| APOL1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | APOL1 , APO-L, APOL, APOL-I, FSGS4, apolipoprotein L1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 607254, 603743 GeneCards: APOL1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Apolipoprotein L1 is a protein that in humans is encoded by the APOL1 gene. [3] [4] [5] [6] Two transcript variants encoding two different isoforms have been found for this gene. [6]
This gene is found only in humans, African green monkeys, and gorillas. [7] [8]
The gene that encodes the APOL1 protein is 14,522 base pairs long and found on the human chromosome 22, on the long arm at position 13.1 from base pair 36,253,070 to base pair 36,267,530. [4] [9]
The protein is a 398 amino acid protein. It consists of 5 functional domains:
Two coding variants, G1 and G2, have been recently identified with relevance to human phenotypes. The G1 is a pair of two non-synonymous single nucleotide polymorphisms (SNPs) in almost complete linkage disequilibrium. G2 is an in-frame deletion of the two amino acid residues, N388 and Y389.[ citation needed ]
Apolipoprotein L1 (apoL1) is a minor apolipoprotein component of HDL cholesterol which is synthesized in the liver and also in many other tissues, including pancreas, kidney, and brain. APOL1 is found in vascular endothelium, liver, heart, lung, placenta, [7] podocytes, proximal tubules, and arterial cells. [10] The protein as a secreted form that allows it to circulate in the blood. It forms a complex, known as a trypanosome lytic factor (TLF), [11] with high-density lipoprotein 3 (HDL3) particles that also contain apolipoprotein A1 (APOA1) and the hemoglobin-binding, haptoglobin-related protein (HPR). The APOL1 protein acts as the main lytic component in this complex. [11] Once uptaken by the trypanosome, the complex is trafficked to acidic endosomes, where the APOL1 protein may insert into the endosomal membrane. If the endosome is then recycled to the plasma membrane, where it encounters neutral pH conditions, APOL1 may form cation-selective channels. [12]
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. In fact an overabundance of APOL1 within a cell results in autophagy. [13]
APOL1 may play a role in the inflammatory response. Pro-inflammatory cytokines interferon-γ(IFN), tumor necrosis factor-α (TNF-α) and p53 can increase the expression of APOL1. [13]
APOL1 has a role in innate immunity by protecting against Trypanosoma brucei infection, which is a parasite transmitted by the tsetse fly. Trypanosomes endocytose the secreted form of APOL1; APOL1 forms pores on the lysosomal membranes of the trypanosomes which causes in influx of chloride, swelling of the lysosome and lysis of the trypanosome. [5] [14]
Although its intracellular function has not been elucidated, apoL1 circulating in plasma has the ability to kill the trypanosome Trypanosoma brucei that causes sleeping sickness. Recently, two coding sequence variants in APOL1 have been shown to associate with kidney disease in a recessive fashion while at the same time conferring resistance against Trypanosoma brucei rhodesiense . [15] This resistance is due, in part, to decreased binding of the G1 and G2 APOL1 variants to the T. b. rhodesiense virulence factor, serum resistance-associated protein (SRA) as a result of the C-terminal polymorphisms. [16] People who have at least one copy of either the G1 or G2 variant are resistant to infection by trypanosomes, but people who have two copies of either variant are at an increased risk of developing a non-diabetic kidney disease.
The distribution of the variants most associated with kidney disease risk was analyzed in African populations and found to be more prevalent in western compared to northeastern African populations and absent in Ethiopia, [17] consistent with the reported protection from forms of kidney disease known to be associated with the APOL1 variants. [18] In the Yoruba people of Nigeria (West Africa), the prevalence of G1 and G2 risk alleles are 40% and 8% respectively. [15] [19] African nations with high frequencies of APOL1 risk alleles also have large populations of Trypanosomes suggesting that the risk alleles underwent positive selection as a defense mechanism. The existence of these variants are only found on African chromosomes and exist in people with recent African ancestry (<10,000 years).
Many African Americans are descendants of people of West African nations and consequently, also 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%. [15] The existence of 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).
The prevalence of the risk alleles in African Americans with these kidney diseases shown in recent studies are 67% in HIVAN, 66% in FSGS, and 47% in hypertension-attributed ESKD. [20] [21] Hispanic populations such as Dominicans and Puerto Ricans demonstrate a mixture of genetic influences that include African ancestry resulting in a prevalence of the APOL1 variants as well. [22] Studies have also determined the prevalence of each individual allele in FSGS cases as well.
