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Sequence variant at 4q25 near PITX2 associates with appendicitis.

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.

SUBMITTER: Kristjansson RP

PROVIDER: S-EPMC5465083 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Sequence variant at 4q25 near PITX2 associates with appendicitis.

Kristjansson Ragnar P RP Benonisdottir Stefania S Oddsson Asmundur A Galesloot Tessel E TE Thorleifsson Gudmar G Aben Katja K KK Davidsson Olafur B OB Jonsson Stefan S Arnadottir Gudny A GA Jensson Brynjar O BO Walters G Bragi GB Sigurdsson Jon K JK Sigurdsson Snaevar S Holm Hilma H Arnar David O DO Thorgeirsson Gudmundur G Alexiusdottir Kristin K Jonsdottir Ingileif I Thorsteinsdottir Unnur U Kiemeney Lambertus A LA Jonsson Thorvaldur T Gudbjartsson Daniel F DF Rafnar Thorunn T Sulem Patrick P Stefansson Kari K

Scientific reports 20170608 1

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<su ...[more]

PMID: 28596592

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Project description:AimsSingle nucleotide polymorphisms on chromosome 4q25 have been associated with risk of atrial fibrillation (AF) but the exiguous knowledge of the mechanistic links between these risk variants and underlying electrophysiological alterations hampers their clinical utility. Here, we tested the hypothesis that 4q25 risk variants cause alterations in the intracellular calcium homoeostasis that predispose to spontaneous electrical activity.Methods and resultsWestern blotting, confocal calcium imaging, and patch-clamp techniques were used to identify mechanisms linking the 4q25 risk variants rs2200733T and rs13143308T to defects in the calcium homoeostasis in human atrial myocytes. Our findings revealed that the rs13143308T variant was more frequent in patients with AF and that myocytes from carriers of this variant had a significantly higher density of calcium sparks (14.1 ± 4.5 vs. 3.1 ± 1.3 events/min, P = 0.02), frequency of transient inward currents (ITI) (1.33 ± 0.24 vs. 0.26 ± 0.09 events/min, P < 0.001) and incidence of spontaneous membrane depolarizations (1.22 ± 0.26 vs. 0.56 ± 0.17 events/min, P = 0.001) than myocytes from patients with the normal rs13143308G variant. These alterations were linked to higher sarcoplasmic reticulum calcium loading (10.2 ± 1.4 vs. 7.3 ± 0.5 amol/pF, P = 0.01), SERCA2 expression (1.37 ± 0.13 fold, P = 0.03), and RyR2 phosphorylation at ser2808 (0.67 ± 0.08 vs. 0.47 ± 0.03, P = 0.01) but not at ser2814 (0.28 ± 0.14 vs. 0.31 ± 0.14, P = 0.61) in patients carrying the rs13143308T risk variant. Furthermore, the presence of a risk variant or AF independently increased the ITI frequency and the increase in the ITI frequency observed in carriers of the risk variants was exacerbated in those with AF. By contrast, the presence of a risk variant did not affect the amplitude or properties of the L-type calcium current in patients with or without AF.ConclusionsHere, we identify the 4q25 variant rs13143308T as a genetic risk marker for AF, specifically associated with excessive calcium release and spontaneous electrical activity linked to increased SERCA2 expression and RyR2 phosphorylation.

Dataset Information

Sequence variant at 4q25 near PITX2 associates with appendicitis.

Publications

Sequence variant at 4q25 near PITX2 associates with appendicitis.

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