Rare independent mutations in renal salt handling genes contribute to blood pressure variation.
Ji W, Foo JN, O'Roak BJ, Zhao H, Larson MG, Simon DB, Newton-Cheh C, State MW, Levy D, Lifton RP.
Department of Genetics, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA.
Nat Genet. 2008 May;40(5):592-9
The effects of alleles in many genes are believed to contribute to common complex diseases such as hypertension. Whether risk alleles comprise a small number of common variants or many rare independent mutations at trait loci is largely unknown. We screened members of the Framingham Heart Study (FHS) for variation in three genes-SLC12A3 (NCCT), SLC12A1 (NKCC2) and KCNJ1 (ROMK)-causing rare recessive diseases featuring large reductions in blood pressure. Using comparative genomics, genetics and biochemistry, we identified subjects with mutations proven or inferred to be functional. These mutations, all heterozygous and rare, produce clinically significant blood pressure reduction and protect from development of hypertension. Our findings implicate many rare alleles that alter renal salt handling in blood pressure variation in the general population, and identify alleles with health benefit that are nonetheless under purifying selection. These findings have implications for the genetic architecture of hypertension and other common complex traits.
Exemple du rôle de la balance sodée dans le contrôle de la pression artérielle. Les sujets de la cohorte de Framingham (étude des risques cardiovasculaires avec un suivi de 35 ans), hétérozygotes pour une mutation d’un de 3 des gènes responsables du syndrome de Bartter/Gitelman, ont des chiffres de pression artérielle systolique et diastolique significativement plus bas pour toutes les tranches d’âge. Cet effet avait été montré pour de petits groupes, en particulier pour le cotransporteur Na-Cl. Cet article en fait une élégante démonstration dans la durée.
Rosa Vargas Poussou
5/26/2008
5/25/2008
Un transporteur des hexoses (GLUT9) se charge aussi de l'acide urique ...
SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout.
Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CN, Knott SA, Kolcic I, Polasek O, Graessler J, Wilson JF, Marinaki A, Riches PL, Shu X, Janicijevic B, Smolej-Narancic N, Gorgoni B, Morgan J, Campbell S, Biloglav Z, Barac-Lauc L, Pericic M, Klaric IM, Zgaga L, Skaric-Juric T, Wild SH, Richardson WA, Hohenstein P, Kimber CH, Tenesa A, Donnelly LA, Fairbanks LD, Aringer M, McKeigue PM, Ralston SH, Morris AD, Rudan P, Hastie ND, Campbell H, Wright AF.MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK.
Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.
SLC2A9 influences uric acid concentrations with pronounced sex-specific effects.Döring A, Gieger C, Mehta D, Gohlke H, Prokisch H, Coassin S, Fischer G, Henke K, Klopp N, Kronenberg F, Paulweber B, Pfeufer A, Rosskopf D, Völzke H, Illig T, Meitinger T, Wichmann HE, Meisinger C.Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Serum uric acid concentrations are correlated with gout and clinical entities such as cardiovascular disease and diabetes. In the genome-wide association study KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K (n = 1,644), the most significant SNPs associated with uric acid concentrations mapped within introns 4 and 6 of SLC2A9, a gene encoding a putative hexose transporter (effects: -0.23 to -0.36 mg/dl per copy of the minor allele). We replicated these findings in three independent samples from Germany (KORA S4 and SHIP (Study of Health in Pomerania)) and Austria (SAPHIR; Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk), with P values ranging from 1.2 x 10(-8) to 1.0 x 10(-32). Analysis of whole blood RNA expression profiles from a KORA F3 500K subgroup (n = 117) showed a significant association between the SLC2A9 isoform 2 and urate concentrations. The SLC2A9 genotypes also showed significant association with self-reported gout. The proportion of the variance of serum uric acid concentrations explained by genotypes was about 1.2% in men and 6% in women, and the percentage accounted for by expression levels was 3.5% in men and 15% in women.
