2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
Germany, 7 First Department of Internal Medicine, St. Johann Spital, Paracelsus
Private Medical University, Salzburg, Austria, 8 Institute for Community Medicine,
Ernst-Moritz-Arndt University, Greifswald, Germany, 9 Central Hospital of
Augsburg, MONICA/KORA Myocardial Infarction Registry, Augsburg, Germany.
Serum uric acid (UA) levels are correlated with gout and clinical entities
such as cardiovascular disease and diabetes . In a genome-wide
association study (KORA F3-500K, n=1644), we identified a QTL associated
with UA level located on chromosome 4 including 40 SNPs
with P-values below the genome-wide significance level. The most
significant SNPs mapped within intron 4 and 6 of SLC2A9 (effects -
0.18 to -0.36 mg/dL per copy of the minor allele). These findings were
replicated in three independent samples from Germany (KORA S4 and
SHIP) and Austria (SAPHIR) with P-values ranging from 1 .2x10 -8 to
1 .0x10 -32 . The SLC2A9 genotypes in addition showed significant association
with self-reported gout . The proportion of the variance of serum
UA levels explained by genotypes was about 1 .2% in men and 6% in
women. Analysis of whole blood RNA expression profiles from a KORA
F3-500K subgroup (n=117) revealed a significant association between
the SLC2A9 isoform 2 and urate levels . SLC2A9 encodes a transporter
protein that belongs to class II of the facilitative glucose transporter
family . A potential substrate of GLUT9 is fructose, as GLUT9 has the
highest similarity with the fructose transporters GLUT5 and GLUT11 .
Our expression studies allow discrimination between two annotated
isoforms of this gene. The significant association with the shorter protein
GLUT9ΔN argues for a prominent role of the SLC2A9 isoform 2
in the regulation of urate concentrations . The association with the isoform
2 suggests an involvement of the protein in urate excretion .
P06.304
Association of polymorphisms Ala62Thr in ZNF365 gene and Taq
i and Fok i in VDR gene with metabolic alterations in adults with
urolithiasis from Yucatan, mexico
M. M. Medina-Escobedo 1 , L. González-Herrera 2 , S. Villanueva-Jorge 1 , E.
Gala-Trujano 1 , M. Salazar-Canul 1 , G. Martín-Soberanis 3 ;
1 Hospital General “O’Horán” S.S.Y., Mérida, Mexico, 2 CIR “Dr. Hideyo-Noguchi”,
Universidad Autónoma de Yucatán, Mérida, Mexico, 3 Hospital General No.
12 “Lic. Benito Juárez”, IMSS, Yucatán, México, Mérida, Mexico.
Urolithiasis (UL) is an endemic health problem in Yucatan, Mexico . Hypocitraturia,
hypercalciuria and hyperurocosuria are frequent metabolic
alterations in UL . Polymorphisms Ala62Thr in ZNF365 gene and Taq
I and Fok I in VDR gene have been associated to UL . Polymorphisms
might affect the metabolic pathways involved in UL, so we analyzed
the association of these polymorphisms with metabolic alterations in
adults with UL from Yucatan, Mexico . 169 patients, 59 males (34 .9%)
and 110 females (65.1%) were analyzed. UL was confirmed by RX
and ultrasonography . 24 hours urine excretion of Na, K, Ca, P, Mg,
uric acid, oxalates and citrates were determined . Polymorphisms were
determined in DNA samples by PCR-RFLPs . Genotypic and allelic frequencies
of each polymorphism were compared between patients with
metabolic alterations and patients with normal metabolism . Metabolic
alterations found were hypercalciuria 16 .6%, hyperuricosuria 13 .6%,
hyperphosphaturia 7 .7%, hypomagnesuria 1 .2%, hyperoxaluria 24 .9%
and hypocitraturia 61 .5% . Genetic frequencies obtained for VDR were:
Taq I (tt 1 .2%, tT 30 .8%, TT 68 .0%), Fok I (ff 20 .7%, fF 53 .5%, FF
26 .0%) and for ZNF365 (AA 8 .9%, AG 29 .0%, GG 62 .1%) . Polymorphisms
in the VDR gene were not associated with metabolic alterations
(p>0 .05), whereas allele G of ZNF365 gene was associated with
hypocitraturia (p=0 .044) . Mean concentrations of K, Mg and citrate in
urine excretion were significantly lower (p