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血液中的离子钙与钙敏感受体羧基末端尾部的聚集多态性相关。

Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor.

作者信息

Scillitani Alfredo, Guarnieri Vito, De Geronimo Simona, Muscarella Lucia Anna, Battista Claudia, D'Agruma Leonardo, Bertoldo Francesco, Florio Cinzia, Minisola Salvatore, Hendy Geoffrey N, Cole David E C

机构信息

Unit of Endocrinology, Hospital Casa Sollievo della Sofferenza, Istituto di Ricovero e Cura a Carattere Scientifico, viale dei Cappuccini, 71013 San Giovanni Rotondo (FG), Italy.

出版信息

J Clin Endocrinol Metab. 2004 Nov;89(11):5634-8. doi: 10.1210/jc.2004-0129.

Abstract

Blood ionized calcium (iCa) is a quantitative trait subject to genetic influence. iCa is maintained in a narrow range through the action of the calcium-sensing receptor (CASR) controlling PTH secretion and calcium excretion. A CASR single nucleotide polymorphism (SNP) prevalent in Caucasian populations (A986S) has shown significant association with iCa in a cohort of young women, but association with the neighboring SNPs, R990G and Q1011E, has not been examined. We studied 377 unrelated adults (184 men and 193 women) recruited as healthy adults from a blood donor clinic. The subjects were not taking any medications, nor did they have disorders of calcium metabolism. Relative frequencies for the CASR 986S, 990G, and 1011E minor alleles were 24%, 4%, and 3% respectively. At the A986S locus, subjects with the AA genotype had significantly lower iCa (P = 0.0001) than subjects with one or two S alleles (mean +/- se, 1.221 +/- 0.003 vs. 1.239 +/- 0.003 mmol/liter). For the R990G site, subjects with the RR genotype had higher iCa than those with one copy of the 990G allele (1.230 +/- 0.002 vs. 1.213 +/- 0.007 mmol/liter; P = 0.032). With respect to the 1011 locus, iCa was lower in QQ genotype subjects than in the QE group (1.227 +/- 0.002 vs. 1.255 +/- 0.008 mmol/liter; P = 0.002). After resolution of phase for the doubly heterozygous subjects, analysis was conducted on haplotypes across all three loci. As expected, subjects with SRQ and ARE haplotypes are relatively hypercalcemic, and those with AGQ are hypocalcemic, relative to subjects with the common ARQ haplotype. Multiple regression analysis with clinical covariates (age, sex and menopausal status, creatinine, and PTH) showed that 16.5% of the total variance in iCa may be explained, and the seven CASR haplotypes contribute significantly (P < 0.0001) and substantially (49.1% of the explained variance) to the model, with the following corrected iCa means: ARQ/AGQ, 1.21 +/- 0.01; ARQ/ARQ, 1.22 +/- 0.01; ARQ/SRQ, 1.24 +/- 0.01; SRQ/AGQ, 1.24 +/- 0.03; SRQ/SRQ, 1.25 +/- 0.01; ARQ/ARE, 1.25 +/- 0.01; and SRQ/ARE, 1.27 +/- 0.01. Our data confirm the association between iCa and the A986S locus and suggest that R990G and Q1011E are also predictive. Given the significant between-population variations in frequency of variant alleles in this CASR SNP cluster, tri-locus haplotyping may prove to be more informative in studies of association between variation in CASR and disease.

摘要

血液离子钙(iCa)是一种受遗传影响的数量性状。通过控制甲状旁腺激素(PTH)分泌和钙排泄的钙敏感受体(CASR)的作用,iCa维持在一个狭窄的范围内。在白种人群体中普遍存在的一种CASR单核苷酸多态性(SNP)(A986S)在一组年轻女性中显示出与iCa有显著关联,但尚未研究其与相邻SNP,即R990G和Q1011E的关联。我们研究了从一家献血诊所招募的377名无亲缘关系的成年人(184名男性和193名女性),这些人被招募时均为健康成年人。受试者未服用任何药物,也没有钙代谢紊乱。CASR 986S、990G和1011E次要等位基因的相对频率分别为24%、4%和3%。在A986S位点,AA基因型的受试者的iCa显著低于有一个或两个S等位基因的受试者(P = 0.0001)(均值±标准误,1.221±0.003 vs. 1.239±0.003 mmol/升)。对于R990G位点,RR基因型的受试者的iCa高于有一个990G等位基因拷贝的受试者(1.230±0.002 vs. 1.213±0.007 mmol/升;P = 0.032)。关于1011位点,QQ基因型受试者的iCa低于QE组(1.227±0.002 vs. 1.255±0.008 mmol/升;P = 0.002)。在对双重杂合受试者进行相位解析后,对所有三个位点的单倍型进行了分析。正如预期的那样,与常见的ARQ单倍型的受试者相比,具有SRQ和ARE单倍型的受试者相对血钙过高,而具有AGQ单倍型的受试者则血钙过低。对临床协变量(年龄、性别和绝经状态、肌酐和PTH)进行的多元回归分析表明,iCa总变异的16.5%可以得到解释,七种CASR单倍型对模型有显著贡献(P < 0.0001)且贡献很大(占解释变异的49.1%),校正后的iCa均值如下:ARQ/AGQ,1.21±0.01;ARQ/ARQ,1.22±0.01;ARQ/SRQ,1.24±0.01;SRQ/AGQ,1.24±0.03;SRQ/SRQ,1.25±0.01;ARQ/ARE,1.25±0.01;以及SRQ/ARE,1.27±0.01。我们的数据证实了iCa与A986S位点之间的关联,并表明R990G和Q1011E也具有预测性。鉴于该CASR SNP簇中变异等位基因频率在不同人群之间存在显著差异,三位点单倍型分型在研究CASR变异与疾病之间的关联中可能会提供更多信息。

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