Biology Reference
In-Depth Information
Besides our studies, one genome-wide linkage study considered IgE
levels specific to Ascaris as part of an overall assessment of the genetics of
allergen-specific IgE levels in relation to asthma.
52
A total of 653 family
members from eight large pedigrees from Costa Rica were characterized
for both IgE specific to Ascaris and 387 STR markers spaced across the
autosomes. The heritability of IgE specific to Ascaris was 0.33 indicating
that approximately one-third of the variation was attributable to genetic
factors. The linkage analysis revealed a suggestive linkage of IgE to
Ascaris on chromosome 7q (LOD 2.72) at a position of 153 cM.
As outlined above, to date, six QTLs have been unambiguously linked
to risk for Ascaris infection.
44,45
In addition, four suggestive linkages for
genes influencing traits related to Ascaris infection have been found.
45,52
FURTHER ASSOCIATION MAPPING OF THE
CHROMO
SOME 13 QTL USING HIGH DEN
SITY SNPs
Recent technological advances have dramatically changed the search
for genes influencing complex traits such as risk for Ascaris infection.
Rather than having only about 400 markers spaced across the genome, it
is now possible to type hundreds of thousands of SNPs in large numbers
of samples very efficiently and cost effectively. Following up on our
linkage signal on chromosome 13, we typed 912 people for a total of
500,000 SNPs using the Illumina 660W-Quad DNA analysis kit. For the
purposes of this chapter, we focus only on the chromosome 13 QTL
region in an attempt to fine-map this QTL in hopes of identifying the
underlying causal gene(s). We employed a standard measured genotype
analysis for each SNP allowing for residual heritability as described
above.
Figure 12.2
shows the results of our QTL region-specific associa-
tion analyses in the approximately 10.25 Mb corresponding to the 13 cM
QTL linkage support interval. In this region, we typed a total of 2387
SNP markers that passed quality control procedures. In
Figure 12.2
,
the solid horizontal line shows the cut-off for QTL region-wide signifi-
cance accounting for the number of effectively independent tests
(a procedure which also takes into account the LD between SNPs). One
significant association result stands out involving the SNP rs12866842.
The minor allele of this SNP was associated with increased worm burden
(p
10
6
). This SNP is located in an intergenic region between the
TNFSF13B and IRS2 genes. Both of these genes are viable candidates for
a gene influencing susceptibility to Ascaris infection. We have long noted
the potential role of TNFSF13B and its potential relevance for helminthic
infection has been described above. IRS2 is important in nitric oxide
(NO) production, an important mediator of inflammation. Our localiza-
tion results from linkage analysis and QTL region-specific association
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