Cargando…
Analysis of Low Frequency Protein Truncating Stop-Codon Variants and Fasting Concentration of Growth Hormone
BACKGROUND: The genetic background of Growth Hormone (GH) secretion is not well understood. Mutations giving rise to a stop codon have a high likelihood of affecting protein function. OBJECTIVES: To analyze likely functional stop codon mutations that are associated with fasting plasma concentration...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472854/ https://www.ncbi.nlm.nih.gov/pubmed/26086970 http://dx.doi.org/10.1371/journal.pone.0128348 |
_version_ | 1782377130788651008 |
---|---|
author | Hallengren, Erik Almgren, Peter Engström, Gunnar Persson, Margaretha Melander, Olle |
author_facet | Hallengren, Erik Almgren, Peter Engström, Gunnar Persson, Margaretha Melander, Olle |
author_sort | Hallengren, Erik |
collection | PubMed |
description | BACKGROUND: The genetic background of Growth Hormone (GH) secretion is not well understood. Mutations giving rise to a stop codon have a high likelihood of affecting protein function. OBJECTIVES: To analyze likely functional stop codon mutations that are associated with fasting plasma concentration of Growth Hormone. METHODS: We analyzed stop codon mutations in 5451 individuals in the Malmö Diet and Cancer study by genotyping the Illumina Exome Chip. To enrich for stop codon mutations with likely functional effects on protein function, we focused on those disrupting >80% of the predicted amino acid sequence, which were carried by ≥10 individuals. Such mutations were related to GH concentration, measured with a high sensitivity assay (hs-GH) and, if nominally significant, to GH related phenotypes, using linear regression analysis. RESULTS: Two stop codon mutations were associated with the fasting concentration of hs-GH. rs121909305 (NP_005370.1:p.R93*) [Minor Allele Frequency (MAF) = 0.8%] in the Myosin 1A gene (MYO1A) was associated with a 0.36 (95%CI, 0.04 to 0.54; p=0.02) increment of the standardized value of the natural logarithm of hs-GH per 1 minor allele and rs35699176 (NP_067040.1:p.Q100*) in the Zink Finger protein 77 gene (ZNF77) (MAF = 4.8%) was associated with a 0.12 (95%CI, 0.02 to 0.22; p = 0.02) increase of hs-GH. The mutated high hs-GH associated allele of MYO1A was related to lower BMI (β-coefficient, -0.22; p = 0.05), waist (β-coefficient, -0.22; p = 0.04), body fat percentage (β-coefficient, -0.23; p = 0.03) and with higher HDL (β-coefficient, 0.23; p = 0.04). The ZNF77 stop codon was associated with height (β-coefficient, 0.11; p = 0.02) but not with cardiometabolic risk factors. CONCLUSION: We here suggest that a stop codon of MYO1A, disrupting 91% of the predicted amino acid sequence, is associated with higher hs-GH and GH-related traits suggesting that MYO1A is involved in GH metabolism and possibly body fat distribution. However, our results are preliminary and need replication in independent populations. |
format | Online Article Text |
id | pubmed-4472854 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-44728542015-06-29 Analysis of Low Frequency Protein Truncating Stop-Codon Variants and Fasting Concentration of Growth Hormone Hallengren, Erik Almgren, Peter Engström, Gunnar Persson, Margaretha Melander, Olle PLoS One Research Article BACKGROUND: The genetic background of Growth Hormone (GH) secretion is not well understood. Mutations giving rise to a stop codon have a high likelihood of affecting protein function. OBJECTIVES: To analyze likely functional stop codon mutations that are associated with fasting plasma concentration of Growth Hormone. METHODS: We analyzed stop codon mutations in 5451 individuals in the Malmö Diet and Cancer study by genotyping the Illumina Exome Chip. To enrich for stop codon mutations with likely functional effects on protein function, we focused on those disrupting >80% of the predicted amino acid sequence, which were carried by ≥10 individuals. Such mutations were related to GH concentration, measured with a high sensitivity assay (hs-GH) and, if nominally significant, to GH related phenotypes, using linear regression analysis. RESULTS: Two stop codon mutations were associated with the fasting concentration of hs-GH. rs121909305 (NP_005370.1:p.R93*) [Minor Allele Frequency (MAF) = 0.8%] in the Myosin 1A gene (MYO1A) was associated with a 0.36 (95%CI, 0.04 to 0.54; p=0.02) increment of the standardized value of the natural logarithm of hs-GH per 1 minor allele and rs35699176 (NP_067040.1:p.Q100*) in the Zink Finger protein 77 gene (ZNF77) (MAF = 4.8%) was associated with a 0.12 (95%CI, 0.02 to 0.22; p = 0.02) increase of hs-GH. The mutated high hs-GH associated allele of MYO1A was related to lower BMI (β-coefficient, -0.22; p = 0.05), waist (β-coefficient, -0.22; p = 0.04), body fat percentage (β-coefficient, -0.23; p = 0.03) and with higher HDL (β-coefficient, 0.23; p = 0.04). The ZNF77 stop codon was associated with height (β-coefficient, 0.11; p = 0.02) but not with cardiometabolic risk factors. CONCLUSION: We here suggest that a stop codon of MYO1A, disrupting 91% of the predicted amino acid sequence, is associated with higher hs-GH and GH-related traits suggesting that MYO1A is involved in GH metabolism and possibly body fat distribution. However, our results are preliminary and need replication in independent populations. Public Library of Science 2015-06-18 /pmc/articles/PMC4472854/ /pubmed/26086970 http://dx.doi.org/10.1371/journal.pone.0128348 Text en © 2015 Hallengren et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Hallengren, Erik Almgren, Peter Engström, Gunnar Persson, Margaretha Melander, Olle Analysis of Low Frequency Protein Truncating Stop-Codon Variants and Fasting Concentration of Growth Hormone |
title | Analysis of Low Frequency Protein Truncating Stop-Codon Variants and Fasting Concentration of Growth Hormone |
title_full | Analysis of Low Frequency Protein Truncating Stop-Codon Variants and Fasting Concentration of Growth Hormone |
title_fullStr | Analysis of Low Frequency Protein Truncating Stop-Codon Variants and Fasting Concentration of Growth Hormone |
title_full_unstemmed | Analysis of Low Frequency Protein Truncating Stop-Codon Variants and Fasting Concentration of Growth Hormone |
title_short | Analysis of Low Frequency Protein Truncating Stop-Codon Variants and Fasting Concentration of Growth Hormone |
title_sort | analysis of low frequency protein truncating stop-codon variants and fasting concentration of growth hormone |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4472854/ https://www.ncbi.nlm.nih.gov/pubmed/26086970 http://dx.doi.org/10.1371/journal.pone.0128348 |
work_keys_str_mv | AT hallengrenerik analysisoflowfrequencyproteintruncatingstopcodonvariantsandfastingconcentrationofgrowthhormone AT almgrenpeter analysisoflowfrequencyproteintruncatingstopcodonvariantsandfastingconcentrationofgrowthhormone AT engstromgunnar analysisoflowfrequencyproteintruncatingstopcodonvariantsandfastingconcentrationofgrowthhormone AT perssonmargaretha analysisoflowfrequencyproteintruncatingstopcodonvariantsandfastingconcentrationofgrowthhormone AT melanderolle analysisoflowfrequencyproteintruncatingstopcodonvariantsandfastingconcentrationofgrowthhormone |