CKD has a heritable
component. Atleast partly this is due to the heritability of diabetes and
hypertension; though racial predeliction in African-Americans, asian
susceptibility to IgA are all examples of further genetic links to CKD. In
Nature medicine, a GWAS attempted to identify susceptibility loci to (i) CKD
(eGFR Creat < 60 ml/min), (ii) eGFR creatinine and (iii) eGFR CystatinC. GWA studies are
usually structured in four parts (1) collection of a large number of blood
sample from individuals with the disease/trait of interest and from a control
group; (2) DNA isolation and genotyping; (3) statistical tests for associations
between the SNPs and the disease/trait; (4) replication of identified associations
in an independent population sample and examination of functional implications
experimentally. This study used four populations-based cohorts from prior
studies (ARIC, CHS, FHS, RS; n=19,877;
with 2,388 CKD cases). They then validated the associations identified in 21,466 independent participants (with
1,932 CKD cases).
Seven SNPs at or
upstream of the Uromodulin (Tamm-Horsfall protein) locus emerged most strongly associated with
CKD . These SNPs were also associated
with both eGFR creat and eGFR Cystatin.
The minor T allele at rs12917707 was associated with a 20% reduced risk
of CKD. UMOD mutations are associated with autosomal-dominant forms of kidney
disease, medullary cystic kidney disease type 2 (MCKD2), familial juvenile
hyperuricemic nephropathy (FJHN), and glomerulocystic kidney disease (GCKD).
Oddly, in UMOD knockout mice, decreased creatinine clearance has been observed
but without significant kidney damage. These mice develop increased
calcium-oxalate urolithiasis with high calcium diets and appear to be more
susceptible to UTI. These populations included DM-2 and HTN – both of which
cause significant glomerular changes. It appears however, that SNPs in UMOD, a
tubular protein, are most strongly
associated with eGFR.
With eGFR-creatinine,
a SNP in Shroom3, an actin binding protein emerged next strongly associated
after UMOD. This SNP is intronic. Homozygous Shroom3 deficient mice die
neonatally from open neural tube defects. In general, shroom3 appears to help
modulate epithelial morphogenesis; but the association with kidney disease
needs to be studied further. SNPs in GATM – gene coding for a protein important
in creatine synthesis were significantly related to eGFR Creatinine. An
intronic SNP between Cystatin C and Cystatin 9
emerged as associated with eGFR Cystatin. Again these SNPs are likely to
represent abnormalities in biosynthesis rather than decreased excretion and
CKD.
Ref:
Post by Madhav Menon, MD
Dr. Menon is a Renal Fellow in training at the Mount Sinai School of Medicine, NY
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