Research Group Heussler (Malaria I) - Bernhard-Nocht-Institut für ...

Data of twin studies and evidence for ethnic differences
indicate a considerable influence of the host genetic
background on the susceptibility to H. pylori. To define
the infection state of humans, H. pylori reactive serum
IgG concentrations using whole bacterial lysates as
antigen have been found a reliable tool and have widely
been used in genetic and epidemiological studies.
Project Description and Results
The study group comprised 111 Senegalese siblings,
aged 5 to 60 years, forming 143 sibpairs of 34 nuclear
families. The participants were characterized regarding
their susceptibility to H.-pylori infection by determining
serum IgG reactive to whole H.-pylori lysates. For
control, serum anti-phosphorylcholine IgG, which is
produced in reaction to ubiquitous dental-plaque
bacteria, was measured and found not to be correlated
to anti-H. pylori IgG (r=0.12, p=0.2). The study group
was genetically typed with 400 genome-wide short-tandem-repeat
markers. A quantitative-trait linkage (QTL)
analysis using as phenotypes the levels of anti-H. pylori
IgG yielded a broad peak covering approximately 90 cM
on the long arm of chromosome 6 and a maximum LOD
score of 2.4 at marker position D6S1009 (Figure 1).
As D6S1009 is located less than 1 cM apart from the
IFNGR1 gene encoding chain 1 of the IFN-g receptor
and as IFN-γ has been implicated in host defence to
helicobacter infection, an additional marker FA1
located in intron 6 of IFNGR1 was included in the
analysis. This raised the LOD score to 3.4. Sequencing
of the entire IFNGR1 gene in 20 siblings with extreme
phenotypes revealed a number of genetic variants, of
which –56C->T, H318P, and L450P were found
associated with high antibody concentrations in a
transmission diseqilibrium test applied to 111 parent-
Figure 2: Schematic representation of possible influences of
IFNGR1 variants on signalling by the IFNγ receptor: Promoter
variants may cause reduced expression as indicated by the grey
colour of the schematic receptor structure, and structural variants
in the C-terminal, cytoplasmatic tail of the receptor might alter
the accessibility of the tyrosin (Y) residue to be phosphorylated
by the receptor-bound janus kinases (JAK1, JAK2), as indicated
by kinks in the schematic receptor structure.
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child trios (p=0.03). Furthermore, including these
variants in the linkage analysis raised the LOD score to
4.2 and the information content of the markers from
0.73 to 0.94. The frequencies of –56C->T, H318P and
L450P were assessed in 100 chromosomes of unrelated
individuals each from the Senegalese study
population and from a German volunteer group; the
variants were found among Africans significantly more
frequently than among Germans (54 vs 36 affected
chromosomes, respectively).
Our findings confirm studies in animal models indicating
that IFN-γ signalling plays an essential role in the host
defence against H. pylori infection. The difference
between Senegalese and Germans in the frequencies
of the susceptibility alleles may contribute to explain
the „African enigma“ of high prevalences and relatively
low pathogenicity of H. pylori in African populations.
Moreover, our study provides further proof of principle
for the value of genome-wide linkage studies in the
analysis of susceptibility to infection and other complex
genetic traits.
Selected Publications
• Thye T, Burchard GD, Nilius M, Müller-Myhsok B,
Horstmann RD (2003).
Genome-wide linkage analysis identifies polymorphism
in the human interferon-y receptor affecting
Helicobacter pylori infection.
Am J Hum Genet 72: 448-453
Cooperating Partners
• Gerd D. Burchard, Clinical Department, BNI
• Manfred Nilius, University of Magdeburg
Investigators
• Thorsten Thye
• Rolf D. Horstmann,
• Bertram Müller-Myhsok
• Birgit Muntau
Tropical Medicine Section