1st JAMAICAN PAEDIATRIC NEPHROLOGY CONFERENCE

Jamaica Conference Centre

Kingston Jamaica October 4th 2014  

 

in association with

Genes,  ethnicity  and    nephro1c  syndrome    

Rulan  S.  Parekh    Professor  of  Pediatrics  and  Medicine  

University  of  Toronto  

Disclosures    

•  None  

Learning  Objec1ves  

At  the  end  of  this  session  you  will  be  able  to:  

1.  Understand  the  impact  of  ethnicity  on  kidney  disease  outcomes  

2.  Understand  geneDc  risk  leading  to  progression  of  kidney  disease  

Outline  

•  GeneDc  causes  of  nephroDc  syndrome  and  FSGS  •  Burden  of  FSGS/ESRD  among  African  Americans    •  Discovery  of  chromosome  22  and  progression  of  FSGS  

•  Clinical  ImplicaDons  

Gene1c  risk  

•  SuscepDbility  for  nephroDc  syndrome  •  Risk  for  progression  to  end  stage  renal  disease  

Genes  Associated  with      Nephro1c  Syndrome  (Mendelian)  

•  Known  modes  of  inheritance  – Autosomal  dominant/recessive/  X-­‐linked  

•  EsDmated  25%  of  all  steroid  resistant  focal  segmental  glomerulosclerosis  have  geneDc  disorders  – OveresDmated  geneDc  risk?  – DefiniDon  of  steroid  resistance  varies  – Clinical  protocols  also  vary  by  center    

Genes  Associated  with      Nephro1c  Syndrome  (Mendelian)  

 

TA  Manolio  et  al.  Nature  461,  747-­‐753  (2009)    

Odds  RaDo  

Feasibility  of  iden1fying  gene1c  variants  by  risk  allele  frequency  and  strength  of  gene1c  effect    

 

Architecture  of    kidney  disease  

FSGS  

Genes  

Environment  

CKD  

Genes  

Environment  

ESRD  

Genes  

Environment  

Disease  suscep1bility      Disease  Progression  

Gene1c  risk  

•  SuscepDbility  for  nephroDc  syndrome  •  Risk  for  progression  to  end  stage  renal  disease  

On  average,  two  humans  are  iden1cal  in  99.1%  of  their  DNA  composi1on  

•  HapMap  demonstrated  that  most  variaDons  are  observed  in  the  populaDons  sampled  but  many  do  have  difference  in  allele  frequencies  

Why  do  we  think  that  genes  contribute  kidney  disease?  

•  Clustering  of  kidney  disease  among  families  •  Family  history  of  kidney  disease  or  ESRD  increases  risk  significantly  

–  Family  history  of  2  members  with  kidney  disease  OR    of  ESRD  10.4    (95%CI  2.7-­‐40)  

•  Familial  clustering  of  specific  phenotypes  –  FSGS  –  IgA  nephropathy  –  DiabeDc  nephropathy  

•  Heritability  of  kidney  funcDon    –  33-­‐82%  

•  Ancestry    –  African  Americans  –  Asians  –  Europeans  

Appel,  L.  J.  et  al.  Arch  Intern  Med  2008;168:832-­‐839.  

Cumula1ve  incidence  of  composite  outcome    in    the  AASK  trial  and  cohort    

 

USRDS  2007  

In  2006,    rates  of  ESRD    Whites            279  per  million  popula1on    African  Americans  1010  per  million  popula1on  (~4.2  1mes  greater  than  Whites)  Na1ve  Americans    489  per  million  popula1on  (~1.9  1mes  greater  than  Whites)  Asians                                              388  per  million  popula1on  (~1.3  1mes  greater  than  Whites)  

Incidence  by  race  in  the  US  New  cases  of  ESRD    

Incidence  of  reported  ESRD  by  primary  diagnosis  in  the  US  (2002-­‐2006)  

0

5

10

15

20

25

30

35

40

45

Diabetes Hypertension Glomerular Other

AllWhiteAfrican  American

FSGS  most  common  and  African  Americans  >  Whites  

Approaches  to  iden1fying  genes  for  ESRD  •  Linkage  studies  

–  IdenDfy  families  with  affected  members  

–  Determine  if  suscepDbility  gene  (allele)  is  cosegregaDng  with  disease  in  the  family  

