medwireNews: Researchers have identified 10 novel single nucleotide polymorphisms (SNPs) that may help to predict the risk for familial short stature (FSS) in Han Chinese children.

For the study, the team genetically profiled 1163 Taiwanese children of Han Chinese ancestry who were diagnosed with FFS, defined as a height below the 3rd percentile in children who also had one or both parents with a height below the 3rd percentile, a bone age appropriate for chronological age, normal annual growth rate and onset of puberty, and normal biochemistry findings.

Fuu-Jen Tsai, from China Medical University Hospital in Taichung, Taiwan, and co-authors explain that they created a genetic risk score using data from a training group of 930 patients and 1071 individuals without FSS who were all aged less than 61 years with a height above the 75th percentile for age and gender.

As reported in The Journal of Clinical Endocrinology & Metabolism, the team identified 10 novel SNPs associated with FSS risk, including SNPs in the known genes COL6A5, LOC105374144, UGT2B17, IQCM and PGM5P2, with odds ratios (ORs) for FSS ranging from 1.90 to 15.32.

A further nine SNPs previously linked to human height in genome-wide association studies were also associated with FSS, namely those in DNM3, ANAPC13, LCORL, GPR126, QSOX2, ATF7-ATP5G2, CDK10, CABLES1 and UQCC1, with ORs for FSS ranging from 1.22 to 4.55.

The cumulative effect of the 10 novel variants was determined, with individuals in the second and third quartile for a polygenic risk score having significant ORs for FSS of 3.02 and 23.56 compared with those in the lowest reference quartile of the score. There were no controls in the fourth quartile but 64.7% of FSS patients were in this group, the researchers say, suggesting “that there was a cumulative effect of these 10 novel SNPs on FSS risk.”

However, the authors note that these 10 SNPs were unable to differentiate between control individuals in the 97th percentile and controls considered short when defined as 3rd percentile or 25th percentile.

The area under the receiver operating characteristic curve value for the training group was 0.949 for discriminating between FSS patients and controls using the 10 novel SNPs, and the value was 0.954 when combining these with the nine SNPs in previously known genes related to human height.

The corresponding values in a validation group of 233 patients and 215 controls were 0.940 and 0.948.

The team highlights several of the novel SNPs, such as rs367599822 within UGT2B17, a gene implicated in a variety of metabolic processes including the regulation of sex hormones, and osteoclast and chondrocyte differentiation in the bones.

This warrants “further investigations in the role of UGT2B17 in the cell proliferations and differentiations of chondrocyte/osteocyte progenitor cells”, the team suggests.

Similarly, COL6A5 is one of six genes required for the production of collagen IV, which plays a role in the development of fetal bone and helps maintain chondrocyte integrity in adults, the researchers say.

Finally, when the 10 novel SNPs were assessed among 2146 male and 2022 female controls with height information, a 1-unit difference in genetic predisposition score was associated with a reduction of 0.290 cm and 0.244 cm in height, respectively.

And when using the nine human height-related SNPs in these male and female cohorts, each 1-unit difference in genetic predispositions score was associated with a 0.224 cm and 0.083 cm decrease in height, respectively.

“These results suggest that the 10 novel and 9 reported genetic SNPs were associated with height reduction” in the general population, the researchers conclude.

By Lynda Williams

medwireNews is an independent medical news service provided by Springer Healthcare. © 2020 Springer Healthcare part of the Springer Nature group

J Clin Endocrinol Metab 2020; doi:10.1210/clinem/dgaa131

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