Kriszt Agnes, Losonczy Gergely, Berta András, Vereb György, Takács Lili
Department of Ophthalmology, University of Debrecen Medical and Health Science Center, Debrecen, Hungary; Department of Biophysics and Cell Biology, University of Debrecen Medical and Health Science Center, Debrecen, Hungary.
Acta Ophthalmol. 2014 Nov;92(7):e562-8. doi: 10.1111/aos.12389. Epub 2014 Mar 16.
Complex segregation analysis of 60 unrelated sporadic keratoconus (KC) families was performed to reveal the presumed mode of inheritance in our dataset.
Sixty probands, 212 family members and 212 age and gender matched healthy controls underwent clinical and videokeratographic examination. Family aggregation and distribution of videokeratography parameters were examined. Segregation of KSI, KISA and 6mm Fourier asymmetry alone or in covariate analysis with gender or the presence of Fleischer ring, exploring mendelian and non-mendelian models of inheritance was tested using complex segregation analysis with the S.A.G.E. program package.
In 145 relatives of probands, the estimated prevalence of manifest KC was 7.6% (95% CI: 3.3-11.9) based on KISA index, indicating strong familial aggregation. All examined videokeratography indices were able to differentiate between KC and non-KC family members as well as normal controls (anova p < 0.001). Hypotheses accepted as most parsimonius models of inheritance (p > 0.1) for all indices indicated the presence of a non-mendelian major gene effect (MG). Inclusion of Fleischer ring as covariate improved the fit of MG models. Mendelian, Sporadic and polygenic models were consistently rejected.
Complex segregation analysis indicates a strong genetic contribution to the transmission of keratoconus. Inheritance is most probably due to a non-mendelian major gene effect. Low genotype-phenotype correlation in sporadic KC families can make linkage studies difficult, thus genome wide association studies, epigenetic and pathway analyses may provide more information on disease pathogenesis in non-familial keratoconus.
对60个无亲缘关系的散发性圆锥角膜（KC）家族进行复杂分离分析，以揭示我们数据集中推测的遗传模式。
60名先证者、212名家庭成员以及212名年龄和性别匹配的健康对照者接受了临床和角膜地形图检查。检查了家族聚集情况以及角膜地形图参数的分布。单独或在与性别或Fleischer环的存在进行协变量分析中，对角膜散光指数（KSI）、角膜散光不对称指数（KISA）和6mm傅里叶不对称性进行分离分析，使用S.A.G.E.程序包进行复杂分离分析，以检验孟德尔和非孟德尔遗传模式。
在先证者的145名亲属中，基于KISA指数估计的明显圆锥角膜患病率为7.6%（95%可信区间：3.3 - 11.9），表明存在强烈的家族聚集性。所有检查的角膜地形图指数都能够区分圆锥角膜家族成员和非圆锥角膜家族成员以及正常对照者（方差分析p < 0.001）。所有指数被接受为最简约遗传模式（p > 0.1）的假设表明存在非孟德尔主基因效应（MG）。将Fleischer环作为协变量纳入可改善MG模型的拟合度。孟德尔、散发性和多基因模型均被一致拒绝。
复杂分离分析表明圆锥角膜的遗传因素对其传递有很强的影响。遗传方式很可能是由于非孟德尔主基因效应。散发性圆锥角膜家族中低基因型 - 表型相关性可能使连锁研究变得困难，因此全基因组关联研究、表观遗传学和通路分析可能会为非家族性圆锥角膜的疾病发病机制提供更多信息。
