Monday, September 12, 2011

Topic Discussions: Genome-wide association studies (GWAS) in CKD

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.


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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