Genome-wide association studies identified a locus on chromosome 4q21.1, spanning the FAM47E, STBD1, CCDC158, and SHROOM3 genes, as associated with kidney function markers. Functional studies implicated SHROOM3, encoding an actin-binding protein involved in cell shaping, into podocyte barrier damage. Despite the locus was also found associated with electrolytes, hematological and cardiovascular traits, systematic explorations of functional variants across all the genes in the locus are lacking. We reconstructed haplotypes covering the whole locus on 12,834 participants to the Cooperative Health Research in South Tyrol (CHRIS) study, using genotypes imputed on a whole-exome sequencing reference panel of a subsample of 3,422 participants. Haplotypes included 146 exonic and intronic variants over the four genes and were tested for association with 73 serum, urine and anthropometric traits, 172 serum metabolite and 148 plasma protein concentrations using linear regression models. We identified 11 haplotypes with 2% to 24% frequency. Compared to the most common haplotype, most haplotypes were associated with higher levels of the creatinine-based estimated glomerular filtration rate and lower serum magnesium levels. The second most common haplotype (12% frequency) was additionally associated with lower dodecanoyl-, hydroxyvaleryl- and tiglyl-carnitine serum concentrations. A haplotype of 4% frequency was also associated with lower red blood cell count, hemoglobin, and hematocrit levels. A haplotype of 2% frequency was associated with serum glutamine and putrescine concentrations. Cluster analysis revealed distinct groups of traits and of haplotypes. The FAM47E-SHROOM3 locus exhibits haplotype variability that corresponds to marked pleiotropic effects, implicating the existence of population subgroups with distinct biomarker profiles.

中文翻译：

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一般人群样本中 FAM47E-SHROOM3 单倍型组成的表型谱

全基因组关联研究确定了染色体 4q21.1 上的一个位点，涵盖 FAM47E、STBD1、CCDC158 和 SHROOM3 基因，与肾功能标志物相关。功能研究表明 SHROOM3（编码参与细胞塑造的肌动蛋白结合蛋白）与足细胞屏障损伤有关。尽管还发现该基因座与电解质、血液学和心血管特征相关，但缺乏对该基因座中所有基因的功能变异的系统探索。我们使用对 3,422 名参与者子样本的全外显子组测序参考组推算的基因型，重建了覆盖南蒂罗尔合作健康研究 (CHRIS) 研究的 12,834 名参与者整个基因座的单倍型。单倍型包括四个基因的 146 个外显子和内含子变异，并使用线性回归模型测试了其与 73 种血清、尿液和人体测量特征、172 种血清代谢物和 148 种血浆蛋白浓度的关联。我们鉴定了 11 种频率为 2% 至 24% 的单倍型。与最常见的单倍型相比，大多数单倍型与基于肌酐的估计肾小球滤过率水平较高和血清镁水平较低相关。第二个最常见的单倍型（频率为 12%）还与较低的十二酰肉碱、羟基戊酰肉碱和替甘酰肉碱血清浓度相关。频率为 4% 的单倍型也与较低的红细胞计数、血红蛋白和血细胞比容水平相关。频率为 2% 的单倍型与血清谷氨酰胺和腐胺浓度相关。聚类分析揭示了不同的特征组和单倍型。 FAM47E-SHROOM3 基因座表现出与显着的多效性效应相对应的单倍型变异性，暗示存在具有不同生物标志物特征的群体亚群。