Institute of Human Genetics, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
Eur J Hum Genet. 2013 Apr;21(4):410-4. doi: 10.1038/ejhg.2012.193. Epub 2012 Aug 29.
Restless legs syndrome (RLS) is a common multifactorial disease. Some genetic risk factors have been identified. RLS susceptibility also has been related to iron. We therefore asked whether known iron-related genes are candidates for association with RLS and, vice versa, whether known RLS-associated loci influence iron parameters in serum. RLS/control samples (n = 954/1814 in the discovery step, 735/736 in replication 1, and 736/735 in replication 2) were tested for association with SNPs located within 4 Mb intervals surrounding each gene from a list of 111 iron-related genes using a discovery threshold of P = 5 × 10(-4). Two population cohorts (KORA F3 and F4 with together n = 3447) were tested for association of six known RLS loci with iron, ferritin, transferrin, transferrin-saturation, and soluble transferrin receptor. Results were negative. None of the candidate SNPs at the iron-related gene loci was confirmed significantly. An intronic SNP, rs2576036, of KATNAL2 at 18q21.1 was significant in the first (P = 0.00085) but not in the second replication step (joint nominal P-value = 0.044). Especially, rs1800652 (C282Y) in the HFE gene did not associate with RLS. Moreover, SNPs at the known RLS loci did not significantly affect serum iron parameters in the KORA cohorts. In conclusion, the correlation between RLS and iron parameters in serum may be weaker than assumed. Moreover, in a general power analysis, we show that genetic effects are diluted if they are transmitted via an intermediate trait to an end-phenotype. Sample size formulas are provided for small effect sizes.
不宁腿综合征（RLS）是一种常见的多因素疾病。已经确定了一些遗传风险因素。RLS 易感性也与铁有关。因此，我们想知道已知的与铁有关的基因是否是与 RLS 相关的候选基因，反之亦然，已知的与 RLS 相关的基因座是否会影响血清中的铁参数。在发现阶段，RLS/对照组样本（n = 954/1814）和复制 1 阶段（n = 735/736）、复制 2 阶段（n = 736/735）分别在一个包含 111 个铁相关基因的列表中，针对位于每个基因周围 4 Mb 区间内的 SNP 进行了与 RLS 相关的基因座与铁、铁蛋白、转铁蛋白、转铁蛋白饱和度和可溶性转铁蛋白受体的关联测试，发现阈值为 P = 5 × 10(-4)。使用两个人群队列（KORA F3 和 F4，共 n = 3447）测试了六个已知 RLS 基因座与铁、铁蛋白、转铁蛋白、转铁蛋白饱和度和可溶性转铁蛋白受体的关联，结果为阴性。在铁相关基因座的候选 SNP 中，没有一个被证实是显著的。在 18q21.1 处的 KATNAL2 基因的内含子 SNP rs2576036 在第一阶段是显著的（P = 0.00085），但在第二阶段复制中并不显著（联合名义 P 值 = 0.044）。特别是，HFE 基因中的 rs1800652（C282Y）与 RLS 无关。此外，在 KORA 队列中，已知 RLS 基因座的 SNP 也没有显著影响血清铁参数。总之，RLS 与血清铁参数之间的相关性可能比假设的要弱。此外，在一般的功效分析中，我们表明，如果遗传效应通过中间性状传递到终表型，那么遗传效应就会被稀释。提供了小效应量的样本量公式。
