Kitsios Georgios D, Dahabreh Issa J, Trikalinos Thomas A, Schmid Christopher H, Huggins Gordon S, Kent David M
Institute for Clinical Research and Health Policy Studies, Tufts Medical Center and Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, MA 02111, USA.
Circ Cardiovasc Genet. 2011 Feb;4(1):58-67. doi: 10.1161/CIRCGENETICS.110.957738. Epub 2010 Dec 13.
Variability in phenotypic characterization of coronary artery disease (CAD) may contribute to the heterogeneity of genetic association studies, and more consistency in phenotype definitions might improve replication of genetic associations. We assessed the extent of phenotypic heterogeneity and quantified its impact in a large literature sample of association studies.
We searched for large (≥15 studies) meta-analyses of genetic associations and reviewed all studies included therein. From each primary study, we extracted phenotypic definitions, demographics, study design characteristics, and genotypic data. For each association, we assessed the magnitude and heterogeneity of genetic effects within and across CAD phenotypes, using meta-analytic methodologies. A total of 965 individual studies investigating 32 distinct variants in 22 genes were included, from which we grouped CAD phenotypes into 3 categories: acute coronary syndromes (ACS) (426 [44%] studies); angiographically documented disease (323 [34%] studies); and broad, not otherwise specified CAD (216 [22%] studies). These clinical phenotypes were overlapping. Subgroup meta-analyses by phenotype showed discordant results, but phenotypic classification generally explained small proportions of between-study heterogeneity. Differences between phenotypic groups were minimized for associations with robust statistical support. No CAD phenotype was consistently associated with larger or more homogeneous genetic effects in meta-analyses.
Substantial phenotypic heterogeneity exists in CAD genetic associations, but differences in phenotype definition make a small contribution to between-study heterogeneity. We did not find a consistent effect in terms of the magnitude or homogeneity of summary effects for a specific phenotype to support its preferential use in genetic studies or meta-analyses for CAD.
冠状动脉疾病（CAD）表型特征的变异性可能导致基因关联研究的异质性，而表型定义的更高一致性可能会改善基因关联的重复性。我们评估了表型异质性的程度，并在大量关联研究的文献样本中量化了其影响。
我们搜索了大型（≥15项研究）基因关联的荟萃分析，并审查了其中包含的所有研究。从每项原始研究中，我们提取了表型定义、人口统计学、研究设计特征和基因型数据。对于每一项关联，我们使用荟萃分析方法评估CAD表型内和跨CAD表型的基因效应的大小和异质性。总共纳入了965项个体研究，这些研究调查了22个基因中的32个不同变体，从中我们将CAD表型分为3类：急性冠状动脉综合征（ACS）（426项[44%]研究）；血管造影记录的疾病（323项[34%]研究）；以及广泛的、未另行指定的CAD（216项[22%]研究）。这些临床表型相互重叠。按表型进行的亚组荟萃分析显示结果不一致，但表型分类通常只能解释研究间异质性的一小部分。对于具有强有力统计支持的关联而言，表型组之间的差异被最小化。在荟萃分析中，没有一种CAD表型始终与更大或更一致的基因效应相关。
CAD基因关联中存在大量表型异质性，但表型定义的差异对研究间异质性的贡献较小。我们未发现特定表型在汇总效应的大小或一致性方面存在一致的效应，以支持其在CAD基因研究或荟萃分析中的优先使用。
