Association of ion transporters with CLD.

Objective
The autosomal recessive disease congenital chloride diarrhea (CLD), caused by loss-of-function mutations in the solute carrier family 26 member 3 (SLC26A3) gene, shows association with inflammatory bowel disease (IBD). However, it is unclear whether IBD risk is associated with genetic or immune signatures. SLC26A3 interacts with several ion transporters linked to intestinal inflammation, such as cystic fibrosis transmembrane conductance regulator (CFTR) and solute carrier family 9 member 3 (SLC9A3) causing congenital sodium diarrhea. We hypothesized that other epithelial channels affecting intestinal salt balance might modulate CLD phenotype or IBD risk.
Materials and methods
We analyzed 495 gene variants within 33 ion transporters among 28 patients with CLD and 44,443 population controls.
Results
We found three intronic variants at or near the CFTR locus (rs17132543, rs2283054 and rs76622533) showing statistically significant (P < 1.42x10-5) associations with CLD.
Conclusions
These data demonstrate enrichment of rare variants at the CFTR locus in chromosomes harboring the Finnish founder mutation for CLD.

研究目的：
由溶质载体家族26成员3（solute carrier family 26 member 3, SLC26A3）基因功能丧失突变引发的常染色体隐性遗传病先天性氯化物腹泻（congenital chloride diarrhea, CLD），与炎症性肠病（inflammatory bowel disease, IBD）存在关联。但目前尚不明确IBD风险是否与遗传或免疫特征相关。SLC26A3可与多种与肠道炎症相关的离子转运蛋白相互作用，例如囊性纤维化跨膜传导调节因子（cystic fibrosis transmembrane conductance regulator, CFTR）以及可导致先天性钠腹泻的溶质载体家族9成员3（solute carrier family 9 member 3, SLC9A3）。本研究假设，其他影响肠道盐平衡的上皮通道可能会调控CLD表型或IBD风险。
材料与方法：
本研究对28例CLD患者与44443名人群对照者的33种离子转运蛋白内的495个基因变异进行了分析。
结果：
本研究发现CFTR基因座及其附近的3个内含子变异（rs17132543、rs2283054与rs76622533）与CLD具有统计学意义上的显著关联（P < 1.42×10^-5）。
结论：
本研究数据表明，在携带芬兰CLD奠基者突变的染色体中，CFTR基因座存在罕见变异富集现象。