Rs17618244

rs17618244, a coding SNP that is known as Arg728Gln in the Klotho-beta (KLB) gene involved in the regulation of bile acid synthesis, gives rise to both the rs17618244(G) (Arg728) and rs17618244(A) (Gln728) alleles. KLB encodes a type I membrane protein that is similar to the protein product of Klotho (41.2% identical to the amino acid sequence of Klotho), which has been previously shown to affect mouse aging and longevity. Both Klotho and KLB are members of the Klotho protein family, which can be classified under the glycosidase family 1 superfamily.

The major allele rs17618244(G) is associated with markedly decreased protein stability and increased colonic transit in patients with diarrhea-pre-dominant irritable bowel syndrome (IBS-D), but not with any symptom-based subgroups of IBS. In a study in which 400 patients with IBS-D, constipation-pre-dominant irritable bowel syndrome (IBS-C), or alternating-type IBS were compared against nearly 300 healthy controls, the authors showed that the rs17618244(G) allele is significantly associated with accelerated 24-hour colonic transit compared to the rs17618244(A) allele in both the overall cohort (P= .0007) and the IBS-D cohort (P= .0018). Bonferroni cutoff values (of ?= 0.0033 and ?= 0.0125, respectively) were used to correct for multiple comparisons, and results were also adjusted for prior cholecystectomy status. Of the 15 SNPs tested, only rs17618244 yielded statistically significant results. At 48 hours, the association was less but still statistically significant after multiple hypothesis testing corrections: for the overall cohort P= .025, and for the IBS-D cohort P= .0113. Using a protein stability assay, it was determined that the t&#189; for KLB rs17618244(G) is about 3 hours while the t&#189; for KLB rs17618244(A) is >10 hours, thus demonstrating the functional effects of KLB rs17618244. The FGF19-FGFR4-KLB (fibroblast growth factor; FGF) pathway is involved in the down-regulation of bile acid synthesis: KLB interacts with FGFR4 to upregulate FGF19-mediated inhibition of bile acid production. By extension, decreased KLB rs17618244 stability leads to ileal bile absorption overload secondary to excess bile production and release, thus resulting in accelerated colonic transit and diarrhea. As such, the authors hypothesized that KLB rs17618244 might interact with one or more of three identified FGFR4 coding SNPs. For IBS-D patients, 24-hour colonic transit association with KLB rs17618244 corresponded with significant interactions between KLB rs17618244 and either FGFR4 rs1966265 (Val10Ile, P= .0025) or FGFR4 rs351855 (Gly388Arg, P= .0023). Results were corrected for multiple comparisons using the Bonferroni method.

The rs17618244(G) allele is also associated with greater sodium chenodeoxycholate (CDC) response in IBS-C patients. A small study involving 36 female patients with IBS-C showed that CDC, which normally accelerates colonic transit, only works at a high oral dose of 1,000mg daily for four days for rs17618244(G;A) rs17618244(A;A) patients but at both low and high doses (500mg and 1,000mg daily dose for four days, respectively) for rs17618244(G;G) patients. Through a genotype-by-treatment stratification for the IBS-C female patients, the authors demonstrated that the rs17618244(G) allele is significantly associated with accelerated ascending colonic transit compared to the rs17618244(A) allele (uncorrected P= .0088). In this study, 15 SNPs were tested and only KLB rs17618244 and one other SNP showed a statistically significant association. The authors suggest that this genetic association can be utilized to pre-screen IBS patients more likely to be responsive to CDC pharmacotherapy.