Concept Map: APOL1 Mediated Kidney Disease (AMKD)

 

Topic Discussion: Pre eclampsia and APOL1

 This ASN 2021, I heard an interesting lecture and realized some novel associations with pre-eclampsia(PEC) and APOL1 gene mutations. 

Here are some interesting findings.

1. Black women have a higher risk of PEC their White counterparts.
2. Reidy et all showed that it is the FETAL not maternal APOL1 renal risk variant that is associated with PEC in Black women.

3. Some other studies showed that PEC was associated with the maternal G1 and not the G2 allele

4. In Blacks in Ohio, INFANT APOL1 genotype was associated with PEC

5. Recent study in AJKD, found that APOL1 kidney risk variants in Black mother and infant pairs of women of African American origin had higher risk of PEC compared to Haitian women. PEC was higher with maternal and fetal APOL1 genotype discordance, an effect driven by the African American mother-infant pairs. 

6. None of the published studies assessed if the mother’s APOL1 genotype conferred preeclampsia risk independently of the fetal APOL1 genotype, although in African Americans both the maternal and fetal APOL1 renal risk variants appear to increase risk if an APOL1 genotype discordance exists.

7. Experimental data support the hypothesis that APOL1 renal risk variants mediate preeclampsia. APOL1 levels, APOL1-derived peptides, and APOL1 autoantibodies have been linked to preeclampsia. Sedor's team showed that transgenic mice that expressed APOL1 using the nephrin promoter developed a pregnancy-associated phenotype characterized by hypertension, proteinuria, and seizures, which was more severe in transgenic animals with an APOL1 kidney risk variants transgene compared to reference. 

Overall, this is fascinating as we learn regarding the risk of PEC and APOL1 risk variants. It appears that fetal variants of the gene may be more important here.. the story continues to evolve... Stay tuned..

Concept Map: APOL1 Nephropathy

APOL1 gene nephropathy has now emerged as a potential new entity given the linkage to African American ancestry and having these alleles that were protective against sleeping sickness and then leading to more HTN proteinuric and non proteinuric renal disease in AA.  Below is a summary concept map on this topic and how having these alleles and then a SECOND HIT concept might be necessary for disease phenotype.  There are likely two disease phenotypes- FSGS variants and then the tubular non proteinuric variants. African Americans with arterionephrosclerosis who possess two APOL1 risk variants more often lack obsolescent glomerulosclerosis and have greater degrees of (solidified and disappearing) glomerulosclerosis, thyroidization-type tubular atrophy, and microcystic tubular dilation than patients with fewer than two risk variants in the non proteinuric patient lists.  
Also, there is some emerging data that JC and BK virus might be protective for the kidney relatives of patients with APOL1 nephropathy.

References:

Pathology of Non proteinuric Renal diseases in APOL1 nephropathy
Second hit concept
Protective viruses for APOL1 nephropathy

CLINICAL CASE 48: Answers and Summary

AFRICAN ANCESTRY GENETIC VARIANT APOL1 GENE HAS BEEN NOW ASSOCIATED WITH GLOMERULAR DISEASES. WHICH OF THE FOLLOWING REGARDING APOL1 ARE TRUE?

1.APOL1 can be localized to podocytes and media of medium artery and arterioles in the kidneys-  22% 2.APOL1 Variants Increase Risk for FSGS and HIVAN but Not IgA Nephropathy -33% 3.African Americans carrying two copies of the G1 APOL1 risk allele need early age hemodialysis -22% 4.Case-control studies suggest that African Americans with genetic variants in both copies of APOL1  have increased risk for hypertension-attributable ESRD and focal segmental glomerulosclerosis  -77% 5.APOL1 sits next to MYH9 gene  - 100% 6.African americans with APOL1 risk allele have more increased risk of non diabetic CKD - 44%

Gene variants of MHY9 locus were being considered as possible risk factors for FSGS and high incidence of kidney diseases in the african american population for the last decade.  A further risk assessment was just done by the same investigators and 1641 European Americans were compared to 1800 African Americans and new locus was discovered.

This phenomenon might be epigenetic from protection from the Sleeping sickness disease caused by the tsetse fly. Apparently on the same chromosome 22, APOL1(apolipoprotein -1) and MHY9 sit next to each other.  The studies are now showing that due to natural selection and linkage disequilibrium, the APOL1 gene might be the strong candidate for a gene that is responsible for increased incidence of renal disease in African Origin Americans. Recent JASN articles in Nov 2011 issue also shed light on newer findings as described above: Having the APOL-1 variant can lead to more arterilopathy and renal vessel changes and that was confirmed on biopsy findings.  Interestingly, only certain glomerular diseases are at risk- FSGS types including HIVAN but not IgA nephropathy or diabetic nephropathy.  Given the severity of the disease, these patients need dialysis at an earlier age.  More copies of this gene- more you are at risk of FSGS and ESRD.

So all the above statements are correct.

Ref:

http://www.ncbi.nlm.nih.gov/pubmed/21997398

http://www.ncbi.nlm.nih.gov/pubmed/21997394

http://www.ncbi.nlm.nih.gov/pubmed/21997392

http://www.ncbi.nlm.nih.gov/pubmed/22135313