Saadatagah Seyedmohammad, Jose Merin, Dikilitas Ozan, Alhalabi Lubna, Miller Alexandra A, Fan Xiao, Olson Janet E, Kochan David C, Safarova Maya, Kullo Iftikhar J
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
NPJ Genom Med. 2021 Apr 14;6(1):28. doi: 10.1038/s41525-021-00190-z.
We investigated monogenic and polygenic causes of hypercholesterolemia in a population-based cohort, excluding secondary hypercholesterolemia, and using an established framework to identify pathogenic variants. We studied 1682 individuals (50.2 ± 8.6 years, 41.3% males) from southeast Minnesota with primary hypercholesterolemia (low-density lipoprotein cholesterol (LDL-C) ≥155 mg/dl in the absence of identifiable secondary causes). Familial hypercholesterolemia (FH) phenotype was defined as a Dutch Lipid Clinic Network (DLCN) score ≥6. Participants underwent sequencing of LDLR, APOB, and PCSK9, and genotyping of 12 LDL-C-associated single-nucleotide variants to construct a polygenic score (PGS) for LDL-C. The presence of a pathogenic/likely pathogenic variant was considered monogenic etiology and a PGS ≥90th percentile was considered polygenic etiology. The mean LDL-C level was 187.3 ± 32.3 mg/dl and phenotypic FH was present in 8.4% of the cohort. An identifiable genetic etiology was present in 17.1% individuals (monogenic in 1.5% and polygenic in 15.6%). Phenotypic and genetic FH showed poor overlap. Only 26% of those who met the clinical criteria of FH had an identifiable genetic etiology and of those with an identifiable genetic etiology only 12.9% met clinical criteria for FH. Genetic factors explained 7.4% of the variance in LDL-C. In conclusion, in adults with primary hypercholesterolemia, 17.1% had an identifiable genetic etiology and the overlap between phenotypic and genetic FH was modest.
我们在一个基于人群的队列中研究了高胆固醇血症的单基因和多基因病因，排除了继发性高胆固醇血症，并使用既定框架来识别致病变异。我们研究了来自明尼苏达州东南部的1682名原发性高胆固醇血症患者（年龄50.2±8.6岁，男性占41.3%），这些患者低密度脂蛋白胆固醇（LDL-C）≥155mg/dl且无明确的继发性病因。家族性高胆固醇血症（FH）表型定义为荷兰脂质诊所网络（DLCN）评分≥6。参与者接受了LDLR、APOB和PCSK9的测序，以及12个与LDL-C相关的单核苷酸变异的基因分型，以构建LDL-C的多基因评分（PGS）。存在致病性/可能致病性变异被视为单基因病因，PGS≥第90百分位数被视为多基因病因。平均LDL-C水平为187.3±32.3mg/dl，8.4%的队列存在表型FH。17.1%的个体存在可识别的遗传病因（单基因病因占1.5%，多基因病因占15.6%）。表型和遗传FH的重叠性较差。符合FH临床标准的患者中只有26%有可识别的遗传病因，而在有可识别遗传病因的患者中，只有12.9%符合FH临床标准。遗传因素解释了LDL-C变异的7.4%。总之，在原发性高胆固醇血症的成年人中，17.1%有可识别的遗传病因，表型和遗传FH之间的重叠程度适中。