The prevalence of the G1 risk allele in African Americans with FSGS 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. [15] [21] FSGS is a kidney disease that affects younger individuals therefore, its effects are slightly different from the effects of general non-diabetic ESKD. In a recent study, 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 also have a tendency to manifest FSGS at relatively young ages; FSGS begins between the ages of 15 and 39 in 70% of individuals with two APOL1 risk alleles and 42% of individuals with of 0 or 1 risk alleles. [21]
Although possession of the APOL1 risk variants increases susceptibility to non-diabetic kidney disease, not all people who possess these variants develop kidney disease, which indicates another factor may initiate progression of kidney disease. [23] Similarly in HIV positive patients, although the majority of African-American patients with HIVAN have two APOL1 risk alleles other as yet unknown factors in the host, including genetic risk variants and environmental or viral factors, may influence the development of this disorder in those with zero or one APOL1 risk allele. Kidney Int. 2012 Aug;82(3):338-43. The African American population has a total lifetime risk of developing FSGS 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. [21]
People with these allelic variants who develop ESKD begin dialysis at an earlier age than ESKD patients without the risk alleles. On average, those with two risk alleles begin dialysis approximately 10 years earlier than ESKD patients without the risk variants. [22] [24] The mean ages of initiation of dialysis of African American ESKD patients with two risk alleles, one risk allele, or no risk alleles are approximately 48yrs, 53yrs, and 58 yrs, respectively. [22] [24] Compared to African American ESKD patients, Hispanic ESKD patients with two APOL1 risk variants start dialysis at an earlier age, 41 yrs.
Although, the age of initiation of dialysis is earlier with one risk allele this effect is only seen in those with the G1 variant. In a study, ~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. [22]
Kidneys from donors containing two APOL1 variants experience allograft failure more rapidly than donors with 0 or 1 variants. [25] Kidney recipients who have copies of the APOL1 risk variants, but do not receive kidneys from donors with the risk variants do not have decreased survival rates of the donated kidneys. [26] These observations together suggest that the genotype of the donor only affects allograft survival.
Haptoglobin is the protein that in humans is encoded by the HP gene. In blood plasma, haptoglobin binds with high affinity to free hemoglobin released from erythrocytes, and thereby inhibits its deleterious oxidative activity. Compared to Hp, hemopexin binds to free heme. The haptoglobin-hemoglobin complex will then be removed by the reticuloendothelial system.
Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as either acute kidney failure, which develops rapidly and may resolve; and chronic kidney failure, which develops slowly and can often be irreversible. Symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications of acute and chronic failure include uremia, hyperkalaemia, and volume overload. Complications of chronic failure also include heart disease, high blood pressure, and anaemia.
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, anemia, kidney dysfunction, and infections may occur. Complications may include hypercalcemia and amyloidosis.
In genetics and bioinformatics, a single-nucleotide polymorphism is a germline substitution of a single nucleotide at a specific position in the genome that is present in a sufficiently large fraction of considered population.
Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications can relate to hormonal dysfunction of the kidneys and include high blood pressure, bone disease, and anemia. Additionally CKD patients have markedly increased cardiovascular complications with increased risks of death and hospitalization.
Diabetic nephropathy, also known as diabetic kidney disease, is the chronic loss of kidney function occurring in those with diabetes mellitus. Diabetic nephropathy is the leading causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally. The triad of protein leaking into the urine, rising blood pressure with hypertension and then falling renal function is common to many forms of CKD. Protein loss in the urine due to damage of the glomeruli may become massive, and cause a low serum albumin with resulting generalized body swelling (edema) so called nephrotic syndrome. Likewise, the estimated glomerular filtration rate (eGFR) may progressively fall from a normal of over 90 ml/min/1.73m2 to less than 15, at which point the patient is said to have end-stage renal disease. It usually is slowly progressive over years.
Hypertensive kidney disease is a medical condition referring to damage to the kidney due to chronic high blood pressure. It manifests as hypertensive nephrosclerosis. It should be distinguished from renovascular hypertension, which is a form of secondary hypertension, and thus has opposite direction of causation.
The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor that recognizes apolipoprotein B100 (ApoB100), which is embedded in the outer phospholipid layer of very low-density lipoprotein (VLDL), their remnants—i.e. intermediate-density lipoprotein (IDL), and LDL particles. The receptor also recognizes apolipoprotein E (ApoE) which is found in chylomicron remnants and IDL. In humans, the LDL receptor protein is encoded by the LDLR gene on chromosome 19. It belongs to the low density lipoprotein receptor gene family. It is most significantly expressed in bronchial epithelial cells and adrenal gland and cortex tissue.
Trypanosoma brucei is a species of parasitic kinetoplastid belonging to the genus Trypanosoma that is present in sub-Saharan Africa. Unlike other protozoan parasites that normally infect blood and tissue cells, it is exclusively extracellular and inhabits the blood plasma and body fluids. It causes deadly vector-borne diseases: African trypanosomiasis or sleeping sickness in humans, and animal trypanosomiasis or nagana in cattle and horses. It is a species complex grouped into three subspecies: T. b. brucei, T. b. gambiense and T. b. rhodesiense. The first is a parasite of non-human mammals and causes nagana, while the latter two are zoonotic infecting both humans and animals and cause African trypanosomiasis.
Focal segmental glomerulosclerosis (FSGS) is a histopathologic finding of scarring (sclerosis) of glomeruli and damage to renal podocytes. This process damages the filtration function of the kidney, resulting in protein presence in the urine due to protein loss. FSGS is a leading cause of excess protein loss—nephrotic syndrome—in children and adults. Signs and symptoms include proteinuria and edema. Kidney failure is a common long-term complication of the disease. FSGS can be classified as primary, secondary, or genetic, depending on whether a particular toxic or pathologic stressor or genetic predisposition can be identified as the cause. Diagnosis is established by renal biopsy, and treatment consists of glucocorticoids and other immune-modulatory drugs. Response to therapy is variable, with a significant portion of patients progressing to end-stage kidney failure. An American epidemiological study 20 years ago demonstrated that FSGS is estimated to occur in 7 persons per million, with males and African-Americans at higher risk.
Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in the Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene APOE.
The sodium-chloride symporter (also known as Na+-Cl− cotransporter, NCC or NCCT, or as the thiazide-sensitive Na+-Cl− cotransporter or TSC) is a cotransporter in the kidney which has the function of reabsorbing sodium and chloride ions from the tubular fluid into the cells of the distal convoluted tubule of the nephron. It is a member of the SLC12 cotransporter family of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by the SLC12A3 gene (solute carrier family 12 member 3) located in 16q13.
Apolipoprotein C-III also known as apo-CIII, and apolipoprotein C3, is a protein that in humans is encoded by the APOC3 gene. Apo-CIII is secreted by the liver as well as the small intestine, and is found on triglyceride-rich lipoproteins such as chylomicrons, very low density lipoprotein (VLDL), and remnant cholesterol.
Apolipoprotein D (ApoD) is a protein that in humans is encoded by the APOD gene. Unlike other lipoproteins, which are mainly produced in the liver, apolipoprotein D is mainly produced in the brain and testes. It is a 29 kDa glycoprotein discovered in 1963 as a component of the high-density lipoprotein (HDL) fraction of human plasma. It is the major component of human mammary cyst fluid. The human gene encoding it was cloned in 1986 and the deduced protein sequence revealed that ApoD is a member of the lipocalin family, small hydrophobic molecule transporters. ApoD is 169 amino acids long, including a secretion peptide signal of 20 amino acids. It contains two glycosylation sites and the molecular weight of the mature protein varies from 20 to 32 kDa.
Apolipoprotein A-V is a protein that in humans is encoded by the APOA5 gene on chromosome 11. It is significantly expressed in liver. The protein encoded by this gene is an apolipoprotein and an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of several lipoprotein fractions including VLDL, HDL, chylomicrons. It is believed that apoA-V affects lipoprotein metabolism by interacting with LDL-R gene family receptors. Considering its association with lipoprotein levels, APOA5 is implicated in metabolic syndrome. The APOA5 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
Myosin-9 also known as myosin, heavy chain 9, non-muscle or non-muscle myosin heavy chain IIa (NMMHC-IIA) is a protein which in humans is encoded by the MYH9 gene.
Upstream stimulatory factor 1 is a protein that in humans is encoded by the USF1 gene.
Sickle cell nephropathy is a type of nephropathy associated with sickle cell disease which causes kidney complications as a result of sickling of red blood cells in the small blood vessels. The hypertonic and relatively hypoxic environment of the renal medulla, coupled with the slow blood flow in the vasa recta, favors sickling of red blood cells, with resultant local infarction. Functional tubule defects in patients with sickle cell disease are likely the result of partial ischemic injury to the renal tubules.
Most cases of type 2 diabetes involved many genes contributing small amount to the overall condition. As of 2011 more than 36 genes have been found that contribute to the risk of type 2 diabetes. All of these genes together still only account for 10% of the total genetic component of the disease.
Katalin Susztak (Suszták) is a Hungarian American scientist and nephrologist at the Perelman School of Medicine at the University of Pennsylvania. She is a professor of medicine and genetics, and currently the codirector of the Complications Unit at the Institute for Diabetes, Obesity and Metabolism. Her laboratory made major contributions to the current understanding of kidney disease development. She is also the founder of the Transformative Research In DiabEtic NephropaThy (TRIDENT), a collaborative network of physicians and basic scientists, to find cures for diabetic kidney disease.
