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

This study is performed at Rigshospitalet Department of Growth and Reproduction in collaboration with University of Lund.

Genetic variation, e.g. single nucleotide polymorphisms (SNPs), in 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 single nucleotide polymorphism (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, while in women the SNP is associated with altered serum FSH levels, age at pubertal onset and ovarian follicular growth in prepubertal girls. 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 via direct microRNA. A micro RNA (miRNA) is a small non-coding RNA molecule. Epigenetics refers to a modification of DNA, protein, or RNA, resulting in changes to 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.

miRNA circulates in exosomes, that can serve as endocrine messengers (like hormones). Exosomes are cell-derived vesicles that are present in many and perhaps all biological fluids. Circulating exosomes hence represent an intriguing new source of clinical information to be investigated in different endocrine diseases. Measurements of exosomal miRNA can be used as a non-invasive diagnostic to measure gonadal function.

The aim of this study is to investigate gonadotropin-related polymorphisms and circulating miRNA exocomes influence on the testis function.

An existing cohort of 1.000 healthy Danish men will be analysed. A panel of 100 genetic variants will be tested on a smaller subset of men with diverse andrological diseases like impaired semen quality, testosterone deficiency and testicular cancer. The idea is to connect genetic variants to classical semen analysis and levels of circulating miRNA. The hope is to document circulating miRNA as an early biomarker for testis cancer development.

The study will be repeated and verified in a Swedish cohort not yet defined.

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