Background: Sexual maturation is closely linked to growth, suggesting common pathways between the reproductive development and the growth hormone/insulin-like growth factor-I (GH/IGF-I) axis. IGF-I bioavailability is regulated by Pregnancy associated plasma protein-A (PAPP-A), Pregnancy associated plasma protein-A2 (PAPP-A2) and Stanniocalcin 2 (STC2). A large genome-wide association study (GWAS) identified PAPP-A, PAPP-A2 and STC2 to represent loci strongly associated with adult height.
Aims: The aim of this study was to explore the association between height, serum IGF-I, genotypes of PAPP-A, PAPP-A2, STC2 and pubertal timing in a large cohort of healthy girls and in a cohort of girls diagnosed with short and tall stature.
Method: 1572 girls were recruited from two population-based cohorts of healthy Danish children (n=1382), a cohort of patients with short stature (n=124) and tall stature (n=67). Anthropometrics, assessment of pubertal stages and IGF-I SDS were included. The girls were genotyped for PAPPA (rs751543), PAPPA2 (rs1325598) and STC2 (rs889014). A Mendelian randomization approach was used to assess the association between height and puberty.
Results: A dose-dependent association between the minor allele of PAPPA2 and height was observed. Girls homozygous for the minor allele (TT) were -0.27 [-0.47; -0.08] SDS shorter and CT heterozygotic girls were -0.09 [-0.25; 0.06] SDS shorter compared to CC major allele carriers (P=0.03). The association remained significant after correcting for IGF-I. We found no significant association between PAPPA and STC2 and height.
Age of pubertal onset was significantly later in girls with short stature (11.19 [10.86;11.52] years) and earlier in the tall girls (9.25 [8.82;9.69] years) compared to girls with normal stature 9.96 [9.85;10.07] years (P<0.01). Age at menarche was significantly later in girls with short stature 13.96 [13.55;14.37] years compared to girls with normal stature 13.09 [13.00;13.18] years (P<0.01). Adjusting for BMI did not essentially change the estimates. The genotypes were not associated with pubertal onset and menarche.
Girls within the highest IGF-I SDS quintile (Q5) had earlier pubertal onset (B2) and age at menarche compared to girls in Q1-Q4 (P<0.01).
Conclusion: We found a significant association between PAPPA2 genotype and height in this large well-characterized cohort of girls. Height and IGF-I SDS, but not PAPP-A, PAPP-A2 and STC2 genotypes, were negatively associated with age at pubertal onset and menarche.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology