title: APOL1 variants increase risk for FSGS and HIVAN but not IgA nephropathy.
abstract: A chromosome 22q13 locus strongly associates with increased risk for idiopathic focal segmental glomerulosclerosis (FSGS), HIV-1-associated nephropathy (HIVAN), and hypertensive ESRD among individuals of African descent. Although initial studies implicated MYH9, more recent analyses localized the strongest association within the neighboring APOL1 gene. In this replication study, we examined the six top-most associated variants in APOL1 and MYH9 in an independent cohort of African Americans with various nephropathies (44 with FSGS, 21 with HIVAN, 32 with IgA nephropathy, and 74 healthy controls). All six variants associated with FSGS and HIVAN (additive ORs, 1.8 to 3.0; P values 3 × 10(-2) to 5 × 10(-5)) but not with IgA nephropathy. In conditional and haplotype analyses, two APOL1 haplotypes accounted for virtually all of the association with FSGS and HIVAN on chromosome 22q13 (haplotype P value = 5.6 × 10(-8)). To assess the role of MYH9 deficiency in nephropathy, we crossbred Myh9-haploinsufficient mice (Myh9(+/-)) with HIV-1 transgenic mice. Myh9(+/-) mice were healthy and did not demonstrate overt proteinuria or nephropathy, irrespective of the presence of the HIV-1 transgene. These data further support the strong association of genetic variants in APOL1 with susceptibility to FSGS and HIVAN among African Americans.
authors: Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors: Natalia
authors: N
authors: Papeta
authors: Krzysztof
authors: K
authors: Kiryluk
authors: Ami
authors: A
authors: Patel
authors: Roel
authors: R
authors: Sterken
authors: Nilgun
authors: N
authors: Kacak
authors: Holly J
authors: HJ
authors: Snyder
authors: Phil H
authors: PH
authors: Imus
authors: Anand N
authors: AN
authors: Mhatre
authors: Anil K
authors: AK
authors: Lawani
authors: Bruce A
authors: BA
authors: Julian
authors: Robert J
authors: RJ
authors: Wyatt
authors: Jan
authors: J
authors: Novak
authors: Christina M
authors: CM
authors: Wyatt
authors: Michael J
authors: MJ
authors: Ross
authors: Jonathan A
authors: JA
authors: Winston
authors: Mary E
authors: ME
authors: Klotman
authors: David J
authors: DJ
authors: Cohen
authors: Gerald B
authors: GB
authors: Appel
authors: Vivette D
authors: VD
authors: D'Agati
authors: Paul E
authors: PE
authors: Klotman
authors: Ali G
authors: AG
authors: Gharavi
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000208:ethnology / Q000235:genetics*; D001741:Black or African American / Q000235:genetics* / Q000706:statistics & numerical data; D000818:Animals; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D004195:Disease Models, Animal; D014644:Genetic Variation; D005922:Glomerulonephritis, IGA / Q000208:ethnology / Q000235:genetics*; D005923:Glomerulosclerosis, Focal Segmental / Q000208:ethnology / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008075:Lipoproteins, HDL / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D020409:Molecular Motor Proteins / Q000235:genetics; D018995:Myosin Heavy Chains / Q000235:genetics; D024507:Nonmuscle Myosin Type IIA / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D008075:Lipoproteins, HDL; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; C525088:Myh9 protein, mouse; D024507:Nonmuscle Myosin Type IIA; D018995:Myosin Heavy Chains