Genetic Variation in Circadian Rhythm Genes CLOCK and ARNTL as Risk Factor for Male Infertility

Alenka Hodžić,Borut Peterlin,Cane Tulić,Momčilo Ristanović,Ivana Novaković,Aleš Maver,Branko Zorn,Francesc Palau

doi:10.1371/journal.pone.0059220

Alenka Hodžić, Borut Peterlin + Show 6 more

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https://doi.org/10.1371/journal.pone.0059220

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Abstract

BackgroundThe circadian system has a major role in maintaining homeostasis and proper body functions including reproductive capacity. The aim of this study was to examine whether there is an association between genetic variability in the primary clock genes CLOCK and ARNTL and male infertility in humans.Methodology/Principal FindingsWe performed a case-control study, where we searched for an association between polymorphisms of CLOCK and ARNTL genes and male infertility in 961 Slovenian and Serbian Caucasian men. The study group consisted of 517 patients with idiopathic infertility and a control group of 444 fertile men. A statistically significant difference was found in genotype distribution between the two groups in the CLOCK gene: rs11932595 (p = 6·10−5, q = 4·10−4, OR equaled 1.9 with 95% CI 1.4–2.7), rs6811520 (p = 2·10−3, q = 8·10−3, OR = 1.7 with 95% CI 1.2–2.2) and rs6850524 (p = 0.01, q = 0.02, OR = 1.4 with 95% CI 1.1–1.9). Further analyses of haplotypes were consistent with genotyping results.Conclusions/SignificanceWe provide evidence that genetic variability in the CLOCK gene might be associated with male infertility warranting further confirmation and mechanistic investigations.

Highlights

Infertility affects about 9% couples [1] and male factors contribute to approximately half of them [2]
Conclusions/Significance: We provide evidence that genetic variability in the CLOCK gene might be associated with male infertility warranting further confirmation and mechanistic investigations
Genotype frequencies of investigated polymorphisms were in accordance with those predicted by the Hardy-Weinberg equilibrium in the study and in the control group (p,0.05), with the exception of rs12363415, which was excluded from further analyses

Summary

Introduction

Infertility affects about 9% couples [1] and male factors contribute to approximately half of them [2]. There is a growing body of evidence that circadian rhythms have a major role in maintaining homeostasis and proper body function including reproductive capacity [6]. This is highlighted most obviously in mutant mouse models whereby mutations in the Bmal gene significantly reduce fertility in male mice [7]. The circadian system has a major role in maintaining homeostasis and proper body functions including reproductive capacity. The aim of this study was to examine whether there is an association between genetic variability in the primary clock genes CLOCK and ARNTL and male infertility in humans

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