Zemunik Tatijana, Boban Mladen, Lauc Gordan, Janković Stipan, Rotim Kresimir, Vatavuk Zoran, Bencić Goran, Dogas Zoran, Boraska Vesna, Torlak Vesela, Susac Jelena, Zobić Ivana, Rudan Diana, Pulanić Drazen, Modun Darko, Mudnić Ivana, Gunjaca Grgo, Budimir Danijela, Hayward Caroline, Vitart Veronique, Wright Alan F, Campbell Harry, Rudan Igor
University of Split School of Medicine, Soltanska 2, 21000 Split, Croatia.
Croat Med J. 2009 Feb;50(1):23-33. doi: 10.3325/cmj.2009.50.23.
To identify genetic variants underlying biochemical traits--total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, uric acid, albumin, and fibrinogen, in a genome-wide association study in an isolated population where rare variants of larger effect may be more easily identified.
The study included 944 adult inhabitants of the island of Korcula, as a part of larger DNA-based genetic epidemiological study in 2007. Biochemical measurements were performed in a single laboratory with stringent internal and external quality control procedures. Examinees were genotyped using Human Hap370CNV chip by Illumina, with a genome-wide scan containing 346027 single nucleotide polymorphisms (SNP).
A total of 31 SNPs were associated with 7 investigated traits at the level of P<1.00 x 10(-5). Nine of SNPs implicated the role of SLC2A9 in uric acid regulation (P=4.10 x 10(-6)-2.58 x 10(-12)), as previously found in other populations. All 22 remaining associations fell into the P=1.00 x 10(-5)-1.00 x 10(-6) significance range. One of them replicated the association between cholesteryl ester transfer protein (CETP) and HDL, and 7 associations were more than 100 kilobases away from the closest known gene. Nearby SNPs, rs4767631 and rs10444502, in gene kinase suppressor of ras 2 (KSR2) on chromosome 12 were associated with LDL cholesterol levels, and rs10444502 in the same gene with total cholesterol levels. Similarly, rs2839619 in gene PBX/knotted 1 homeobox 1 (PKNOX1) on chromosome 21 was associated with total and LDL cholesterol levels. The remaining 9 findings implied possible associations between phosphatidylethanolamine N-methyltransferase (PEMT) gene and total cholesterol; USP46, RAP1GDS1, and ZCCHC16 genes and triglycerides; BCAT1 and SLC14A2 genes and albumin; and NR3C2, GRIK2, and PCSK2 genes and fibrinogen.
Although this study was underpowered for most of the reported associations to reach formal threshold of genome-wide significance under the assumption of independent multiple testing, replications of previous findings and consistency of association between the identified variants and more than one studied trait make such findings interesting for further functional follow-up studies. Changed allele frequencies in isolate population may contribute to identifying variants that would not be easily identified in much larger samples in outbred populations.
在一个隔离人群的全基因组关联研究中，识别影响生化性状（总胆固醇、低密度脂蛋白（LDL）胆固醇、高密度脂蛋白（HDL）胆固醇、甘油三酯、尿酸、白蛋白和纤维蛋白原）的基因变异，在这样一个隔离人群中，可能更容易识别出具有较大效应的罕见变异。
该研究纳入了科尔丘拉岛的944名成年居民，作为2007年一项更大规模的基于DNA的遗传流行病学研究的一部分。生化检测在一个单一实验室进行，采用了严格的内部和外部质量控制程序。受试者使用Illumina公司的Human Hap370CNV芯片进行基因分型，全基因组扫描包含346027个单核苷酸多态性（SNP）。
共有31个SNP在P<1.00×10⁻⁵水平与7个研究性状相关。其中9个SNP表明SLC2A9在尿酸调节中的作用（P=4.10×10⁻⁶ - 2.58×10⁻¹²），这与之前在其他人群中发现的一致。其余22个关联均处于P=1.00×10⁻⁵ - 1.00×10⁻⁶的显著范围内。其中一个重复了胆固醇酯转运蛋白（CETP）与HDL之间的关联，7个关联距离最接近的已知基因超过100千碱基。位于12号染色体上的ras 2激酶抑制基因（KSR2）附近的SNP，rs4767631和rs10444502，与LDL胆固醇水平相关，同一基因中的rs10444502与总胆固醇水平相关。同样，位于21号染色体上的PBX/knotted 1同源盒1基因（PKNOX1）中的rs2839619与总胆固醇和LDL胆固醇水平相关。其余9项发现暗示了磷脂酰乙醇胺N-甲基转移酶（PEMT）基因与总胆固醇之间可能存在关联；USP46、RAP1GDS1和ZCCHC16基因与甘油三酯之间可能存在关联；BCAT1和SLC
