprotein deficiency due to apolipoprotein A-I Tomioka (codon 138 deletion)". Atherosclerosis. 207 (1): 157–61. doi:10.1016/j.atherosclerosis.2009.04.018. PMID 19473658.
  19. ↑ Al-Sarraf A, Al-Ghofaili K, Sullivan DR, Wasan KM, Hegele R, Frohlich J (2010). "Complete Apo AI deficiency in an Iraqi Mandaean family: case studies and review of the literature". J Clin Lipidol. 4 (5): 420–6. doi:10.1016/j.jacl.2010.05.001. PMID 21122686.
  20. ↑ Miccoli R, Zhu Y, Daum U, Wessling J, Huang Y, Navalesi R; et al. (1997). "A natural apolipoprotein A-I variant, apoA-I (L141R)Pisa, interferes with the formation of alpha-high density lipoproteins (HDL) but not with the formation of pre beta 1-HDL and influences efflux of cholesterol into plasma". J Lipid Res. 38 (6): 1242–53. PMID 9215551.
  21. ↑ Daum U, Leren TP, Langer C, Chirazi A, Cullen P, Pritchard PH; et al. (1999). "Multiple dysfunctions of two apolipoprotein A-I variants, apoA-I(R160L)Oslo and apoA-I(P165R), that are associated with hypoalphalipoproteinemia in heterozygous carriers". J Lipid Res. 40 (3): 486–94. PMID 10064737.
  22. ↑ 22.0 22.1 22.2 Anthanont P, Asztalos BF, Polisecki E, Zachariah B, Schaefer EJ (2015). "Case report: A novel apolipoprotein A-I missense mutation apoA-I (Arg149Ser)Boston associated with decreased lecithin-cholesterol acyltransferase activation and cellular cholesterol efflux". J Clin Lipidol. 9 (3): 390–5. doi:10.1016/j.jacl.2015.02.005. PMID 26073399.
  23. ↑ 23.0 23.1 Lee EY, Klementowicz PT, Hegele RA, Asztalos BF, Schaefer EJ (2013). "HDL deficiency due to a new insertion mutation (ApoA-INashua) and review of the literature". J Clin Lipidol. 7 (2): 169–73. doi:10.1016/j.jacl.2012.10.011. PMC 4565164. PMID 23415437.
  24. ↑ 24.0 24.1 Haase CL, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A (2012). "Population-based resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach". PLoS Genet. 8 (11): e1003063. doi:10.1371/journal.pgen.1003063. PMC 3510059. PMID 23209431.
  25. ↑ Soutar AK, Hawkins PN, Vigushin DM, Tennent GA, Booth SE, Hutton T; et al. (1992). "Apolipoprotein AI mutation Arg-60 causes autosomal dominant amyloidosis". Proc Natl Acad Sci U S A. 89 (16): 7389–93. PMC 49715. PMID 1502149.
  26. ↑ Das M, Wilson CJ, Mei X, Wales TE, Engen JR, Gursky O (2016). "Structural Stability and Local Dynamics in Disease-Causing Mutants of Human Apolipoprotein A-I: What Makes the Protein Amyloidogenic?". J Mol Biol. 428 (2 Pt B): 449–62. doi:10.1016/j.jmb.2015.10.029. PMC 4744490. PMID 26562506.
  27. ↑ Franceschini G, Sirtori CR, Capurso A, Weisgraber KH, Mahley RW (1980). "A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family". J Clin Invest. 66 (5): 892–900. doi:10.1172/JCI109956. PMC 371523. PMID 7430351.
  28. ↑ Funke H, von Eckardstein A, Pritchard PH, Karas M, Albers JJ, Assmann G (1991). "A frameshift mutation in the human apolipoprotein A-I gene causes high density lipoprotein deficiency, partial lecithin: cholesterol-acyltransferase deficiency, and corneal opacities". J Clin Invest. 87 (1): 371–6. doi:10.1172/JCI114997. PMC 295069. PMID 1898657.
  29. ↑ Takata K, Saku K, Ohta T, Takata M, Bai H, Jimi S; et al. (1995). "A new case of apoA-I deficiency showing codon 8 nonsense mutation of the apoA-I gene without evidence of coronary heart disease". Arterioscler Thromb Vasc Biol. 15 (11): 1866–74. PMID 7583566.
  30. ↑ Anthanont P, Polisecki E, Asztalos BF, Diffenderfer MR, Barrett PH, Millar JS; et al. (2014). "A novel ApoA-I truncation (ApoA-IMytilene) associated with decreased ApoA-I production". Atherosclerosis. 235 (2): 470–6. doi:10.1016/j.atherosclerosis.2014.05.935. PMID 24950002.
  31. ↑ "Orphanet: Apolipoprotein A I deficiency".
  32. ↑ Yamakawa-Kobayashi K, Yanagi H, Fukayama H, Hirano C, Shimakura Y, Yamamoto N; et al. (1999). "Frequent occurrence of hypoalphalipoproteinemia due to mutant apolipoprotein A-I gene in the population: a population-based survey". Hum Mol Genet. 8 (2): 331–6. PMID 9931341.
