Page 126 - Read Online

Cao et al. J Transl Genet Genom 2019;3:4. I https://doi.org/10.20517/jtgg.2018.16 Page 5 of 12
[36]
Stanescu et al. reported two loci, phospholipase A2 receptor 1 (PLA2R1) and human leukocyte antigen
(HLA)-DQA1, strongly associated with IMN risk among 556 European patients. The associations were
further strengthened when the two loci were evaluated simultaneously. These findings are consistent with
the fact that the PLA2R1-encoded protein, M-type PLA2R1, is the major autoantigen in humans with IMN.
Moreover, a large cross-sectional study involving over 2000 Chinese individuals detected anti-PLA2R
antibodies in 73% of subjects, who carried both risk alleles but none in those with no mutation in these two
genes, suggesting that the interaction between PLA2R1 and HLA-DQA1 variants contributes to the presence
[38]
[37]
of anti-PLA2R antibodies . Interestingly, Sekula et al. reported that mutations in PLA2R1 were specific
to IMN, whereas HLA-DQA1 variants (encoding major histocompatibility complex, class II, DQ alpha 1)
were also associated with other kidney diseases including type 1 DN, lupus nephritis and focal segmental
glomerular sclerosis (FSGS) in adults. By sequencing the entire major histocompatibility complex region in
[39]
over 200 DNA samples, Le et al. reported a strong association between PLA2R-related IMN and HLA-
DRB1*15:01 and HLA-DRB3*02:02 alleles in the Chinese population. How exactly mutations in PLA2R
finally result in the generation of anti-PLA2R antibodies remains to be elucidated [Table 2].

Anti-PLA2R1 antibodies are detected in nearly 70% of patients with IMN. Measurement of anti-PLA2R
antibodies has been translated into clinical practice for diagnosing IMN, and emerging studies indicate
[40]
it can also be used to predict the response to immunosuppressive therapy and long-term outcomes .
Considering that genetic mutation is an upstream event, detection of risk variants might provide early
diagnostic and prognostic information on IMN [41,42] . However, long-term prospective studies are still
required to establish the statistical likelihood of individuals with high-risk genotypes developing IMN over
their lifetime.

IgA nephropathy
IgA nephropathy (IgAN) is a major cause of renal failure worldwide. IgAN perfectly exemplifies how
multiple gene interactions can affect kidney injury because the combined distribution of risk-associated
alleles strongly correlates with its geographic prevalence gradient; it is highest in Asian, intermediate in
[43]
European, and lowest in African countries . In the past 5 years, several reviews and meta-analyses have
discussed GWAS findings for IgAN [44-48] .

The increasing number of larger GWASs in different populations has unveiled numerous IgAN-associated
loci, including complement factor H-related (CFHR) genes [49-51] , or those encoding defensing (DEFA) [47,52] ,
[53]
[46]
[54]
HLA , sprouty RTK signaling antagonist 2 (SPRY2) , vav guanine nucleotide exchange factor 3 (VAV3) ,
[55]
core 1 synthase, glycoprotein-N-acetylgalactosamine 3-beta-galactosyltransferase 1 (C1GALT1) , and tumor
[56]
necrosis factor superfamily member 13 (TNFSF13) .
[53]
In 2010, Feehally et al. reported a genome-wide analysis in an IgAN cohort selected from the UK
Glomerulonephritis DNA Bank. Their results suggested that the HLA locus contained the strongest common
susceptibility alleles responsible for genetic predisposition to IgAN in the European population. Factor H, a
component of the alternative pathway, is present in the mesangial immune deposits, which can be activated
[57]
[49]
by IgA1, and contributes to IgAN progression . Gharavi et al. performed targeted follow-up evaluations
in Chinese and European cohorts including 1,950 patients and 1,920 controls, and detected a common
deletion in CFHR1 and CFHR3 at position 1q32 and a locus at position 22q12 in IgAN individuals. Deletions
[50]
in CFHR1 and CFHR3 were related to a reduced risk of IgAN. In contrast, Jullien et al. reported deletion
variants of CFHR1 and CFHR3, which were associated with mesangial immune deposits but not with IgAN
[51]
progression. Zhai et al. recruited 500 IgAN patients and 576 healthy controls and sequenced all exons,
intronic flanking regions, and the untranslated regions of CFHR5. They reported 32 variants in CFHR5
(including 28 rare and 4 common variants). Rare variants in CFHR5 may further increase the genetic
predisposition to IgAN, which indicates that CFHR5 is a susceptibility gene for IgAN.