Introduction:
Most genetic variants for chronic kidney disease (CKD) have been identified in non-coding regions, with functional roles that are difficult to interpret.
Hypothesis:
A whole exome sequencing study focusing on coding variants will reveal novel mechanisms of kidney function and CKD.
Methods:
We performed whole exome sequencing analyses of cystatin C among 29,789 UK Biobank (UKB) participants with further confirmation among 4,297 white and 607 African American participants of the Health and Retirement Study (HRS). Conditional analyses for loci achieving exome-wide significance (
P
<3.5х10
-7
) were conducted in UKB using both the exome (n=29,789) and imputed GWAS data (n=295,122). Genomic findings were tested for relevance to baseline estimated glomerular filtration rate (eGFR) and stringently adjudicated CKD progression events among participants of the Chronic Renal Insufficiency Cohort (CRIC) by race and smoking status, using a base model and a full model (
Table
).
Results:
We identified a common missense variant,
CST9
rs2983640, in a previously reported locus (
CST3
intron rs13038305), of which the minor G allele was associated with lower serum cystatin C level (UKB: beta=-0.03 mg/L,
P
=7.64х10
-92
; HRS whites: beta=-0.05 mg/L,
P
=4.71х10
-6
; HRS African Americans: beta=-0.03 mg/L,
P
=0.64; and multi-ethnic meta-analysis beta=-0.03 mg/L,
P
=2.46х10
-91
). After controlling for the
CST3
variant, the G allele was associated with higher cystatin C level (UKB exome: beta=0.003 mg/L,
P
=0.04; UKB GWAS: beta=0.003 mg/L,
P
=1.47х10
-10
). Similar associations were identified in white CRIC participants (direct effect: beta=-0.05 mg/L,
P
=0.005; conditional effect: beta=0.004 mg/L,
P
=0.86). The
CST9
rs2983640 G allele was associated with lower baseline eGFR (base model beta=-0.33 ml/min/1.73 m
2
,
P
=1.98х10
-6
) and higher hazard of developing CKD progression independent of the reported
CST3
variant (
Table
).
Conclusions:
We identified a novel missense variant influencing cystatin C level and CKD progression.
Cystatin-C is associated with partial recovery of kidney function and progression to chronic kidney disease in living kidney donors