  33. ↑ Lund-Katz S, Phillips MC (2010). "High density lipoprotein structure-function and role in reverse cholesterol transport". Subcell Biochem. 51: 183–227. doi:10.1007/978-90-481-8622-8_7. PMC 3215094. PMID 20213545.
  34. ↑ Hellerstein M, Turner S (2014). "Reverse cholesterol transport fluxes". Curr Opin Lipidol. 25 (1): 40–7. doi:10.1097/MOL.0000000000000050. PMID 24362356.
  35. ↑ Oram JF (2002). "ATP-binding cassette transporter A1 and cholesterol trafficking". Curr Opin Lipidol. 13 (4): 373–81. PMID 12151852.
  36. ↑ Iatan I, Bailey D, Ruel I, Hafiane A, Campbell S, Krimbou L; et al. (2011). "Membrane microdomains modulate oligomeric ABCA1 function: impact on apoAI-mediated lipid removal and phosphatidylcholine biosynthesis". J Lipid Res. 52 (11): 2043–55. doi:10.1194/jlr.M016196. PMC 3196236. PMID 21846716.
  37. ↑ Jonas A (2000). "Lecithin cholesterol acyltransferase". Biochim Biophys Acta. 1529 (1–3): 245–56. PMID 11111093.
  38. ↑ Krieger M (1999). "Charting the fate of the "good cholesterol": identification and characterization of the high-density lipoprotein receptor SR-BI". Annu Rev Biochem. 68: 523–58. doi:10.1146/annurev.biochem.68.1.523. PMID 10872459.
  39. ↑ Sorci-Thomas MG, Thomas MJ (2002). "The effects of altered apolipoprotein A-I structure on plasma HDL concentration". Trends Cardiovasc Med. 12 (3): 121–8. PMID 12007737.
  40. ↑ Wilson PW, Abbott RD, Castelli WP (1988). "High density lipoprotein cholesterol and mortality. The Framingham Heart Study". Arteriosclerosis. 8 (6): 737–41. PMID 3196218.
  41. ↑ Emerging Risk Factors Collaboration. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK; et al. (2009). "Major lipids, apolipoproteins, and risk of vascular disease". JAMA. 302 (18): 1993–2000. doi:10.1001/jama.2009.1619. PMC 3284229. PMID 19903920. Review in: Ann Intern Med. 2010 Feb 16;152(4):JC-212
  42. ↑ Assmann G, Schulte H, von Eckardstein A, Huang Y (1996). "High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport". Atherosclerosis. 124 Suppl: S11–20. PMID 8831911.
  43. ↑ Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F; et al. (2004). "Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study". Lancet. 364 (9438): 937–52. doi:10.1016/S0140-6736(04)17018-9. PMID 15364185.
  44. ↑ Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE; et al. (2014). "HDL cholesterol efflux capacity and incident cardiovascular events". N Engl J Med. 371 (25): 2383–93. doi:10.1056/NEJMoa1409065. PMC 4308988. PMID 25404125.
  45. ↑ 45.0 45.1 Asztalos BF, Tani M, Schaefer EJ (2011). "Metabolic and functional relevance of HDL subspecies". Curr Opin Lipidol. 22 (3): 176–85. doi:10.1097/MOL.0b013e3283468061. PMID 21537175.
  46. ↑ Favari E, Calabresi L, Adorni MP, Jessup W, Simonelli S, Franceschini G; et al. (2009). "Small discoidal pre-beta1 HDL particles are efficient acceptors of cell cholesterol via ABCA1 and ABCG1". Biochemistry. 48 (46): 11067–74. doi:10.1021/bi901564g. PMID 19839639.
  47. ↑ Santos RD, Asztalos BF, Martinez LR, Miname MH, Polisecki E, Schaefer EJ (2008). "Clinical presentation, laboratory values, and coronary heart disease risk in marked high-density lipoprotein-deficiency states". J Clin Lipidol. 2 (4): 237–47. doi:10.1016/j.jacl.2008.06.002. PMID 21291740.
  48. ↑ Rader DJ, deGoma EM (2012). "Approach to the patient with extremely low HDL-cholesterol". J Clin Endocrinol Metab. 97 (10): 3399–407. doi:10.1210/jc.2012-2185. PMC 3462950. PMID 23043194.
  49. ↑ Gibson CM, Korjian S, Tricoci P, Daaboul Y, Alexander JH, Steg PG; et al. (2016). "Rationale and design of Apo-I Event Reduction in Ischemic Syndromes I (AEGIS-I): A phase 2b, randomized, placebo-controlled, dose-ranging trial to investigate the safety and tolerability of CSL112, a reconstituted, infusible, human apoA-I, after acute myocardial infarction". Am Heart J. 180: 22–8. doi:10.1016/j.ahj.2016.06.017. PMID 27659879.


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