•  AssociaDon  studies  –  IdenDfy  affected  and  unaffecteds  –  Compare  differences  in  allele  

frequencies    •  Candidate  genes  •  Mapping  by  Admixture  Linkage  Disequilibrium  (MALD)  

•  Genome  wide  associaDon  study  (GWAS)  

 AssociaDon                          No  AssociaDon  

 Affected    Unaffected          Affected  Unaffected  

West  Africans  

Europeans  

Admixture  Mapping    A  approach  to  idenDfy  disease  genes  in  an  admixed  popula1on,  such  as  African  Americans,  who  derived  from  the  mixing  of  the  two  geneDcally  isolated  populaDons  (West  Africans  and  Europeans)  

African    Americans  

1  generaDon  ago  

2  generaDons  ago  

3  generaDons  ago  

4  generaDons  ago  

Admixture  creates  a  mosaic  

Two  African  chromosomes  

Two  European  

chromosomes  

One  African,  one  European  chromosome  

Today  

How  does  admixture  mapping  work?  

African  chromosome  

European  chromosome  

 

 

Disease  locus  

These  cases  will  be  enriched  in  African  ancestry  at  the  disease  locus  compared  to  controls  

Cases  with  disease  (higher  risk  in  African)  

Nat  Gen  Oct.  2008  40(10):  1185-­‐92  

Admixture  mapping  can  iden1fy  novel  suscep1bility  locus  for  ESRD  

Strong  evidence  of  excess  African  ancestry  on  chromosome  22q12:    95%  CI  contained  22  genes  

Nat  Gen  Oct.  2008  40(10)  

Admixture  mapping  can  iden1fy  novel  suscep1bility  locus  for  FSGS  

•  Data  recently  available  from  the  1000  Genome  Project  •  Region  of  interest  highlighted  by  admixture  mapping  •  APOL1  has  potenDal  “protecDve”  effects  from  infecDous  risk  •  APOL1,  2,  3,  4  are  all  important  in  selecDon  •  Frequency  of  the  APOL1  variants  (similar  to  MYH9)  is  high  indicaDng  gene  or  gene-­‐  environment  interacDon  

•  Mechanism  of  APOL1  leading  to  kidney  disease  is  unclear  

APOL1  associa1on  with  FSGS  

Haplotype    SNPs   Pafern  on  Inheritance  

FSGS  Frequency  

Control  Frequency  

G1-­‐nonsynomous  coding  variants  

rs73885319    rs60910145  

Recessive   52%   18%  

G2-­‐  deleDon    of  2  aminoacids  

rs71785313   Recessive   23%   15%  

Replica1on  Studies  of  APOL1  

•  HIVAN-­‐3-­‐5  Dmes  higher  risk  •  Proteinuria-­‐1-­‐2  Dmes  higher  risk  •  ESRD-­‐  2  Dmes  higher  risk  •  FSGS-­‐  3-­‐5  Dmes  higher  risk  

•  Always  among  African  Americans  •  Risk  alleles  only  present  in  those  with  west  african  ancestry  

 

Associa1on  but  what  about  progression?  

1.92  (1.19,  3.10)  p=0.008  

 

ESRD-­‐free  survival  by  APOL1  risk  alleles  among  prevalent    CKD    (n=179)  

Does  blood  pressure  modify  risk?  

AASK Exposure, Outcome and Analysis •  Exposure: SNPs on chromosome 22

3 SNPs in APOL1 4 SNPs in MYH9

•  Outcome: Composite of ESRD or doubling of serum creatinine (halving of GFR in intervention-based analysis)

•  Analysis: Time to event analysis using Cox proportional hazard models- and effect of BP

rs16996616  

rs71785313  

rs73885319  

rs60910145  

rs4821481  

rs3752462  

rs2032487  

rs4821480  

MYH9

APOL1

E1 Haplotype

G1 Haplotype

6bp deletion

0.00

0.25

0.50

0.75

1.00

Prop

ortio

n Su

rvivi

ng

0 2 4 6 8 10Follow-up (years)

0  copy  of    APOL1  risk  variants  

1  copy  of    APOL1  risk  variants  

2  copies  of    APOL1  risk  variants  

HR  1.9  (P<0.001)  comparing  2  copies  to  all  others  

Two copies of the APOL1 risk variants associated with faster CKD progression in 693 AAs in AASK  

0.00

0.25

0.50

0.75

1.00

Prop

ortio

n Su

rviv

ing

0 2 4 6 8 10Follow-up (years)

