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. 2017 Jun 8;7(1):3119.
doi: 10.1038/s41598-017-03353-0.

Sequence Variant at 4q25 Near PITX2 Associates With Appendicitis

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Free PMC article

Sequence Variant at 4q25 Near PITX2 Associates With Appendicitis

Ragnar P Kristjansson et al. Sci Rep. .
Free PMC article

Abstract

Appendicitis is one of the most common conditions requiring acute surgery and can pose a threat to the lives of affected individuals. We performed a genome-wide association study of appendicitis in 7,276 Icelandic and 1,139 Dutch cases and large groups of controls. In a combined analysis of the Icelandic and Dutch data, we detected a single signal represented by an intergenic variant rs2129979 [G] close to the gene PITX2 associating with increased risk of appendicitis (OR = 1.15, P = 1.8 × 10-11). We only observe the association in patients diagnosed in adulthood. The marker is close to, but distinct from, a set of markers reported to associate with atrial fibrillation, which have been linked to PITX2. PITX2 has been implicated in determination of right-left symmetry during development. Anomalies in organ arrangement have been linked to increased prevalence of gastrointestinal and intra-abdominal complications, which may explain the effect of rs2129979 on appendicitis risk.

Conflict of interest statement

R.P.K., S.B., A.O., G.T., O.B.D., S.J., S.S., H.H., G.T., I.J., U.T., T.J., D.F.G., T.R., P.S., and K.S. who are affiliated with deCODE genetics/Amgen declare competing financial interests as employees. The remaining authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Manhattan plot for the combined Icelandic and Dutch appendicitis GWAS (N = 8,566). Only one region, 4q25, harbors a genome-wide significant signal. Variants are plotted by chromosomal position (x-axis) and -log10P values (y-axis). Individual Manhattan plots for the Icelandic and Dutch groups are shown in Supplementary Figures 4 and 5, respectively. Variants with P > 0.05 have been omitted.
Figure 2
Figure 2
Locus plot for combined Icelandic and Dutch data showing the association of rs2129979 and surrounding variants at 4q25 with appendicitis (N = 8,566). The leading variant is shown as a purple circle, and other variants are coloured according to correlation (r2) with the leading marker (legend at top-right). −log10P values are shown along the left y-axis, and correspond to the variants depicted in the plot. The right y-axis shows calculated recombination rates at the chromosomal location, plotted as a solid red line. PITX2 is located 177 kb upstream of rs2129979.
Figure 3
Figure 3
Effect of rs2129979 on appendicitis risk in Iceland. Age quintiles are shown on the x-axis, and odds ratio (OR) on the y-axis. The cases (N = 7,297) were stratified by age at diagnosis and logistic regression was performed per quintile with the same group of controls (N = 307,292), adjusting for sex and county. Each grey dot represents the OR of rs2129979 for individuals in the age group in question, and the error bars represent the 95% confidence intervals of the OR.
Figure 4
Figure 4
The associations of both rs2129979 (blue diamond) and rs6843082 (red diamond), and their correlated variants at 4q25, with appendicitis (above; N = 7,427) and atrial fibrillation (below; N = 13,471) in Iceland. Variants correlated to the leading variant appear in the same colour, with the degree of correlation represented by the colour saturation. Individual locus plots for the two phenotypes are shown in Supplementary Figures 6 and 7.

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