Li Changwei, Bazzano Lydia A L, Rao Dabeeru C, Hixson James E, He Jiang, Gu Dongfeng, Gu Charles C, Shimmin Lawrence C, Jaquish Cashell E, Schwander Karen, Liu De-Pei, Huang Jianfeng, Lu Fanghong, Cao Jie, Chong Shen, Lu Xiangfeng, Kelly Tanika N
Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA.
Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA; Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
J Genet Genomics. 2015 Mar 20;42(3):107-17. doi: 10.1016/j.jgg.2015.02.003. Epub 2015 Feb 17.
We conducted a genome-wide linkage scan and positional association study to identify genes and variants influencing blood lipid levels among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. The GenSalt study was conducted among 1906 participants from 633 Han Chinese families. Lipids were measured from overnight fasting blood samples using standard methods. Multipoint quantitative trait genome-wide linkage scans were performed on the high-density lipoprotein, low-density lipoprotein, and log-transformed triglyceride phenotypes. Using dense panels of single nucleotide polymorphisms (SNPs), single-marker and gene-based association analyses were conducted to follow-up on promising linkage signals. Additive associations between each SNP and lipid phenotypes were tested using mixed linear regression models. Gene-based analyses were performed by combining P-values from single-marker analyses within each gene using the truncated product method (TPM). Significant associations were assessed for replication among 777 Asian participants of the Multi-ethnic Study of Atherosclerosis (MESA). Bonferroni correction was used to adjust for multiple testing. In the GenSalt study, suggestive linkage signals were identified at 2p11.2‒2q12.1 [maximum multipoint LOD score (MML) = 2.18 at 2q11.2] and 11q24.3‒11q25 (MML = 2.29 at 11q25) for the log-transformed triglyceride phenotype. Follow-up analyses of these two regions revealed gene-based associations of charged multivesicular body protein 3 (CHMP3), ring finger protein 103 (RNF103), AF4/FMR2 family, member 3 (AFF3), and neurotrimin (NTM) with triglycerides (P = 4 × 10(-4), 1.00 × 10(-5), 2.00 × 10(-5), and 1.00 × 10(-7), respectively). Both the AFF3 and NTM triglyceride associations were replicated among MESA study participants (P = 1.00 × 10(-7) and 8.00 × 10(-5), respectively). Furthermore, NTM explained the linkage signal on chromosome 11. In conclusion, we identified novel genes associated with lipid phenotypes in linkage regions on chromosomes 2 and 11.
我们进行了一项全基因组连锁扫描和定位关联研究，以在盐敏感性遗传流行病学网络（GenSalt）研究的参与者中识别影响血脂水平的基因和变异。GenSalt研究在来自633个汉族家庭的1906名参与者中进行。使用标准方法从过夜空腹血样中测量血脂。对高密度脂蛋白、低密度脂蛋白和对数转换后的甘油三酯表型进行了多点数量性状全基因组连锁扫描。使用密集的单核苷酸多态性（SNP）面板，进行单标记和基于基因的关联分析，以跟进有前景的连锁信号。使用混合线性回归模型测试每个SNP与血脂表型之间的加性关联。通过使用截短乘积法（TPM）合并每个基因内单标记分析的P值来进行基于基因的分析。在动脉粥样硬化多族裔研究（MESA）的777名亚洲参与者中评估显著关联的重复性。使用Bonferroni校正来调整多重检验。在GenSalt研究中，对于对数转换后的甘油三酯表型在2p11.2‒2q12.1[在2q11.2处最大多点LOD得分（MML）=2.18]和11q24.3‒11q25（在11q25处MML=2.29）发现了提示性连锁信号。对这两个区域的后续分析揭示了带电荷多囊泡体蛋白3（CHMP3）、环指蛋白103（RNF103）、AF4/FMR2家族成员3（AFF3）和神经调节蛋白（NTM）与甘油三酯的基于基因的关联（P分别为4×10⁻⁴、1.00×10⁻⁵、2.00×10⁻⁵和1.00×10⁻⁷）。AFF3和NTM与甘油三酯的关联在MESA研究参与者中均得到了重复（P分别为1.00×10⁻⁷和8.00×10⁻⁵）。此外，NTM解释了11号染色体上的连锁信号。总之，我们在2号和11号染色体的连锁区域中鉴定出了与血脂表型相关的新基因。
