Apolipoprotein L1 is a protein that in humans is encoded by the APOL1 gene.

The  gene has two transcript variants encoding two different isoforms (G1 or G2).

Chromosome 22 

The APOL1 gene that encodes the protein is 14,522 base pairs long and found on the human chromosome 22.

The protein is a 398 amino acid protein. 

It consists of 5 functional domains.

Apolipoprotein L1 (apoL1) is a minor apoprotein component of HDL (High-density lipoprotein, or good cholesterol).

Two common variants of the APOL1 gene accounts for much of the excess of non-diabetic chronic kidney disease risk among black individuals in the US.

APOL1 is a member of a family of apolipoproteins which also includes six other proteins and it is a member of bcl2 genes which are involved in autophagic cell death. 

An overabundance of APOL1 within a cell results in autophagy.

It  is synthesized in the liver and other tissues, including pancreas, kidney, and brain. 

APOL1 is found in vascular endothelium, liver, heart, lung, placenta, podocytes, proximal tubules, and arterial cells.

APOL1 protein has a secreted form that allows it to circulate in the blood. 

APOL1 forms a complex, known as a trypanosome lytic factor (TLF), with high-density lipoprotein 3 (HDL3) particles that also contain apolipoprotein A1 (APOA1) and the hemoglobin-binding, haptoglobin-related protein (HPR).

The APOL1 protein is the main lytic component in this complex.

The complex is trafficked to acidic endosomes.

APOL1 may play a role in the inflammatory respons, as pro-inflammatory cytokines interferon-γ(IFN), tumor necrosis factor-α (TNF-α) and p53 can increase the expression of APOL1.

The wild-type APOL1 gene confers resistance to Trypanosoma, brucei, the cause of African trypanosomiasis.

It has a role in innate immunity by protecting against Trypanosoma brucei infection, parasite transmitted by the tsetse fly. 

Trypanosomes endocytose the secreted form of APOL1, forming pores on the lysosomal membranes of the trypanosomes which causes in influx of chloride, swelling of the lysosome and lysis of the trypanosome.

ApoL1 circulating in plasma has the ability to kill the trypanosome Trypanosoma brucei that causes sleeping sickness. 

APOL1 is associated with kidney disease in a recessive fashion while at the same time conferring resistance against Trypanosoma brucei.

APOL1 G1 and G2 variant may cause kidney injury by increased transport of monovalent cations.

Many African Americans are descendants of people of West African nations and have a high prevalence of APOL1 risk alleles as well as APOL1 associated kidney diseases. 

The frequency of the risk alleles in African Americans is more than 30%.

People with a high riskAPOL1 genotype have an estimated lifetime risk of developing end stage kidney disease of 15 to 30%.

Polymorphisms in the APOL1 gene are found much more often and persons of African ancestry than in other groups: APOL 1 homozygous risk variants occur in up to 1/3 of blacks conferring increase risks of non-diabetic chronic kidney disease, hypertensive nephrosclerosis, and focal segmental glomerulosclerosis responsible for the increased incidence of end-stage kidney disease among blacks, and increased risk of end-stage kidney disease among black living donors.

Approximately 75% of black individuals in the US with focal segmental glomerulosclerosis have an estimated to have a high risk APOL1 genotype.

Black patients in the US with a high risk ofAPOL1 genotype are more likely to develop hypertension related end-stage kidney disease, lupus, nephritis, focal segmental, glomerulosclerosis, and HIV associated nephropathy.

25.8% of patients with COVID-19 associated kidney disease had collapsing glomerularopathy, and greater than 91% had high riskAPOL1 genotype.

These alleles has been shown to increase the risk of developing diseases such as Focal Segmental Glomerulosclerosis(FSGS), Hypertension Attributed-End Stage Kidney Disease (ESKD), and HIV-Associated Nephropathy(HIVAN).

Persons with two apolipoprotein L1 variants are at a higher risk for proteinuriv chronic kidney disease, and those with chronic kidney disease have an accelerated time to end stage kidney disease is compared with persons without 2 APOLL1 variants.

The prevalence of the G1 risk allele in African Americans with  focal segmental glomerulosclerosis  is 52% and 18-23% in those without FSGS. 

The prevalence of the G2 risk allele in African Americans with FSGS is 23% and 15% in those without FSGS.

FSGS is a kidney disease that affects younger individuals therefore, its effects are slightly different from the effects of general non-diabetic end Stage kidney disease. 

The mean ages of onset of FSGS for African Americans with 2, 1, and 0 APOL1 risk alleles was 32yrs, 36yrs and 39yrs, respectively. 

APOL1 variants have a tendency to manifest FSGS at relatively young ages.

FSGS begins between the ages of 15 to 39 in 70% of individuals with two APOL1 risk alleles and 42% of individuals with of 0 or 1 risk alleles.

Not all people who possess these variants develop kidney disease.

The majority of African-American patients with HIV associated nephropathy have two APOL1 risk alleles.

The African American population has a total lifetime risk of developing focal segmental glomerulosclerosis of 0.8%. 

For those with 0 risk alleles the risk of developing FSGS is 0.2%, 0.3% with 1 risk allele, 4.25% with 2 risk alleles and a 50% chance of developing HIVAN for untreated HIV infected individuals.[22]

People with these allelic variants who develop ESKD, imitate dialysis at an younger age than ESKD patients without the risk alleles (10 years earlier).

African American ESKD patients with two risk alleles, one risk allele, or no risk alleles  begin renal replacement therapy at  48yrs, 53yrs, and 58 yrs, respectively.

Hispanic patients with ESRD and two APOL1 risk variants start dialysis at an earlier age, 41 yrs.

Approximately 96% of patients with two risk alleles started dialysis before the age of 75 compared to 94% for G1 heterozygotes, and 84% for those with no risk alleles.

Kidney transplant donors containing two APOL1 variants experience allograft failure more rapidly than donors with 0 or 1 variants, suggesting that the genotype of the donor only affects allograft survival.

Transplanted kidneys  from deceased donors with a high risk APOL1 genotype had shorter allograft survival compared with low risk APOL1 genotype.

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