Distribution of CFTR variations in an Indonesian enteric fever cohort.
BACKGROUND
Enteric fever is defined by circulating Salmonella serotype Typhi or Paratyphi in the blood. The first step in developing enteric fever is internalization of salmonellae in the gut epithelium. In in vitro experiments, attachment of S. Typhi to the cystic fibrosis transmembrane conductance regulator (CFTR) on the intestinal mucosa is crucial for bacterial uptake. We recently found a microsatellite polymorphism in the CFTR gene, IVS8CA, to be associated with susceptibility to enteric fever in a case-control study in Indonesia.


METHODS
To determine which functional variation in CFTR is associated with susceptibility to enteric fever, we sequenced all 27 exons of the CFTR gene in 25 individuals from Indonesia. Polymorphisms that occurred more than once were genotyped in the full enteric fever cohort of 116 case patients and 322 control subjects.


RESULTS
We identified 12 variants in, or adjacent to, the exons: 1 novel variant (L435V), 3 known mutations (N287K, I556V, Q1352H), and 8 known polymorphisms. Variations that occurred more than once were genotyped in the full cohort. The IVS8 TG(11)TG(12) genotype appears to provide some protection from acquiring enteric fever: having this protective genotype or a variation that is known to affect CFTR protein expression provides modest protection from enteric fever (odds ratio, 0.57; 95% confidence interval, 0.37-0.87; P<.01).


CONCLUSIONS
The findings demonstrate that a correlation exists between variations in the CFTR gene and protection from enteric fever. The IVS8CA polymorphism that was identified previously may, however, be the principal functional variation causing the difference in susceptibility.
van de Vosse
Esther
E
Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands. E.van_de_Vosse@LUMC.nl
de Visser
Adriëtte W
AW
Al-Attar
Sinan
S
Vossen
Rolf
R
Ali
Soegianto
S
van Dissel
Jaap T
JT
D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005091:Exons; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007214:Indonesia; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D014435:Typhoid Fever / Q000235:genetics*
C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator