McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Department of Genetic Medicine, Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Am J Hum Genet. 2022 Oct 6;109(10):1894-1908. doi: 10.1016/j.ajhg.2022.09.004.
Individuals with cystic fibrosis (CF) develop complications of the gastrointestinal tract influenced by genetic variants outside of CFTR. Cystic fibrosis-related diabetes (CFRD) is a distinct form of diabetes with a variable age of onset that occurs frequently in individuals with CF, while meconium ileus (MI) is a severe neonatal intestinal obstruction affecting ∼20% of newborns with CF. CFRD and MI are slightly correlated traits with previous evidence of overlap in their genetic architectures. To better understand the genetic commonality between CFRD and MI, we used whole-genome-sequencing data from the CF Genome Project to perform genome-wide association. These analyses revealed variants at 11 loci (6 not previously identified) that associated with MI and at 12 loci (5 not previously identified) that associated with CFRD. Of these, variants at SLC26A9, CEBPB, and PRSS1 associated with both traits; variants at SLC26A9 and CEBPB increased risk for both traits, while variants at PRSS1, the higher-risk alleles for CFRD, conferred lower risk for MI. Furthermore, common and rare variants within the SLC26A9 locus associated with MI only or CFRD only. As expected, different loci modify risk of CFRD and MI; however, a subset exhibit pleiotropic effects indicating etiologic and mechanistic overlap between these two otherwise distinct complications of CF.
个体患有囊性纤维化 (CF) 会出现胃肠道并发症，这受 CFTR 以外的遗传变异影响。囊性纤维化相关性糖尿病 (CFRD) 是一种独特形式的糖尿病，其发病年龄具有可变性，在 CF 患者中较为常见，而胎粪性肠梗阻 (MI) 是一种严重的新生儿肠梗阻，影响约 20%的 CF 新生儿。CFRD 和 MI 是略微相关的特征，之前的研究表明它们的遗传结构存在重叠。为了更好地了解 CFRD 和 MI 之间的遗传共性，我们使用 CF 基因组计划的全基因组测序数据进行全基因组关联分析。这些分析揭示了与 MI 相关的 11 个位点（6 个以前未识别出）和与 CFRD 相关的 12 个位点（5 个以前未识别出）的变异。其中，SLC26A9、CEBPB 和 PRSS1 位点的变异与这两种疾病都有关联；SLC26A9 和 CEBPB 位点的变异增加了这两种疾病的风险，而 PRSS1 位点的变异，即 CFRD 的高风险等位基因，降低了 MI 的风险。此外，SLC26A9 基因座内的常见和罕见变异仅与 MI 或 CFRD 相关。正如预期的那样，不同的位点改变 CFRD 和 MI 的风险；然而，一部分表现出多效性效应，表明这两种 CF 截然不同的并发症之间存在病因和机制上的重叠。
