Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
International Centre for Diarrhoeal Disease Research, Bangladesh, Dhaka, Bangladesh.
J Infect Dis. 2023 Oct 18;228(8):979-989. doi: 10.1093/infdis/jiad068.
Diarrhea is the second leading cause of death in children under 5 years old worldwide. Known diarrhea risk factors include sanitation, water sources, and pathogens but do not fully explain the heterogeneity in frequency and duration of diarrhea in young children. We evaluated the role of host genetics in diarrhea.
Using 3 well-characterized birth cohorts from an impoverished area of Dhaka, Bangladesh, we compared infants with no diarrhea in the first year of life to those with an abundance, measured by either frequency or duration. We performed a genome-wide association analysis for each cohort under an additive model and then meta-analyzed across the studies.
For diarrhea frequency, we identified 2 genome-wide significant loci associated with not having any diarrhea, on chromosome 21 within the noncoding RNA AP000959 (C allele odds ratio [OR] = 0.31, P = 4.01 × 10-8), and on chromosome 8 within SAMD12 (T allele OR = 0.35, P = 4.74 × 10-7). For duration of diarrhea, we identified 2 loci associated with no diarrhea, including the same locus on chromosome 21 (C allele OR = 0.31, P = 1.59 × 10-8) and another locus on chromosome 17 near WSCD1 (C allele OR = 0.35, P = 1.09 × 10-7).
These loci are in or near genes involved in enteric nervous system development and intestinal inflammation and may be potential targets for diarrhea therapeutics.
腹泻是全球 5 岁以下儿童的第二大死亡原因。已知的腹泻危险因素包括卫生、水源和病原体，但不能完全解释幼儿腹泻频率和持续时间的异质性。我们评估了宿主遗传学在腹泻中的作用。
我们比较了孟加拉国达卡贫困地区三个特征良好的出生队列中，在生命的第一年没有腹泻的婴儿与那些腹泻频繁或持续时间长的婴儿。我们对每个队列在加性模型下进行了全基因组关联分析，然后对研究进行了荟萃分析。
对于腹泻频率，我们在 21 号染色体上发现了与没有任何腹泻相关的 2 个全基因组显著位点，位于非编码 RNA AP000959 内（C 等位基因的优势比 [OR] = 0.31，P = 4.01×10-8），以及 8 号染色体上的 SAMD12 内（T 等位基因 OR = 0.35，P = 4.74×10-7）。对于腹泻持续时间，我们发现了与没有腹泻相关的 2 个位点，包括 21 号染色体上的相同位点（C 等位基因 OR = 0.31，P = 1.59×10-8）和 17 号染色体上 WSCD1 附近的另一个位点（C 等位基因 OR = 0.35，P = 1.09×10-7）。
这些位点位于或靠近参与肠神经系统发育和肠道炎症的基因附近，可能是腹泻治疗的潜在靶点。
