RH GR3: Identification of genetic and epigenetic variation influencing gonadal function

This study is performed at the Department of Growth and Reproduction, Rigshospitalet, Denmark.

Background
The influence of genetic variation, e.g. single nucleotide polymorphisms (SNPs), on gonadal function has achieved increasing interest. SNP’s are the most common type of genetic variation among people. Each SNP represents a difference in a single DNA building block, called a nucleotide. The pituitary follicle-stimulating hormone (FSH) plays a key role in human reproduction. A SNP located within the promoter region of the gene that codes for FSH is associated with female and male reproductive changes. In men, the SNP is associated with reduced serum FSH levels, total sperm count/concentration and bi-testicular volume. Thus, it is possible that this and other polymorphisms might be involved in the known direct association between semen quality and serum testosterone levels.

New research indicates that epigenetic regulation is affected not only by classical SNPs but also directly by microRNAs (miRNAs). A miRNA is a small non-coding RNA molecule. Epigenetics refers to a modification of DNA, protein, or RNA, resulting in changes of the function and/or regulation of these molecules, without altering their primary sequences. Nearly every aspect of biology is influenced by epigenetics, making it one of the most important fields in science.

miRNAs are found in circulation and can serve as endocrine messengers like hormones as well as markers of disease. Hence, circulating miRNAs represent an intriguing new source of clinical information to be investigated in different endocrine diseases and cancer. Measurements of miRNAs can be used as a non-invasive diagnostic method to diagnose testicular cancer and potentially as a measure of gonadal function.

Aim
The aim of this study is to investigate the influence of gonadotropin-related SNPs on male reproductive parameters and the potential of miRNAs and other small RNAs as markers of testicular cancer.

Results
A panel of ~100 genetic variants will be analysed in an existing cohort of 1,000 healthy Danish men. A subset of the SNPs will be tested on men with diverse andrological diseases like impaired semen quality, testosterone deficiency and testicular cancer. We have investigated SNPs nearby the gene coding for JMJD1C and found that these SNPs are associated with testis size and levels of SHBG, FSH, testosterone and inhibin B in healthy Danish men (Mørup et al. 2017). We also found an association between one of the JMJD1C SNPs and age at pubertal onset of boys.

Furthermore, a cohort of men with and without testicular cancer will be recruited. Serum and seminal plasma from these men will be used to study the potential of circulating miRNAs and other small RNAs as biomarkers of testicular cancer. We have recruited almost 300 men for this study and have collected nearly 800 blood samples. These samples are now being analysed. We have also collected seminal plasma samples from 80 of these men and will use them to identify new markers of early stages of testicular cancer.

Reference: Mørup, Nina et al. 2017. “Polymorphisms in JMJD1C Are Associated with Pubertal Onset in Boys and Reproductive Function in Men.Scientific Reports 7(1): 1–8.

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