A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level.
BACKGROUND
Serum creatinine (S CR) is the most important biomarker for a quick and non-invasive assessment of kidney function in population-based surveys. A substantial proportion of the inter-individual variability in S CR level is explicable by genetic factors.


METHODS
We performed a meta-analysis of genome-wide association studies of S CR undertaken in five population isolates ('discovery cohorts'), all of which are part of the European Special Population Network (EUROSPAN) project. Genes showing the strongest evidence for an association with SCR (candidate loci) were replicated in two additional population-based samples ('replication cohorts').


RESULTS
After the discovery meta-analysis, 29 loci were selected for replication. Association between SCR level and polymorphisms in the collagen type XXII alpha 1 (COL22A1) gene, on chromosome 8, and in the synaptotagmin-1 (SYT1) gene, on chromosome 12, were successfully replicated in the replication cohorts (p value = 1.0 x 10(-6) and 1.7 x 10(-4), respectively). Evidence of association was also found for polymorphisms in a locus including the gamma-aminobutyric acid receptor rho-2 (GABRR2) gene and the ubiquitin-conjugating enzyme E2-J1 (UBE2J1) gene (replication p value = 3.6 x 10(-3)). Previously reported findings, associating glomerular filtration rate with SNPs in the uromodulin (UMOD) gene and in the schroom family member 3 (SCHROOM3) gene were also replicated.


CONCLUSIONS
While confirming earlier results, our study provides new insights in the understanding of the genetic basis of serum creatinine regulatory processes. In particular, the association with the genes SYT1 and GABRR2 corroborate previous findings that highlighted a possible role of the neurotransmitters GABAA receptors in the regulation of the glomerular basement membrane and a possible interaction between GABAA receptors and synaptotagmin-I at the podocyte level.
Pattaro
Cristian
C
Institute of Genetic Medicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy. cristian.pattaro@eurac.edu
De Grandi
Alessandro
A
Vitart
Veronique
V
Hayward
Caroline
C
Franke
Andre
A
Aulchenko
Yurii S
YS
Johansson
Asa
A
Wild
Sarah H
SH
Melville
Scott A
SA
Isaacs
Aaron
A
Polasek
Ozren
O
Ellinghaus
David
D
Kolcic
Ivana
I
Nöthlings
Ute
U
Zgaga
Lina
L
Zemunik
Tatijana
T
Gnewuch
Carsten
C
Schreiber
Stefan
S
Campbell
Susan
S
Hastie
Nick
N
Boban
Mladen
M
Meitinger
Thomas
T
Oostra
Ben A
BA
Riegler
Peter
P
Minelli
Cosetta
C
Wright
Alan F
AF
Campbell
Harry
H
van Duijn
Cornelia M
CM
Gyllensten
Ulf
U
Wilson
James F
JF
Krawczak
Michael
M
Rudan
Igor
I
Pramstaller
Peter P
PP
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001324:Autoantigens / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood*; D017523:Croatia; D055106:Genome-Wide Association Study; D005858:Germany; D006801:Humans; D008875:Middle Aged; D024041:Non-Fibrillar Collagens / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011963:Receptors, GABA-A / Q000235:genetics*; D015203:Reproducibility of Results; D050863:Synaptotagmin I / Q000235:genetics*; D044465:White People / Q000235:genetics*; D055815:Young Adult; D000097805:Collagen Type XVII
D001324:Autoantigens; D003404:Creatinine; D024041:Non-Fibrillar Collagens; D011963:Receptors, GABA-A; D050863:Synaptotagmin I; D000097805:Collagen Type XVII; C106350:GABRR2 protein, human