Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy
Linkage disequilibrium pattern and age-at-diagnosis are critical for replicating genetic associations across ethnic groups in leprosy
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DOI：
10.1007/s00439-012-1227-6
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发表时间：
2013-01-01
期刊：
影响因子：
5.3
通讯作者：
Schurr, Erwin
中科院分区：
文献类型：
--
作者：
Alter, Andrea;Fava, Vinicius Medeiros;Schurr, Erwin
遗传关联研究的持续挑战之一是跨种族群体复制遗传标记-疾病关联。在这里，我们进行了PARK 2/PACRG单核苷酸多态性与麻风病的高密度关联定位，并确定了69个单核苷酸多态性显着相关的198例越南麻风病家庭。共有56个相关的SNPs定位于PARK 2/PACRG的重叠启动子区域。对于该区域，多变量分析确定了属于两个主要SNP箱（rs 1333955，rs7744433）和两个单个SNP箱（rs 2023004，rs6936895）的四个SNP，这些SNP捕获了越南患者之间相关性的组合统计学证据（P = 1.1 x 10（-5））。接下来，我们从北方印度招募了364例麻风病例和370例对照的病例对照样本。我们对所有受试者进行了149个SNP的基因分型，这些SNP捕获了越南样本中> 80%的遗传变异，并发现24个SNP与麻风病显著相关。多因素分析发现3个SNPs（rs 1333955、rs 9356058和rs 2023004）与麻风病相关（P < 10（-8））。因此，两个SNPs（rs 1333955和rs 2023004）在两个种族群体之间通过多变量分析重复。连锁不平衡模式的显着差异解释了两个民族之间的单变量分析的一些差异。此外，在越南样本中，两个启动子区域SNP仓的关联强度在年轻麻风患者中显著更强。在印度样本中也观察到了同样的趋势，但由于患者的诊断年龄较高，年龄效应不太明显。
One of the persistent challenges of genetic association studies is the replication of genetic marker-disease associations across ethnic groups. Here, we conducted high-density association mapping of PARK2/PACRG SNPs with leprosy and identified 69 SNPs significantly associated with leprosy in 198 single-case Vietnamese leprosy families. A total of 56 associated SNPs localized to the overlapping promoter regions of PARK2/PACRG. For this region, multivariate analysis identified four SNPs belonging to two major SNP bins (rs1333955, rs7744433) and two single SNP bins (rs2023004, rs6936895) that capture the combined statistical evidence (P = 1.1 x 10(-5)) for association among Vietnamese patients. Next, we enrolled a case-control sample of 364 leprosy cases and 370 controls from Northern India. We genotyped all subjects for 149 SNPs that capture > 80 % of the genetic variation in the Vietnamese sample and found 24 SNPs significantly associated with leprosy. Multivariate analysis identified three SNPs (rs1333955, rs9356058 and rs2023004) that capture the association with leprosy (P < 10(-8)). Hence, two SNPs (rs1333955 and rs2023004) were replicated by multivariate analysis between both ethnic groups. Marked differences in the linkage disequilibrium pattern explained some of the differences in univariate analysis between the two ethnic groups. In addition, the strength of association for two promoter region SNP bins was significantly stronger among young leprosy patients in the Vietnamese sample. The same trend was observed in the Indian sample, but due to the higher age-at-diagnosis of the patients the age effect was less pronounced.