Genetic Variation in Premature Adrenarche
نویسنده
چکیده
Premature adrenarche (PA) is defined as adrenarcheal levels of adrenal androgens before the age of 8 yrs in girls and the age of 9 yrs in boys leading to androgenic signs ranging from pubarche to oily skin and adult type body odor. PA has been connected with adverse metabolic features and increased risk for ovarian hyperandrogenism. The pathogenesis of PA is considered polygenic. However, underlying genetic factors remain largely unknown. We aimed to determine the role of genetic variation of PA candidate genes in a case-control cohort of prepubertal PA children (63 girls and 10 boys) and their ageand gender-matched controls (79 girls and 18 boys). The following candidate genes with previously described polymorphisms were selected based on the current knowledge of PA: ACTH receptor (MC2R), androgen receptor (AR), low density lipoprotein receptor-related protein 5 (LRP5), transcription factor 7-like 2 (TCF7L2), and fat mass and obesity associated gene (FTO). We compared genotype distributions between the PA and control groups, and used single marker association analyses to relate genetic variants with clinical phenotype. The minor variant of the single nucleotide polymorphism (SNP) MC2R -2 T>C was more frequent in subjects with premature pubarche than in children with milder signs of PA and controls. The minor variant was associated with a higher ratio of ACTH to cortisol in the control group, in agreement with previous studies that have shown decreased ACTH sensitivity due to the polymorphism. In children with PA, the minor variant associated with higher androstenedione level and ratio of androstenedione to cortisol, suggesting shifting of steroidogenesis from corticosteroids to androgens. The length of CAGn at Xchromosomal AR correlates inversely with the activity of AR. Children with PA had a shorter CAGn repeat than the controls, and the difference became even stronger when we took the X-chromosome inactivation into account. The lean PA children with a BMI below the median of the group had a shorter CAGn than the PA children with higher BMI or the controls with the same BMI. More active AR may have a significant role in the pathogenesis of PA in these lean children. Minor variants at SNPs A1330V and N740N of LRP5 were associated with higher dehydroepiandrosterone sulfate and cholesterol levels in control children, but no association between genetic variants at LRP5 and clinical parameters was observed in the children with PA. The minor variant at rs7903146 of TCF7L2 was more frequent in lean PA children. The minor variant at rs9939609 of FTO was not more frequent in children with PA, suggesting that this genetic variant in FTO has no major role in the increased BMI of PA children. The power of the study was limited, and the results need to be confirmed in different populations. However, the value of the study lies in the use of unbiased controls and in the precise phenotyping of all the children from a homogenous population. In conclusion, MC2R -2 T>C may have a role in the pathogenesis of premature pubarche. Lean PA children show a different genotype, with a shorter CAGn repeat, indicating a more active AR, and increased frequency of the minor variant at rs7903146 of TCF7L2 in comparison to PA children with higher BMI. National Library of Medicine Classification: WS 450 Medical Subject Headings: Adrenarche/genetics; Adrenocorticotropic Hormone; Androstenedione; Body Mass Index; Body Weight; Case-Control Studies; Cholesterol; Dehydroepiandrosterone Sulfate; Genes; Genetic Markers; Genetics; Genetic Variation; Genotype; Phenotype; Polymorphism, Genetic; Receptors, Androgen; Receptors, Corticotropin; LDL-Receptor Related Proteins; Proteins/genetics; TCF Transcription Factors/genetics; Polymorphism, Single Nucleotide/ genetics; Puberty, Precocious/genetics; X Chromosome
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