Major LOXL1 risk allele is reversed in exfoliation glaucoma in a black South African population
Major LOXL1 risk allele is reversed in exfoliation glaucoma in a black South African population
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发表时间：
2010-04
期刊：
影响因子：
2.2
通讯作者：
S. Williams;Benjamin T. Whigham;Yutao Liu;T. Carmichael;X. Qin;S. Schmidt;M. Ramsay;M. Hauser;R. Allingham;R. Allingham
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作者：
S. Williams;Benjamin T. Whigham;Yutao Liu;T. Carmichael;X. Qin;S. Schmidt;M. Ramsay;M. Hauser;R. Allingham;R. Allingham
目的研究南非祖先人群中赖氨酸氧化酶样1 （LOXL1）基因变异是否与脱落性青光眼（XFG）和原发性开角型青光眼（POAG）相关。方法采用标准的临床检查技术，从南非约翰内斯堡索韦托圣约翰眼科医院招募患有XFG、POAG的南非黑人受试者和年龄匹配的未受影响的对照组。XFG组、POAG组和正常对照组各收集50人。采用基于pcr的Sanger法对LOXL1的完整编码区进行测序。使用Fisher精确检验比较XFG或POAG与对照之间鉴定的序列变异的等位基因频率。结果鉴定出大量编码变异，包括rs1048661 （R141L）、rs3825942 （G153D）、S159A、S161L、rs41435250 （A320A）、rs13329473 （F489F）和T567A。XFG和南非对照受试者rs3825942和rs1048661等位基因频率差异显著（p分别=5.2×10−13和1.7×10−5）。rs1048661的G等位基因（编码精氨酸）是风险等位基因，与其他人群相似。rs3825942的A等位基因（编码天冬氨酸）是危险等位基因，与其他多个群体中报道的G等位基因（编码甘氨酸）形成鲜明对比。POAG与对照组之间LOXL1编码变异的等位基因频率差异无统计学意义。这是首次在非洲XFG祖先人群中进行LOXL1的遗传关联研究。我们已经证实了LOXL1和XFG变体之间的关联。迄今为止，主要易感变异rs3825942的G等位基因一直显示在多个人群中增加XFG的风险。令人惊讶的是，我们在南非人群中发现了与相反等位基因的强烈关联。这表明LOXL1的其他未知因果变异有助于XFG的遗传风险。
Purpose To investigate whether variants in the lysyl oxidase-like 1 (LOXL1) gene are associated with exfoliation glaucoma (XFG) and primary open-angle glaucoma (POAG) in an ancestral population from South Africa. Methods Black South African subjects with XFG, POAG, and age matched unaffected controls were recruited from the St. John Eye Hospital in Soweto, Johannesburg, South Africa, using standard clinical examination techniques. Fifty individuals were collected for each of the three groups: XFG, POAG, and normal controls. The complete coding region of LOXL1 was sequenced using the PCR-based Sanger method. The allele frequencies of the identified sequence variants were compared between XFG or POAG and controls using Fisher’s exact test. Results A large number of coding variants were identified, including rs1048661 (R141L), rs3825942 (G153D), S159A, S161L, rs41435250 (A320A), rs13329473 (F489F), and T567A. The allele frequencies of both rs3825942 and rs1048661 differed significantly between the XFG and control subjects from South Africa (p=5.2×10−13 and 1.7×10−5, respectively). The G allele for rs1048661 (encoding arginine) was the risk allele which is similar to other populations. The A allele of rs3825942 (encoding aspartic acid) was the risk allele, in sharp contrast to the G allele (encoding glycine) reported in multiple other populations. There was no significant difference in the allele frequencies of coding variants in LOXL1 between POAG and control subjects. Conclusions This represents the first genetic association study of LOXL1 in an ancestral African population with XFG. We have confirmed the association between variants of LOXL1 and XFG. To date, the G allele of the major susceptibility variant rs3825942 has consistently been shown in multiple populations to increase the risk of XFG. Surprisingly, we have found a strong association with the opposite allele in the South African population. This suggests that other as yet unknown causal variants of LOXL1 contribute to the genetic risk of XFG.