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281.
Rare independent mutations in renal salt handling genes contribute to blood pressure variation 总被引:1,自引:0,他引:1
Ji W Foo JN O'Roak BJ Zhao H Larson MG Simon DB Newton-Cheh C State MW Levy D Lifton RP 《Nature genetics》2008,40(5):592-599
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. 相似文献
282.
Yeager M Orr N Hayes RB Jacobs KB Kraft P Wacholder S Minichiello MJ Fearnhead P Yu K Chatterjee N Wang Z Welch R Staats BJ Calle EE Feigelson HS Thun MJ Rodriguez C Albanes D Virtamo J Weinstein S Schumacher FR Giovannucci E Willett WC Cancel-Tassin G Cussenot O Valeri A Andriole GL Gelmann EP Tucker M Gerhard DS Fraumeni JF Hoover R Hunter DJ Chanock SJ Thomas G 《Nature genetics》2007,39(5):645-649
Recently, common variants on human chromosome 8q24 were found to be associated with prostate cancer risk. While conducting a genome-wide association study in the Cancer Genetic Markers of Susceptibility project with 550,000 SNPs in a nested case-control study (1,172 cases and 1,157 controls of European origin), we identified a new association at 8q24 with an independent effect on prostate cancer susceptibility. The most significant signal is 70 kb centromeric to the previously reported SNP, rs1447295, but shows little evidence of linkage disequilibrium with it. A combined analysis with four additional studies (total: 4,296 cases and 4,299 controls) confirms association with prostate cancer for rs6983267 in the centromeric locus (P = 9.42 x 10(-13); heterozygote odds ratio (OR): 1.26, 95% confidence interval (c.i.): 1.13-1.41; homozygote OR: 1.58, 95% c.i.: 1.40-1.78). Each SNP remained significant in a joint analysis after adjusting for the other (rs1447295 P = 1.41 x 10(-11); rs6983267 P = 6.62 x 10(-10)). These observations, combined with compelling evidence for a recombination hotspot between the two markers, indicate the presence of at least two independent loci within 8q24 that contribute to prostate cancer in men of European ancestry. We estimate that the population attributable risk of the new locus, marked by rs6983267, is higher than the locus marked by rs1447295 (21% versus 9%). 相似文献
283.
Haiman CA Patterson N Freedman ML Myers SR Pike MC Waliszewska A Neubauer J Tandon A Schirmer C McDonald GJ Greenway SC Stram DO Le Marchand L Kolonel LN Frasco M Wong D Pooler LC Ardlie K Oakley-Girvan I Whittemore AS Cooney KA John EM Ingles SA Altshuler D Henderson BE Reich D 《Nature genetics》2007,39(5):638-644
After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 x 10(-19) for the strongest association, and P < 1.5 x 10(-4) for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein. 相似文献
284.
Williams ES Stap J Essers J Ponnaiya B Luijsterburg MS Krawczyk PM Ullrich RL Aten JA Bailey SM 《Nature genetics》2007,39(6):696-8; author reply 698-9
285.
Clee SM Yandell BS Schueler KM Rabaglia ME Richards OC Raines SM Kabara EA Klass DM Mui ET Stapleton DS Gray-Keller MP Young MB Stoehr JP Lan H Boronenkov I Raess PW Flowers MT Attie AD 《Nature genetics》2006,38(6):688-693
We previously mapped the type 2 diabetes mellitus-2 locus (T2dm2), which affects fasting insulin levels, to distal chromosome 19 in a leptin-deficient obese F2 intercross derived from C57BL/6 (B6) and BTBR T+ tf/J (BTBR) mice. Introgression of a 7-Mb segment of the B6 chromosome 19 into the BTBR background (strain 1339A) replicated the reduced insulin linked to T2dm2. The 1339A mice have markedly impaired insulin secretion in vivo and disrupted islet morphology. We used subcongenic strains derived from 1339A to localize the T2dm2 quantitative trait locus (QTL) to a 242-kb segment comprising the promoter, first exon and most of the first intron of the Sorcs1 gene. This was the only gene in the 1339A strain for which we detected amino acid substitutions and expression level differences between mice carrying B6 and BTBR alleles of this insert, thereby identifying variation within the Sorcs1 gene as underlying the phenotype associated with the T2dm2 locus. SorCS1 binds platelet-derived growth factor, a growth factor crucial for pericyte recruitment to the microvasculature, and may thus have a role in expanding or maintaining the islet vasculature. Our identification of the Sorcs1 gene provides insight into the pathway underlying the pathophysiology of obesity-induced type 2 diabetes mellitus. 相似文献
286.
Oliver B 《Nature genetics》2006,38(10):1101-1102
287.
Jo-Anne Chan Katherine B. Howell Christine Langer Alexander G. Maier Wina Hasang Stephen J. Rogerson Michaela Petter Joanne Chesson Danielle I. Stanisic Michael F. Duffy Brian M. Cooke Peter M. Siba Ivo Mueller Peter C. Bull Kevin Marsh Freya J.I. Fowkes James G. Beeson 《Cellular and molecular life sciences : CMLS》2016,73(21):4141-4158
288.
A transformation which allows Cholesky decomposition to be used to evaluate the exact likelihood function of an ARIMA model with missing data has recently been suggested. This method is extended to allow calculation of finite sample predictions of future observations. The output from the exact likelihood evaluation may also be used to estimate missing series values. Copyright © 1999 John Wiley & Sons, Ltd. 相似文献
289.
水体沉积物是水中许多有毒有害污染物质的主要归宿地,但同时在适当的条件下也会重新向水体释放而成为水体中污染物的重要来源。因此,沉积物和水体之间的相互作用是揭示污染物质在水体中迁移转化规律的核心问题,是研究污染物质在天然水体中环境行为的热点之一。 相似文献
290.
Thomas G Jacobs KB Yeager M Kraft P Wacholder S Orr N Yu K Chatterjee N Welch R Hutchinson A Crenshaw A Cancel-Tassin G Staats BJ Wang Z Gonzalez-Bosquet J Fang J Deng X Berndt SI Calle EE Feigelson HS Thun MJ Rodriguez C Albanes D Virtamo J Weinstein S Schumacher FR Giovannucci E Willett WC Cussenot O Valeri A Andriole GL Crawford ED Tucker M Gerhard DS Fraumeni JF Hoover R Hayes RB Hunter DJ Chanock SJ 《Nature genetics》2008,40(3):310-315