He Bing, Osterholm Anne-May, Hoverfält Anna, Forsblom Carol, Hjörleifsdóttir Eyrún Edda, Nilsson Ann-Sofie, Parkkonen Maikki, Pitkäniemi Janne, Hreidarsson Astrádur, Sarti Cinzia, McKnight Amy Jayne, Maxwell A Peter, Tuomilehto Jaakko, Groop Per-Henrik, Tryggvason Karl
Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
Am J Hum Genet. 2009 Jan;84(1):5-13. doi: 10.1016/j.ajhg.2008.11.012. Epub 2008 Dec 11.
Diabetic nephropathy (DN) is the primary cause of morbidity and mortality in patients with type 1 diabetes mellitus (T1DM) and affects about 30% of these patients. We have previously localized a DN locus on chromosome 3q with suggestive linkage in Finnish individuals. Linkage to this region has also been reported earlier by several other groups. To fine map this locus, we conducted a multistage case-control association study in T1DM patients, comprising 1822 cases with nephropathy and 1874 T1DM patients free of nephropathy, from Finland, Iceland, and the British Isles. At the screening stage, we genotyped 3072 tag SNPs, spanning a 28 Mb region, in 234 patients and 215 controls from Finland. SNPs that met the significance threshold of p < 0.01 at this stage were followed up by a series of sample sets. A genetic variant, rs1866813, in the noncoding region at 3q22 was associated with increased risk of DN (overall p = 7.07 x 10(-6), combined odds ratio [OR] of the allele = 1.33). The estimated genotypic ORs of this variant in all Finnish samples suggested a codominant effect, resulting in significant association, with a p value of 4.7 x 10(-5) (OR = 1.38; 95% confidence interval = 1.18-1.62). Additionally, an 11 kb segment flanked by rs62408925 and rs1866813, two strongly correlated variants (r(2) = 0.95), contains three elements highly conserved across multiple species. Independent replication will clarify the role of the associated variants at 3q22 in influencing the risk of DN.
糖尿病肾病（DN）是1型糖尿病（T1DM）患者发病和死亡的主要原因，约30%的此类患者会受其影响。我们之前在芬兰人群中通过连锁分析将一个DN基因座定位到3号染色体长臂上。其他几个研究小组此前也报道过与该区域存在连锁关系。为了精细定位这个基因座，我们在T1DM患者中开展了一项多阶段病例对照关联研究，研究对象包括来自芬兰、冰岛和不列颠群岛的1822例肾病患者以及1874例无肾病的T1DM患者。在筛查阶段，我们对来自芬兰的234例患者和215例对照进行基因分型，检测了跨越28 Mb区域的3072个标签单核苷酸多态性（tag SNP）。在此阶段达到p < 0.01显著水平阈值的SNP会在一系列样本集中进行后续研究。位于3q22非编码区的一个基因变异rs1866813与DN风险增加相关（总体p = 7.07 x 10⁻⁶，该等位基因的合并比值比[OR] = 1.33）。在所有芬兰样本中，该变异的估计基因型OR提示存在共显性效应，导致显著关联，p值为4.7 x 10⁻⁵（OR = 1.38；95%置信区间 = 1.18 - 1.62）。此外，由两个强相关变异rs62408925和rs1866813（r² = 0.95）侧翼的一个11 kb片段包含三个在多个物种中高度保守的元件。独立重复研究将阐明3q22处相关变异在影响DN风险中的作用。
