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2013 ; 61
(6
): 889-98
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Overlap between common genetic polymorphisms underpinning kidney traits and
cardiovascular disease phenotypes: the CKDGen consortium
#MMPMID23474010
Olden M
; Teumer A
; Bochud M
; Pattaro C
; Köttgen A
; Turner ST
; Rettig R
; Chen MH
; Dehghan A
; Bastardot F
; Schmidt R
; Vollenweider P
; Schunkert H
; Reilly MP
; Fornage M
; Launer LJ
; Verwoert GC
; Mitchell GF
; Bis JC
; O'Donnell CJ
; Cheng CY
; Sim X
; Siscovick DS
; Coresh J
; Kao WH
; Fox CS
; O'Seaghdha CM
Am J Kidney Dis
2013[Jun]; 61
(6
): 889-98
PMID23474010
show ga
BACKGROUND: Chronic kidney disease is associated with cardiovascular disease. We
tested for evidence of a shared genetic basis to these traits. STUDY DESIGN: We
conducted 2 targeted analyses. First, we examined whether known single-nucleotide
polymorphisms (SNPs) underpinning kidney traits were associated with a series of
vascular phenotypes. Additionally, we tested whether vascular SNPs were
associated with markers of kidney damage. Significance was set to 1.5×10(-4)
(0.05/325 tests). SETTING & PARTICIPANTS: Vascular outcomes were analyzed in
participants from the AortaGen (20,634), CARDIoGRAM (86,995), CHARGE Eye
(15,358), CHARGE IMT (31,181), ICBP (69,395), and NeuroCHARGE (12,385) consortia.
Tests for kidney outcomes were conducted in up to 67,093 participants from the
CKDGen consortium. PREDICTOR: We used 19 kidney SNPs and 64 vascular SNPs.
OUTCOMES & MEASUREMENTS: Vascular outcomes tested were blood pressure, coronary
artery disease, carotid intima-media thickness, pulse wave velocity, retinal
venular caliber, and brain white matter lesions. Kidney outcomes were estimated
glomerular filtration rate and albuminuria. RESULTS: In general, we found that
kidney disease variants were not associated with vascular phenotypes (127 of 133
tests were nonsignificant). The one exception was rs653178 near SH2B3 (SH2B
adaptor protein 3), which showed direction-consistent association with systolic
(P = 9.3 ×10(-10)) and diastolic (P = 1.6 ×10(-14)) blood pressure and coronary
artery disease (P = 2.2 ×10(-6)), all previously reported. Similarly, the 64 SNPs
associated with vascular phenotypes were not associated with kidney phenotypes
(187 of 192 tests were nonsignificant), with the exception of 2 high-correlated
SNPs at the SH2B3 locus (P = 1.06 ×10(-07) and P = 7.05 ×10(-08)). LIMITATIONS:
The combined effect size of the SNPs for kidney and vascular outcomes may be too
low to detect shared genetic associations. CONCLUSIONS: Overall, although we
confirmed one locus (SH2B3) as associated with both kidney and cardiovascular
disease, our primary findings suggest that there is little overlap between kidney
and cardiovascular disease risk variants in the overall population. The
reciprocal risks of kidney and cardiovascular disease may not be genetically
mediated, but rather a function of the disease milieu itself.
|*Polymorphism, Single Nucleotide
[MESH]
|Adaptor Proteins, Signal Transducing
[MESH]
|Adult
[MESH]
|Aged
[MESH]
|Blood Pressure/genetics
[MESH]
|Cardiovascular Diseases/*genetics
[MESH]
|Carotid Intima-Media Thickness
[MESH]
|Female
[MESH]
|Genome-Wide Association Study
[MESH]
|Glomerular Filtration Rate/genetics
[MESH]
|Humans
[MESH]
|Intracellular Signaling Peptides and Proteins
[MESH]