Re-Sequencing of the APOL1-APOL4 and MYH9 Gene Regions in African Americans Does Not Identify Additional Risks for CKD Progression.
BACKGROUND
In African Americans (AAs), APOL1 G1 and G2 nephropathy risk variants are associated with non-diabetic end-stage kidney disease (ESKD) in an autosomal recessive pattern. Additional risk and protective genetic variants may be present near the APOL1 loci, since earlier age ESKD is observed in some AAs with one APOL1 renal-risk variant, and because the adjacent gene MYH9 is associated with nephropathy in populations lacking G1 and G2 variants.


METHODS
Re-sequencing was performed across a ∼275 kb region encompassing the APOL1-APOL4 and MYH9 genes in 154 AA cases with non-diabetic ESKD and 38 controls without nephropathy who were heterozygous for a single APOL1 G1 or G2 risk variant.


RESULTS
Sequencing identified 3,246 non-coding single nucleotide polymorphisms (SNPs), 55 coding SNPs, and 246 insertion/deletions. No new coding variations were identified. Eleven variants, including a rare APOL3 Gln58Ter null variant (rs11089781), were genotyped in a replication panel of 1,571 AA ESKD cases and 1,334 controls. After adjusting for APOL1 G1 and G2 risk effects, these variations were not significantly associated with ESKD. In subjects with <2 APOL1 G1 and/or G2 alleles (849 cases; 1,139 controls), the APOL3 null variant was nominally associated with ESKD (recessive model, OR 1.81; p = 0.026); however, analysis in 807 AA cases and 634 controls from the Family Investigation of Nephropathy and Diabetes did not replicate this association.


CONCLUSIONS
Additional common variants in the APOL1-APOL4-MYH9 region do not contribute significantly to ESKD risk beyond the APOL1 G1 and G2 alleles.
Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, N.C., USA.
Gregory A
GA
Hawkins
David J
DJ
Friedman
Lingyi
L
Lu
David R
DR
McWilliams
Jeff W
JW
Chou
Satria
S
Sajuthi
Jasmin
J
Divers
Rulan S
RS
Parekh
Man
M
Li
Giulio
G
Genovese
Martin R
MR
Pollack
Pamela J
PJ
Hicks
Donald W
DW
Bowden
Lijun
L
Ma
Barry I
BI
Freedman
Carl D
CD
Langefeld
D016263:AIDS-Associated Nephropathy / Q000235:genetics; D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000755:Anemia, Sickle Cell / Q000150:complications; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D000075943:Apolipoproteins L; D018450:Disease Progression; D005260:Female; D020022:Genetic Predisposition to Disease; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006977:Hypertension, Renal / Q000235:genetics; D007676:Kidney Failure, Chronic / Q000235:genetics*; D008075:Lipoproteins, HDL / Q000235:genetics*; D008181:Lupus Nephritis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020409:Molecular Motor Proteins / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000235:genetics*; D009393:Nephritis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D051436:Renal Insufficiency, Chronic / Q000209:etiology / Q000235:genetics*; D017422:Sequence Analysis, DNA
C108666:APOL1 protein, human; C543112:APOL2 protein, human; C543113:APOL4 protein, human; C000609028:APOL3 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; D000075943:Apolipoproteins L; D008075:Lipoproteins, HDL; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D018995:Myosin Heavy Chains