Browsing by Author "Onipinla, Abiodun"

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    Genome-wide scan identifies CDH13 as a novel susceptibility locus contributing to blood pressure determination in two European populations
    (OXFORD UNIV PRESS, 2009) Org, Elin; Eyheramendy, Susana; Juhanson, Peeter; Gieger, Christian; Lichtner, Peter; Klopp, Norman; Veldre, Gudrun; Doering, Angela; Viigimaa, Margus; Sober, Siim; Tomberg, Kaert; Eckstein, Gertrud; Kelgo, Piret; Rebane, Tiina; Shaw Hawkins, Sue; Howard, Philip; Onipinla, Abiodun; Dobson, Richard J.; Newhouse, Stephen J.; Brown, Morris; Dominiczak, Anna; Connell, John; Samani, Nilesh; Farrall, Martin; Caulfield, Mark J.; Munroe, Patricia B.; Illig, Thomas; Wichmann, H. Erich; Meitinger, Thomas; Laan, Maris; KORA; BRIGHT
    Hypertension is a complex disease that affects a large proportion of adult population. Although approximately half of the inter-individual variance in blood pressure (BP) level is heritable, identification of genes responsible for its regulation has remained challenging. Genome-wide association study (GWAS) is a novel approach to search for genetic variants contributing to complex diseases. We conducted GWAS for three BP traits [systolic and diastolic blood pressure (SBP and DBP); hypertension (HYP)] in the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) S3 cohort (n = 1644) recruited from general population in Southern Germany. GWAS with 395 912 single nucleotide polymorphisms (SNPs) identified an association between BP traits and a common variant rs11646213 (T/A) upstream of the CDH13 gene at 16q23.3. The initial associations with HYP and DBP were confirmed in two other European population-based cohorts: KORA S4 (Germans) and HYPEST (Estonians). The associations between rs11646213 and three BP traits were replicated in combined analyses (dominant model: DBP, P = 5.55 x 10(-5), effect -1.40 mmHg; SBP, P = 0.007, effect -1.56 mmHg; HYP, P = 5.30 x 10(-8), OR = 0.67). Carriers of the minor allele A had a decreased risk of hypertension. A non-significant trend for association was also detected with severe family based hypertension in the BRIGHT sample (British). The novel susceptibility locus, CDH13, encodes for an adhesion glycoprotein T-cadherin, a regulator of vascular wall remodeling and angiogenesis. Its function is compatible with the BP biology and may improve the understanding of the pathogenesis of hypertension.
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    Polymorphisms in the WNK1 Gene Are Associated with Blood Pressure Variation and Urinary Potassium Excretion
    (PUBLIC LIBRARY SCIENCE, 2009) Newhouse, Stephen; Farrall, Martin; Wallace, Chris; Hoti, Mimoza; Burke, Beverley; Howard, Philip; Onipinla, Abiodun; Lee, Kate; Shaw Hawkins, Sue; Dobson, Richard; Brown, Morris; Samani, Nilesh J.; Dominiczak, Anna F.; Connell, John M.; Lathrop, G. Mark; Kooner, Jaspal; Chambers, John; Elliott, Paul; Clarke, Robert; Collins, Rory; Laan, Maris; Org, Elin; Juhanson, Peeter; Veldre, Gudrun; Viigimaa, Margus; Eyheramendy, Susana; Cappuccio, Francesco P.; Ji, Chen; Iacone, Roberto; Strazzullo, Pasquale; Kumari, Meena; Marmot, Michael; Brunner, Eric; Caulfield, Mark; Munroe, Patricia B.
    WNK1-a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control-is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively). The major allele (A) of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95% CI: 1.23-4.9), DBP 1.9 mmHg (95% CI: 0.7-3.2) and hypertension, odds ratio (OR: 1.3 [95% CI: 1.0-1.7]). We genotyped this variant in six independent populations (n = 14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p = 7 x 10(-3), combined with BRIGHT data-set p = 2 x 10(-4), n = 17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p<10(-7)). We identified several common haplotypes to be associated with increased BP and multiple low frequency haplotypes significantly associated with lower BP (>10 mmHg reduction) and risk for hypertension (OR<0.60). Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH.
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    SLC2A9 Is a High-Capacity Urate Transporter in Humans
    (PUBLIC LIBRARY SCIENCE, 2008) Caulfield, Mark J.; Munroe, Patricia B.; O'Neill, Deb; Witkowska, Kate; Charchar, Fadi J.; Doblado, Manuel; Evans, Sarah; Eyheramendy, Susana; Onipinla, Abiodun; Howard, Philip; Shaw Hawkins, Sue; Dobson, Richard J.; Wallace, Chris; Newhouse, Stephen J.; Brown, Morris; Connell, John M.; Dominiczak, Anna; Farrall, Martin; Lathrop, G. Mark; Samani, Nilesh J.; Kumari, Meena; Marmot, Michael; Brunner, Eric; Chambers, John; Elliott, Paul; Kooner, Jaspal; Laan, Maris; Org, Elin; Veldre, Gudrun; Viigimaa, Margus; Cappuccio, Francesco P.; Ji, Chen; Iacone, Roberto; Strazzullo, Pasquale; Moley, Kelle H.; Cheeseman, Chris
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