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To the Editor:

In their relevant study, Zweers et al.1 demonstrate that fibroblast growth factor (FGF19) is secreted by human gallbladder epithelial cells. This novel intestinal hormone is also released by ileal enterocytes into the portal circulation in response to bile salt absorption. In target organs, FGF19 binds to FGF receptor 4 (FGFR4) and its coreceptor Klotho-β (KLB), which results in feedback inhibition of hepatic bile salt synthesis and might also stimulate mucin expression. Zweers et al.1 point out that it is unexplored whether genetic variation within the FGF19-FGFR4-KLB axis contributes to cholelithiasis.

Recently, functional FGFR4-KLB variants have been identified.2 To investigate their relevance for gallstone disease, we genotyped common FGFR4 (rs351855, rs376618) and KLB (rs17618244) variants in a cohort of 239 gallstone patients from 107 families (age range, 24-80 years; 86% women) and 248 stone-free controls (age range, 21-78 years; 93% women); patient characteristics of the incipient cohort were reported in Hepatology.3

Table 1 shows that the KLB genotype [AA] is more prevalent in cases than controls. Therefore, we tested for associations between genotypes and gallstone disease using contingency tables (allele frequency difference/positivity, heterozygous/homozygous carriers).3 Individuals who are homozygous for the minor allele [A] are at increased risk of developing gallstones (odds ratio, 3.23; 95% confidence interval, 1.32-7.92; P = 0.007) as compared to carriers of genotype [GG]. Departure of the KLB genotype distribution from Hardy-Weinberg equilibrium in cases (exact test, P < 0.001; Supplementary Fig. 1 rpar; but not in controls supports the association of the KLB polymorphism with gallstones. However, nonparametric linkage analysis in affected sibs3 was negative (P > 0.05). In contrast to the KLB variant, both FGFR4 variants are not associated with gallstones in our cohort (data not shown).

Table 1. KLB Genotype Distribution in Gallstone Carriers and Controls
 CasesControls
  1. Cases: single sibs randomly selected from each sib pair with gallstones; controls: gallstone-free individuals (confirmed by abdominal ultrasound).

[GG]68 (64%)152 (61%)
[GA]26 (24%)87 (35%)
[AA]13 (12%)9 (4%)

In conclusion, this study supports the functional link between KLB and gallstone disease, as suggested by Zweers et al.1 Interestingly, carriers of the KLB risk allele [A] display longer small intestinal transit times as compared to homozygous carriers of the common allele.2 Because slow intestinal transit increases the cholelithogenic state due to hyperabsorption of cholesterol and synthesis of secondary hydrophobic bile salts such as deoxycholate,4 we speculate that intestinal hypomotility contributes to gallstone susceptibility in carriers of the KLB risk variant.

References

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  • 1
    Zweers SJ, Booij KA, Komuta M, Roskams T, Gouma DJ, Jansen PL, et al. The human gallbladder secretes fibroblast growth factor 19 into bile: towards defining the role of fibroblast growth factor 19 in the enterobiliary tract. Hepatology 2012; 55: 575-583.
  • 2
    Wong BS, Camilleri M, Carlson PJ, Guicciardi ME, Burton D, McKinzie S, et al. A Klothobeta variant mediates protein stability and associates with colon transit in irritable bowel syndrome with diarrhea. Gastroenterology 2011; 140: 1934-1942.
  • 3
    Grünhage F, Acalovschi M, Tirziu S, Walier M, Wienker TF, Ciocan A, et al. Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol. Hepatology 2007; 46: 793-801.
  • 4
    Thomas LA, Veysey MJ, Bathgate T, King A, French G, Smeeton NC, et al. Mechanism for the transit-induced increase in colonic deoxycholic acid formation in cholesterol cholelithiasis. Gastroenterology 2000; 119: 806-815.

Marcin Krawczyk M.D.*, Monica Acalovschi M.D.†, Frank Lammert M.D.*, * Department of Medicine II, Saarland University Medical Center, Hamburg, Germany, † Department of Medicine III, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.