APOL1 variants increase risk for FSGS and HIVAN but not IgA nephropathy

Natalia Papeta, Krzysztof Kiryluk, Ami Patel, Roel Sterken, Nilgun Kacak, Holly J. Snyder, Phil H. Imus, Anand N. Mhatre, Anil K. Lawani, Bruce A. Julian, Robert J. Wyatt, Jan Novak, Christina M. Wyatt, Michael J. Ross, Jonathan A. Winston, Mary E. Klotman, David J. Cohen, Gerald B. Appel, Vivette D. D'Agati, Paul E. KlotmanAli G. Gharavi

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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.

Original languageEnglish (US)
Pages (from-to)1991-1996
Number of pages6
JournalJournal of the American Society of Nephrology
Volume22
Issue number11
DOIs
StatePublished - Nov 2011
Externally publishedYes

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AIDS-Associated Nephropathy
Immunoglobulin A
HIV-1
Haplotypes
African Americans
Chromosomes
Focal Segmental Glomerulosclerosis
Segmental glomerulosclerosis
Transgenes
Proteinuria
Transgenic Mice
Chronic Kidney Failure

ASJC Scopus subject areas

  • Nephrology

Cite this

Papeta, N., Kiryluk, K., Patel, A., Sterken, R., Kacak, N., Snyder, H. J., ... Gharavi, A. G. (2011). APOL1 variants increase risk for FSGS and HIVAN but not IgA nephropathy. Journal of the American Society of Nephrology, 22(11), 1991-1996. https://doi.org/10.1681/ASN.2011040434

APOL1 variants increase risk for FSGS and HIVAN but not IgA nephropathy. / Papeta, Natalia; Kiryluk, Krzysztof; Patel, Ami; Sterken, Roel; Kacak, Nilgun; Snyder, Holly J.; Imus, Phil H.; Mhatre, Anand N.; Lawani, Anil K.; Julian, Bruce A.; Wyatt, Robert J.; Novak, Jan; Wyatt, Christina M.; Ross, Michael J.; Winston, Jonathan A.; Klotman, Mary E.; Cohen, David J.; Appel, Gerald B.; D'Agati, Vivette D.; Klotman, Paul E.; Gharavi, Ali G.

In: Journal of the American Society of Nephrology, Vol. 22, No. 11, 11.2011, p. 1991-1996.

Research output: Contribution to journalArticle

Papeta, N, Kiryluk, K, Patel, A, Sterken, R, Kacak, N, Snyder, HJ, Imus, PH, Mhatre, AN, Lawani, AK, Julian, BA, Wyatt, RJ, Novak, J, Wyatt, CM, Ross, MJ, Winston, JA, Klotman, ME, Cohen, DJ, Appel, GB, D'Agati, VD, Klotman, PE & Gharavi, AG 2011, 'APOL1 variants increase risk for FSGS and HIVAN but not IgA nephropathy', Journal of the American Society of Nephrology, vol. 22, no. 11, pp. 1991-1996. https://doi.org/10.1681/ASN.2011040434
Papeta, Natalia ; Kiryluk, Krzysztof ; Patel, Ami ; Sterken, Roel ; Kacak, Nilgun ; Snyder, Holly J. ; Imus, Phil H. ; Mhatre, Anand N. ; Lawani, Anil K. ; Julian, Bruce A. ; Wyatt, Robert J. ; Novak, Jan ; Wyatt, Christina M. ; Ross, Michael J. ; Winston, Jonathan A. ; Klotman, Mary E. ; Cohen, David J. ; Appel, Gerald B. ; D'Agati, Vivette D. ; Klotman, Paul E. ; Gharavi, Ali G. / APOL1 variants increase risk for FSGS and HIVAN but not IgA nephropathy. In: Journal of the American Society of Nephrology. 2011 ; Vol. 22, No. 11. pp. 1991-1996.
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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.",
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AU - Julian, Bruce A.

AU - Wyatt, Robert J.

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AU - Ross, Michael J.

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AU - Gharavi, Ali G.

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