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Cao et al. J Transl Genet Genom 2019;3:4. I https://doi.org/10.20517/jtgg.2018.16 Page 7 of 12

Rare mutations in MYH9 (encoding myosin heavy chain 9) can cause monogenic diseases with kidney
involvement, referred to collectively as Epstein-Fechtner syndrome, and thus represent candidates for ESRD
diagnosis. The locus associated with ESRD was narrowed down subsequently filtered to three functional
sequence variants in the nearby apolipoprotein L1 (APOL1) gene [60,61] . Risk-associated variants of APOL1
(G1 and G2) are strongly linked to human immunodeficiency virus (HIV) associated nephropathy, FSGS,
[62]
and CKD progression among African individuals . They are considered to display such high frequencies
because of a selection event primarily attributed to providing protection from Trypanosoma brucei
rhodesiense [63,64] .

A large number of follow-up studies have been carried out following identification of APOL1 variants, which
represent a milestone in kidney disease genetics. In the African American Study of Kidney Disease and
Hypertension, 58.1% of patients in the APOL1 high-risk group were diagnosed with ESRD or had double the
serum creatinine level. In contrast, only 36.6% of those in the APOL1 low-risk group reached the primary
[65]
outcome .

In the Chronic Renal Insufficiency Cohort study, patients from the APOL1 high-risk group experienced a
[65]
more rapid decline in eGFR and an increased risk of the composite renal outcome than Caucasians . In
recent years, the APOL1-related disease spectrum was extended to systemic lupus erythematosus-associated
[68]
[67]
[66]
glomerulopathy , proteinuria , and HIV-associated nephropathy ; it was not, however, investigated
[69]
among African individuals with IgAN . Taken together, these data suggest that detection of APOL1
variants may serve as a prognostic marker for CKD progression.
As an additional benefit, APOL1 genotyping could improve safety and success of kidney transplantation
[70]
and facilitate the match of kidney donors with receivers. Freedman et al. reported a strong association
between the risk-associated APOL1 genotype of the kidney donor and renal allograft failure. However, the
[71]
genotype of the allograft recipient does not seem to affect allograft survival . These findings raise a critical
[72]
issue: should kidneys from donors with an APOL1 risk-associated genotype be used for transplantation ?
To address this question, the new APOL1 Long-term Kidney Transplantation Outcomes Network is set to
perform a large multicenter cohort study and evaluate the risk exposed by APOL1 genotyping to both donors
and recipients.

DN
Diabetes-related complications represent one of the most severe public healthcare challenges worldwide,
[73]
with great social and economic burden . DN is a prominent complication of diabetes and DN, the primary
[74]
cause of ESRD. Moreover, it is highly heritable, with an incidence of approximately 35% in type 1 diabetes .
Nevertheless, the identification of gene variants strongly associated with DN has been limited.

The onset of albuminuria is regarded as an early landmark of DN progression. By performing meta-analyses
[75]
of GAWSs and subsequent validation in diabetic and nondiabetic populations, Teumer et al. identified
associations between variants of cubilin-encoding CUBN and albuminuria in the overall population,
whereas SNPs in HS6ST1 and RAB38/CTSC exerted a genetic effect on albuminuria only in individuals with
[76]
diabetes. Pezzolesi et al. performed a trans-ethnic meta-analysis of data from the Japanese and Genetics
of Kidneys in Diabetes collections. They reported that loci 11p15.4, near the cysteinyl-tRNA synthetase
(CARS) gene, and 13q33.3 encompassing an intergenic region between the myosin XVI (MYO16) and
insulin receptor substrate 2 (IRS2) genes, were susceptible to kidney disease in both type 1 and 2 diabetes.
[77]
Sandholm et al. performed a GWAS in 3,652 patients from the Finnish Diabetic Nephropathy (FinnDiane)
study. They suggested that rs4972593 on chromosome 2q31.1 was a sex-specific genetic variant related to
ESRD in patients with type 1 diabetes and may provide sex-specific protection against ESRD. A variant
of SCAF8, encoding SR-related CTD associated factor 8, was consistently associated with type 2 DN in