Targeted re-sequencing of linkage region on 2q21 identifies a novel functional variant for hip and knee osteoarthritis
Targeted re-sequencing of linkage region on 2q21 identifies a novel functional variant for hip and knee osteoarthritis
复制标题
2q21 连锁区的靶向重测序确定了髋关节和膝关节骨关节炎的新功能变异
DOI：
10.1016/j.joca.2015.10.019
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发表时间：
2016
影响因子：
7
通讯作者：
Mannikko M
中科院分区：
文献类型：
--
作者：
Taipale M;Jakkula E;Kamarainen O P;Gao P;Skarp S;Barral S;Kiviranta I;Kroger H;Ott J;Wei G H;Ala Kokko L;Mannikko M
该研究的目的是确定遗传变异诱发原发性髋关节和膝关节骨关节炎（OA）在芬兰family.MethodsGenome广泛的分析使用15个独立的家庭（279人），来自芬兰中部确定为有多个人与原发性髋关节和/或膝关节OA。对来自一个对LOD评分贡献最显著的33个成员、四代家族的三个样品进行靶向再测序。此外，外显子组测序进行了三个家庭成员从同一family.ResultsGenome全基因组连锁分析确定了一个易感位点的染色体2 q21与多点LOD得分为3.91。靶向重测序和随后的连锁分析揭示了易感性插入变异rs 11446594。在显性遗传模式下，它位于预测的强增强子元件区域，最大LOD值为3.42。插入产生ELF 3和HMGA 1转录因子的识别序列。他们的DNA结合亲和力是高度增加的A-等位基因相比，野生型null allele.ConclusionA潜在的新功能OA易感性变异的存在下，有针对性的重新测序。该变体位于预测的调控位点，并产生预测在关节软骨稳态中发挥重要作用的ELF 3和HMGA 1转录因子的识别序列。
ObjectiveThe aim of the study was to identify genetic variants predisposing to primary hip and knee osteoarthritis (OA) in a sample of Finnish families.MethodsGenome wide analysis was performed using 15 independent families (279 individuals) originating from Central Finland identified as having multiple individuals with primary hip and/or knee OA. Targeted re-sequencing was performed for three samples from one 33-member, four-generation family contributing most significantly to the LOD score. In addition, exome sequencing was performed in three family members from the same family.ResultsGenome wide linkage analysis identified a susceptibility locus on chromosome 2q21 with a multipoint LOD score of 3.91. Targeted re-sequencing and subsequent linkage analysis revealed a susceptibility insertion variant rs11446594. It locates in a predicted strong enhancer element region with maximum LOD score 3.42 under dominant model of inheritance. Insertion creates a recognition sequence for ELF3 and HMGA1 transcription factors. Their DNA-binding affinity is highly increased in the presence of A-allele compared to wild type null allele.ConclusionA potentially novel functional OA susceptibility variant was identified by targeted re-sequencing. This variant locates in a predicted regulatory site and creates a recognition sequence for ELF3 and HMGA1 transcription factors that are predicted to play a significant role in articular cartilage homeostasis.