Inherited Variants in the COL11A, COL1A, COL5A1, COMP, GSTM1 Genes and the Risk of Carpal Tunnel Syndrome

Abstract

The pathogenesis of most cases of carpal tunnel syndrome is not clearly defined. There are some aspects of the disease that suggest a potential effect of genetic predispositions. Mutations (variants) within the genes encoding various subtypes of collagen synthesis, oligomerisation in the endoplasmic reticulum and inactivation of reactive oxygen species may be involved in the development of carpal tunnel syndrome. The objective of this study was to determine the role of DNA alterations within the COL11A, COL1A, COL5A1, COMP and GSTM1 genes in the pathogenesis of carpal tunnel syndrome based on a Polish population. Study design. In the discovery phase, a total of 96 patients with familial aggregation of CTS were genotyped using a Next Generation Sequencing panel in order to find possible mutations within the studied genes. The potential pathogenicity of the detected variants was investigated using the predictions of several in-silico algorithms and the TaqMan technology. In the association phase of the study, a group of 345 CTS patients and 1035 healthy controls were genotyped. Results. A total of 35 splice-site or exonic non-synonymous variants were detected by NGS. We did not identify any clearly pathogenic or likely pathogenic alternations. The 30 variants were identified as benign or likely benign. Five missense changes were predicted as VUS and selected for association study. The COL5A1 c.1595 C>T (p.Ala532Val) was detected in one out of 345 cases and three out of 1035 controls (P=1, OR=1); this indicates that the variant is a neutral alteration. Four remaining variants – c.2840 C>A, c.5395 G>A, c.1331 C>G, c.1590 C>A – were present in none out of the 345 CTS patients and none out of 1035 controls. Conclusion. The main finding of this study was that there was no independent association between the variants of five examined genes and carpal tunnel syndrome. Four uncertain variants were identified that seem to be extremely rare in the Polish population.

Zusammenfassung

Die Pathogenese der meisten Fälle von Karpaltunnelsyndrom ist nicht eindeutig bestimmt. Es gibt einige Aspekte der Krankheit, die auf die mögliche Wirkung genetischer Veranlagungen hindeuten. Mutationen (Varianten) innerhalb der Gene, die für verschiedene Subtypen der Kollagensynthese, die Oligomerisierung im endoplasmatischen Retikulum und die Inaktivierung reaktiver Sauerstoffspezies kodieren, können an der Entwicklung des Karpaltunnelsyndroms beteiligt sein. Das Ziel dieser Studie war es, die Rolle von DNA-Veränderungen in den Genen COL11A, COL1A, COL5A1, COMP und GSTM1 bei der Pathogenese des Karpaltunnelsyndroms anhand einer polnischen Population zu bestimmen. Studiendesign. In der Entdeckungsphase wurden insgesamt 96 Patienten mit familiärer Aggregation von CTS mit einem Next Generation Sequencing-Panel genotypisiert, um mögliche Mutationen innerhalb der untersuchten Gene zu finden. Die potenzielle Pathogenität der detektierten Varianten wurde mit Hilfe der Vorhersagen mehrerer In-silico-Algorithmen und des TaqMan untersucht. In der Assoziationsphase der Studie wurde eine Gruppe von 345 CTS-Patienten und 1035 gesunden Kontrollpersonen genotypisiert. Befund. Insgesamt wurden 35 Spleißstellen- oder exonische nicht-synonyme Varianten durch NGS nachgewiesen. Wir identifizierten keine eindeutig pathogenen oder wahrscheinlichen pathogenen Veränderungen. Die 30 Varianten wurden als gutartig oder wahrscheinlich gutartig identifiziert. Fünf Missense-Veränderungen wurden als VUS vorhergesagt und für die Assoziationsstudie ausgewählt. Das COL5A1 c.1595 C>T (p.Ala532Val) wurde in einem von 345 Fällen und drei von 1035 Kontrollen (P=1, OR=1) nachgewiesen und weist auf eine neutrale Veränderung hin. Vier verbleibende Varianten: c.2840 C>A, c.5395 G>A, c.1331 C>G, c.1590 C>A waren bei keinem der 345 CTS-Patienten und keiner von 1035 Kontrollen vorhanden. Schlussfolgerung. Das Hauptergebnis dieser Studie war, dass es keinen unabhängigen Zusammenhang zwischen den Varianten von fünf untersuchten Genen und dem Karpaltunnelsyndrom gab. Es wurden vier unsichere Varianten identifiziert, die in der polnischen Bevölkerung äußerst selten zu sein scheinen.

Keywords

carpal tunnel syndrome aetiology - genetic predispositions - COL genes - COMP genes - GSTM1 genes

Schlüsselwörter

Karpaltunnelsyndrom Ätiologie - genetische Veranlagungen - COL-Gene - COMP-Gene - GSTM1-Gene

Publication History

Received: 13 January 2024

Accepted: 19 July 2024

Article published online:
27 September 2024

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