Suviolahti Elina, Oksanen Laura J, Ohman Miina, Cantor Rita M, Ridderstrale Martin, Tuomi Tiinamaija, Kaprio Jaakko, Rissanen Aila, Mustajoki Pertti, Jousilahti Pekka, Vartiainen Erkki, Silander Kaisa, Kilpikari Riika, Salomaa Veikko, Groop Leif, Kontula Kimmo, Peltonen Leena, Pajukanta Päivi
Department of Human Genetics, University of California, Los Angeles, USA.
J Clin Invest. 2003 Dec;112(11):1762-72. doi: 10.1172/JCI17491.
In our previous genome-wide scan of Finnish nuclear families, obesity was linked to chromosome Xq24. Here we analyzed this 15-Mb region by genotyping 9 microsatellite markers and 36 single nucleotide polymorphisms (SNPs) for 11 positional and functional candidate genes in an extended sample of 218 obese Finnish sibling pairs (sibpairs) (BMI > 30 kg/m2). Evidence of linkage emerged mainly from the obese male sibpairs, suggesting a gender-specific effect for the underlying gene. By constructing haplotypes among the obese male sibpairs, we restricted the region from 15 Mb to 4 Mb, between markers DXS8088 and DXS8067. Regional functional candidate genes were tested for association in an initial sample of 117 cases and 182 controls. Significant evidence was observed for association for an SNP in the 3'-untranslated region of the solute carrier family 6 member 14 (SLC6A14) gene (P = 0.0002) and for SNP haplotypes of the SLC6A14 gene (P = 0.0007-0.006). Furthermore, an independent replication study sample of 837 cases and 968 controls from Finland and Sweden also showed significant differences in allele frequencies between obese and non-obese individuals (P = 0.003). The SLC6A14 gene is an interesting novel candidate for obesity because it encodes an amino acid transporter, which potentially regulates tryptophan availability for serotonin synthesis and thus possibly affects appetite control.
在我们之前对芬兰核心家庭进行的全基因组扫描中，肥胖与X染色体q24区域相关联。在此，我们通过对218对肥胖芬兰同胞对（同胞对）（BMI>30 kg/m²）的扩展样本中的11个定位和功能候选基因进行9个微卫星标记和36个单核苷酸多态性（SNP）基因分型，分析了这个15兆碱基区域。连锁证据主要来自肥胖男性同胞对，表明潜在基因存在性别特异性效应。通过构建肥胖男性同胞对之间的单倍型，我们将区域从15兆碱基缩小到标记DXS8088和DXS8067之间的4兆碱基。在117例病例和182例对照的初始样本中，对区域功能候选基因进行了关联测试。观察到溶质载体家族6成员14（SLC6A14）基因3'-非翻译区的一个SNP存在显著关联证据（P = 0.0002）以及SLC6A14基因的SNP单倍型存在显著关联证据（P = 0.0007 - 0.006）。此外，来自芬兰和瑞典的837例病例和968例对照的独立重复研究样本也显示肥胖个体与非肥胖个体之间的等位基因频率存在显著差异（P = 0.003）。SLC6A14基因是肥胖的一个有趣的新候选基因，因为它编码一种氨基酸转运蛋白，可能调节色氨酸用于血清素合成的可用性，从而可能影响食欲控制。
