Balancing the genetic risk of

APOL1 kidney disease variants

Sophie Limou, PhD

sophie.limou@univ-nantes.fr

Paris, ANJH, May 21st, 2019

• 10-15% of the population is affected• 1/57 deaths worldwide due to CKD• No curative treatment

Created from “The American Cancer Society, Cancer Facts & Figures 2015” and

“United States Renal Data System, 2015 USRDS annual data report”.

Chronic and End-stage kidney disease, a major health burden

2

“United States Renal Data System, 2016 USRDS annual data report”.

Chronic and End-stage kidney disease, a major health disparity

3

ESK

D r

ate

/mill

ion

po

pu

lati

on

AA

EA

ESKD primary causeRR

AA:EA

All causes 3.5

Diabetes 4

Hypertension 5

Glomerulonephritis 3

Lupus nephritis 7

FSGS 5

HIVAN >20

Chronic and End-stage kidney disease, a major health disparity

4

ESKD primary causeRR

AA:EA

All causes 3.5

Diabetes 4

Hypertension 5

Glomerulonephritis 3

Lupus nephritis 7

FSGS 5

HIVAN >20

10% increase in African

ancestry in cases

Kopp et al., Nature Genetics 2008.

Mapping the gene(s) for FSGS/HIVAN in AA

5

Mapping the gene(s) for FSGS/HIVAN in AA

Kopp et al., Nature Genetics 2008. 6

Limou et al., ACKD 2014.

G1 G2

APOL1 risk variants are mutually exclusive

Haplotypefrequency

G0 (WT) 0.63

G1 0.24

G2 0.13

Risk allele count

0 RA 40%1 RA 46%2 RA (HR) 14%

7

Riskalleles

G1 G2

HIVAN FSGS Hypertension ESKD

High-risk

genotype

OR 29 (89 in South Africa) 17 7

Cases

72%

Pop. Controls

13%

Cases

HIV+

hypernorma

l controls

8%

72%

Cases

47%

Pop. Controls

12%

Genovese et al., Science 2010; Kopp et al., JASN 2011; Kasembeli et al., JASN 2015; Limou et al., ACKD 2014.

APOL1 genetic variants account for up to 70% of the excess kidney disease risk in AA

8

9

APOL1

APOL1 risk variants exhibit high frequency and unusuallyhigh effect sizes for a common disease

McCarthy et al. Nat Rev Genet 2008.

EA

AA

G1

G2

+

Kopp et al., JASN 2011.

APOL1 variants are restricted to individuals of African descent

10

EA

AA

G1

G2

+

Nadkarni et al., NEJM 2018. 11

<1%1-5%>5-10%>10%

APOL1 variants are restricted to individuals of African descent

G1 allele distribution

Limou et al. ACKD 2014; Cooper et al. eLife 2017.

G2 allele distribution

12

APOL1 variants are restricted to individuals of African descent

• Sequencing of 53 worldwide populations (>2,200 chr.)

Limou et al., KI 2015.

APOL1 selection signature

13

• Pairwise FST fixation index estimates

Limou et al., KI 2015.

0.0 0.1 0.2 0.3 0.4

05

10

15

20

25

Genome-wide Fst estimates

De

nsity

o West Africa populations are significantly differentiated than other SubSaharan African populations for APOL1 G1 (0.20 < FST <0.41)

o Only trends of population differentiation for APOL1 G2 in SubSaharan Africa

Yoruba, Nigeria vs. Bantu, Kenya

G1 FST = 0.32 (top 0.16%)

APOL1 selection signature

14

G2

Limou et al., KI 2015.

APOL1 selection signature

• EHH/iHS long-haplotype testso Evidence of a recent selective sweep in West Africa for APOL1 G1 and G2

15

• APOL1 = human resistance factor against T. brucei infections

T.b. brucei

APOL1

entry

Membrane

insertion

Pore

formation

Trafficking and endo-lysosomal acidification

Parasite

death

Perez-Morga et al., Science 2005.