Un bel exemple de ce que peuvent apporter les études d’association sur génome entier pour comprendre la physiopathologie. En utilisant cette approche, ces deux équipes ont mis en évidence une association entre des polymorphismes introniques ou exoniques du gène SLC2A9 et la concentration d’acide urique. Cette association fortement significative est confirmée sur d’autres populations; l’haplotype moins fréquent est associé à des concentrations d’acide urique plus basses, avec un effet plus fort chez la femme que chez l’homme.
Le gène SLC2A9 code pour GLUT9 qui appartient à la famille de transporteurs des hexoses. GLUT9 participe au transport du fructose et celui-ci était connu pour induire une hyperuricémie (augmentation de la synthèse hépatique). Une de deux équipes montre que GLUT9, exprimé dans l’ovocyte de Xenopus, transporte également de l’acide urique.
Peu-être une piste pour cibler les enfants susceptibles de faire des hyperuricémies par exemple au cours des syndromes de lyse tumorale.
Rosa Vargas-Poussou
Vitart V, Rudan I, Hayward C, Gray NK, Floyd J, Palmer CN, Knott SA, Kolcic I, Polasek O, Graessler J, Wilson JF, Marinaki A, Riches PL, Shu X, Janicijevic B, Smolej-Narancic N, Gorgoni B, Morgan J, Campbell S, Biloglav Z, Barac-Lauc L, Pericic M, Klaric IM, Zgaga L, Skaric-Juric T, Wild SH, Richardson WA, Hohenstein P, Kimber CH, Tenesa A, Donnelly LA, Fairbanks LD, Aringer M, McKeigue PM, Ralston SH, Morris AD, Rudan P, Hastie ND, Campbell H, Wright AF.MRC Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, UK.
Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes.
SLC2A9 influences uric acid concentrations with pronounced sex-specific effects.Döring A, Gieger C, Mehta D, Gohlke H, Prokisch H, Coassin S, Fischer G, Henke K, Klopp N, Kronenberg F, Paulweber B, Pfeufer A, Rosskopf D, Völzke H, Illig T, Meitinger T, Wichmann HE, Meisinger C.Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Serum uric acid concentrations are correlated with gout and clinical entities such as cardiovascular disease and diabetes. In the genome-wide association study KORA (Kooperative Gesundheitsforschung in der Region Augsburg) F3 500K (n = 1,644), the most significant SNPs associated with uric acid concentrations mapped within introns 4 and 6 of SLC2A9, a gene encoding a putative hexose transporter (effects: -0.23 to -0.36 mg/dl per copy of the minor allele). We replicated these findings in three independent samples from Germany (KORA S4 and SHIP (Study of Health in Pomerania)) and Austria (SAPHIR; Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk), with P values ranging from 1.2 x 10(-8) to 1.0 x 10(-32). Analysis of whole blood RNA expression profiles from a KORA F3 500K subgroup (n = 117) showed a significant association between the SLC2A9 isoform 2 and urate concentrations. The SLC2A9 genotypes also showed significant association with self-reported gout. The proportion of the variance of serum uric acid concentrations explained by genotypes was about 1.2% in men and 6% in women, and the percentage accounted for by expression levels was 3.5% in men and 15% in women.
Un bel exemple de ce que peuvent apporter les études d’association sur génome entier pour comprendre la physiopathologie. En utilisant cette approche, ces deux équipes ont mis en évidence une association entre des polymorphismes introniques ou exoniques du gène SLC2A9 et la concentration d’acide urique. Cette association fortement significative est confirmée sur d’autres populations; l’haplotype moins fréquent est associé à des concentrations d’acide urique plus basses, avec un effet plus fort chez la femme que chez l’homme.
Le gène SLC2A9 code pour GLUT9 qui appartient à la famille de transporteurs des hexoses. GLUT9 participe au transport du fructose et celui-ci était connu pour induire une hyperuricémie (augmentation de la synthèse hépatique). Une de deux équipes montre que GLUT9, exprimé dans l’ovocyte de Xenopus, transporte également de l’acide urique.
Peu-être une piste pour cibler les enfants susceptibles de faire des hyperuricémies par exemple au cours des syndromes de lyse tumorale.
Rosa Vargas-Poussou
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