APOL1  non-­‐risk  

APOL1  risk  

APOL1  non-­‐risk  

APOL1  risk  

No  Proteinuria  

Proteinuria  

Pinterac1on=  0.16  

APOL1 risk variants did not modify effects of proteinuria on CKD progression in AASK

 

0.00

0.25

0.50

0.75

1.00

Prop

ortio

n Su

rviv

ing

0 1 2 3 4Follow-up (years)

APOL1  non-­‐risk  Intensive  

APOL1  risk  Standard    

APOL1  risk  Intensive  

APOL1  non-­‐risk  Standard  

Pinterac1on=  0.72  

APOL1 risk variants did not modify effects of BP goals (intensive vs standard) on CKD progression

in AASK  

0.00

0.25

0.50

0.75

1.00

Prop

ortio

n Su

rviv

ing

0 1 2 3 4Follow-up (years)

APOL1  risk  Other  

APOL1  non-­‐risk  ACE-­‐I   APOL1  non-­‐risk  

Other  

APOL1  risk  ACE-­‐I  

Pinterac1on=  0.72  

APOL1 risk variants did not modify effects of drug therapies (ACE-I vs Other) on CKD progression in

AASK  

EA  

AA  APOL1  Non-­‐Risk  

AA  APOL1  Risk  

APOL1-Non Risk AA vs. all EA HR 1.6 (1.1, 2.2)  

APOL1-Risk AA vs. all EA HR 2.7 (1.8, 4.1)

AA with APOL1 Risk Variants Have Faster CKD Progression than EA and AA without APOL1 Risk:

CKD Patients without Diabetes

EA  

AA  APOL1  Non-­‐Risk  

AA  APOL1  Risk  

APOL1-Risk AA vs. all EA HR 2.0 (1.4, 2.7)  

APOL1-Non Risk AA vs. all EA HR 1.4 (1.1, 1.8)  

AA with APOL1 Risk Variants Have Faster CKD Progression than EA and AA without APOL1 Risk:

CKD Patients with Diabetes

Differences in eGFR Slope Comparing AA Risk Groups vs all EAs, Stratified by Diabetes Status  

    Difference  in  eGFR  Slope  

    With  Diabetes       Without  Diabetes  EsDmate  ml/min/yr   P  value       EsDmate  ml/

min/yr   P  value  

 AA  APOL1  risk    vs.  All  EA*   -­‐1.3   <0.001       -­‐1.05   <0.001  

AA  APOL1  non-­‐risk    vs.  All  EA*   -­‐0.4   0.09       0.08     0.65  

AA  APOL1  risk    vs.  AA  APOL1  non-­‐risk -­‐1.1 0.005 -­‐1.2 <0.001

*Adjusted  for  age,  gender,  clinical  site  and  baseline  eGFR,  educaDon,  nephrologist  use  and  ACE/ARB  use,  systolic  blood  pressure,  body  mass  index,  HBA1c  and  smoking  

Challenges  with  APOL1  •  Allele  frequency  is  high  ~11%  APOL1  carriers  of  risk  allele  

•   Need  a  second  hit  to  develop  disease  – Gene  x  gene  or  gene  x  environment  interacDon  

•  SelecDon  panern  is  uncertain  •  Biological  mechanism  unclear  •  Is  it  a  marker  or  is  it  causal?  

Gene1cs  just  got  personal  

When  in  Doubt,  Spit  It  Out    “Spit  Party”  

New  York  Times,  Lifestyles  Sec1on,  2008  

Clinical  u1lity  and  validity    in  gene1c  screening  

•  Need  to  ask:  – Will  you  change  therapy?  – How  will  you  counsel  the  family  given  that  variable    inheritance  panerns  and  penetrance    

– Which  genes  ?  Only  those  with  known  funcDonal  exons  variants?  What  do  we  do  with  discovery  of  new  variants  and  polymorphisms  during  tesDng  

– Not  yet  for  APOL1  

Individualized  medicine  in  nephro1c  syndrome  

•  Ethnicity  does  impact  incidence  and  outcomes  in  nephroDc  syndrome  

•  Individualizing  medical  care:  – Ancestry  (ethnicity)  – Family  and  personal  medical  history  – Personal  circumstances  (stress,  access  to  care,  etc)  – Exposures,  medicines  and  supplements,  etc  

•  GeneDc  informaDon  when  appropriate  and  available  

Ques1ons?