APOL1 and trypanosomes, a co-evolutionary arms race

16

• T.b. rhodesiense and T.b. gambiense have evolved resistance mechanisms against APOL1 lysis

T.b. gambiense

APOL1

entry

TgsGP-mediated

membrane thickening

APOL1

degradation

Parasite

survival

T.b. rhodesiense

APOL1

entry

SRA-mediated

inhibition

APOL1

degradation

Parasite

survival

African sleeping sickness

Vanhamme et al., Nature 2003; Uzureau et al., Nature 2013.

APOL1 and trypanosomes, a co-evolutionary arms race

17

• APOL1 G1 et G2 restore lysis against T.b. rhodesiense

protection against acute trypanosomiasis

WT/WT

WT

G1 G2

Genovese et al., Science 2010; Limou et al., KI 2015.

APOL1 and trypanosomes, a co-evolutionary arms race

18

E. Pays

T.b. rhodesiense

APOL1

G1/G2 entry

No SRA-mediated

inhibition and APOL1

membrane insertion

Pore

formation

Parasite

death

G1 G2

APOL1 and trypanosomes, a co-evolutionary arms race

• APOL1 G1 et G2 restore lysis against T.b. rhodesiense

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protection against acute trypanosomiasis

APOL1 kidney risk alleles (1 or 2) protect from trypanosomiasis

20

Two APOL1 risk alleles (high-risk genotypes) associate with increased CKD/ESKD risk

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Balancing the risk: African sleeping sickness vs. CKD

22

CKD/ESKD riskTrypanosomiasis risk

Mouse

Ψ

Ψ Ψ Ψ

Ψ

Ψ

APOL1 APOL2 APOL4 APOL3 APOL5 APOL6

Human

Orangutan

Chimpanzee

Gorilla

Macaque1

Baboon2

Ψ

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APOL gene family in primates

• Broad innate immunity factor

• Mitochondrial dysfunction

• Autophagy flux and vesicle trafficking

• Controversy around a suPAR-dependent complex

• APOL1 RNA and PKR activation

APOL1 cellular function

Beckerman et al., Nature Med 2017; see Review and previous talk. 24

Recessive model of inheritance? Second hit?

• APOL1 recipient genotype does not impact kidney graft failure

• APOL1 high-risk kidney allografts have more risk to fail

donor recipient

Allo

graf

t su

rviv

al (

%)

Low risk

High risk

Donor genotype

P=0.001

Clinical applications for APOL1 genotyping in kidney transplantation

Reeves-Daniel et al., AJT 2011; Lee et al., AJT 2012; Freedman et al., Transplantation 2016. 25

• Donors w/ APOL1 high-risk genotypes have lower eGFR at donation

• Decline in post-donation eGFR is faster among donors w/ APOL1 high-risk genotypes

Doshi et al. JASN 2018 26

APOL1 and living kidney donation

P=0.02

livingdonor

APOL1 HR

post-donation ESKD risk

• Donation does not increase the rate of kidney function decline

Doshi et al. JASN 2018 27

APOL1 and living kidney donation

• Considering APOL1 genotypes instead of race drastically change the risk associated with kidneys transplanted from AA donors

Better prediction of post-transplantation outcomes

Improved organ allocation

Julian et al. AJT 2017

Low-risk APOL1 genotypes High-risk APOL1 genotypes

Current score(race-based)

Revised score (APOL1-based)

Current score (race-based)

Revised score (APOL1-based)

KDRI 1.5 1.2 1.5 1.9

InterpretationWe exclude

perfectly good donorsWe underestimate

the risk for these donors

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APOL1 and kidney transplantation risk

Translation to clinics: the APOLLO network

• Prospective collection of APOL1 data and outcome follow-up in African-American donors and recipients

• Open questions regarding APOL1 genotyping benefits/ethics:

Kidney allograft survival?

ESKD risk for living kidney donors?

Impact of APOL1-based KDRI score for allograft outcomes?

Freedman et al. CJASN 2018.

B. Freedman

29

Conclusions and Perspectives

• Population studies have revealed strong associations between common

APOL1 genetic variants and CKD/ESKD risk in African Americans

• APOL1 G1 and G2 variants were selected by pathogens (likely Tryps)

• Potential translation to clinics for kidney transplantation

• Genomic approach in populations can unravel novel pathways for kidney

allograft survival

Definitive (?) answers from the APOLLO networkPromise of personalized medicine approach

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Acknowledgments

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