Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor
Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor
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DOI：
10.1210/jc.2004-0129
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发表时间：
2004-11-01
影响因子：
5.8
通讯作者：
Cole, DEC
中科院分区：
文献类型：
--
作者：
Scillitani, A;Guarnieri, V;Cole, DEC
血液离子钙（伊卡）是一个受遗传影响的数量性状。通过控制PTH分泌和钙排泄的钙敏感受体（CASR）的作用，将伊卡维持在一个狭窄的范围内。在一组年轻女性中，一种在高加索人群中普遍存在的CASR单核苷酸多态性（SNP）（A986 S）与伊卡钙显著相关，但与邻近SNP（R990 G和Q1011 E）的相关性尚未研究。我们研究了377名无关的成年人（184名男性和193名女性），他们是从献血者诊所招募的健康成年人。受试者没有服用任何药物，也没有钙代谢紊乱。CASR 986 S、990 G和1011 E次要等位基因的相对频率分别为24%、4%和3%。在A986 S位点，AA基因型受试者的伊卡（P=0.0001）显著低于具有一个或两个S等位基因的受试者（平均值+/-SE，1.221+/-0.003 mmol/L vs. 1.239+/-0.003 mmol/L）。对于R990 G位点，具有RR基因型的受试者的伊卡比具有一个拷贝的990 G等位基因的受试者更高（1.230+/-0.002 vs. 1.213+/-0.007 mmol/L; P=0.032）。关于1011位点，QQ基因型受试者的伊卡比QE组低（1.227+/-0.002 mmol/L vs. 1.255+/-0.008 mmol/L; P=0.002）。双杂合子受试者的相位解析后，对所有三个基因座的单倍型进行分析。正如预期的那样，相对于具有共同ARQ单倍型的受试者，具有SRQ和ARE单倍型的受试者是相对高钙的，而具有AGQ的受试者是低钙的。对临床协变量（年龄、性别和绝经状态、肌酐和PTH）的多元回归分析显示，伊卡总变异的16.5%可以解释，7种CASR单倍型贡献显著（P
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