Rare functional variants in the CRP and G6PC genes modify the relationship between obesity and serum C‐reactive protein in white British population
Abstract Background C‐reactive protein (CRP) is a sensitive biomarker of inflammation with moderate heritability. The role of rare functional genetic variants in relation to serum CRP is understudied. We aimed to examine gene mutation burden of protein‐altering (PA) and loss‐of‐function (LOF) varian...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-12-01
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| Series: | Molecular Genetics & Genomic Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/mgg3.2255 |
| _version_ | 1827196769047412736 |
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| author | Xia Li Alexander Ploner Yunzhang Wang Jonathan K. L. Mak Yi Lu Patrik K. E. Magnusson Juulia Jylhävä Sara Hägg |
| author_facet | Xia Li Alexander Ploner Yunzhang Wang Jonathan K. L. Mak Yi Lu Patrik K. E. Magnusson Juulia Jylhävä Sara Hägg |
| author_sort | Xia Li |
| collection | DOAJ |
| description | Abstract Background C‐reactive protein (CRP) is a sensitive biomarker of inflammation with moderate heritability. The role of rare functional genetic variants in relation to serum CRP is understudied. We aimed to examine gene mutation burden of protein‐altering (PA) and loss‐of‐function (LOF) variants in association with serum CRP, and to further explore the clinical relevance. Methods We included 161,430 unrelated participants of European ancestry from the UK Biobank. Of the rare (minor allele frequency <0.1%) and functional variants, 1,776,249 PA and 266,226 LOF variants were identified. Gene‐based burden tests, linear regressions, and logistic regressions were performed to identify the candidate mutations at the gene and variant levels, to estimate the potential interaction effect between the identified PA mutation and obesity, and to evaluate the relative risk of 16 CRP‐associated diseases. Results At the gene level, PA mutation burdens of the CRP (β = −0.685, p = 2.87e‐28) and G6PC genes (β = 0.203, p = 1.50e‐06) were associated with reduced and increased serum CRP concentration, respectively. At the variant level, seven PA alleles in the CRP gene decreased serum CRP, of which the per‐allele effects were approximately three to seven times greater than that of a common variant in the same locus. The effects of obesity and central obesity on serum CRP concentration were smaller among the PA mutation carriers in the CRP (pinteraction = 0.008) and G6PC gene (pinteraction = 0.034) compared to the corresponding non‐carriers. Conclusion PA mutation burdens in the CRP and G6PC genes are strongly associated with decreased serum CRP concentrations. As serum CRP and obesity are important predictors of cardiovascular risks in clinics, our observations suggest taking rare genetic factors into consideration might improve the delivery of precision medicine. |
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| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2025-03-21T09:50:29Z |
| publishDate | 2023-12-01 |
| publisher | Wiley |
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| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-b783b457074d4aa093cac96a0c0f3c332024-07-06T06:32:39ZengWileyMolecular Genetics & Genomic Medicine2324-92692023-12-011112n/an/a10.1002/mgg3.2255Rare functional variants in the CRP and G6PC genes modify the relationship between obesity and serum C‐reactive protein in white British populationXia Li0Alexander Ploner1Yunzhang Wang2Jonathan K. L. Mak3Yi Lu4Patrik K. E. Magnusson5Juulia Jylhävä6Sara Hägg7School of Public Health and Emergency Management Southern University of Science and Technology Shenzhen ChinaDepartment of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm SwedenDepartment of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm SwedenDepartment of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm SwedenDepartment of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm SwedenDepartment of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm SwedenDepartment of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm SwedenDepartment of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm SwedenAbstract Background C‐reactive protein (CRP) is a sensitive biomarker of inflammation with moderate heritability. The role of rare functional genetic variants in relation to serum CRP is understudied. We aimed to examine gene mutation burden of protein‐altering (PA) and loss‐of‐function (LOF) variants in association with serum CRP, and to further explore the clinical relevance. Methods We included 161,430 unrelated participants of European ancestry from the UK Biobank. Of the rare (minor allele frequency <0.1%) and functional variants, 1,776,249 PA and 266,226 LOF variants were identified. Gene‐based burden tests, linear regressions, and logistic regressions were performed to identify the candidate mutations at the gene and variant levels, to estimate the potential interaction effect between the identified PA mutation and obesity, and to evaluate the relative risk of 16 CRP‐associated diseases. Results At the gene level, PA mutation burdens of the CRP (β = −0.685, p = 2.87e‐28) and G6PC genes (β = 0.203, p = 1.50e‐06) were associated with reduced and increased serum CRP concentration, respectively. At the variant level, seven PA alleles in the CRP gene decreased serum CRP, of which the per‐allele effects were approximately three to seven times greater than that of a common variant in the same locus. The effects of obesity and central obesity on serum CRP concentration were smaller among the PA mutation carriers in the CRP (pinteraction = 0.008) and G6PC gene (pinteraction = 0.034) compared to the corresponding non‐carriers. Conclusion PA mutation burdens in the CRP and G6PC genes are strongly associated with decreased serum CRP concentrations. As serum CRP and obesity are important predictors of cardiovascular risks in clinics, our observations suggest taking rare genetic factors into consideration might improve the delivery of precision medicine.https://doi.org/10.1002/mgg3.2255C‐reactive proteinloss‐of‐function variantsobesityprotein‐altering variantsrare genetic variantsUK Biobank |
| spellingShingle | Xia Li Alexander Ploner Yunzhang Wang Jonathan K. L. Mak Yi Lu Patrik K. E. Magnusson Juulia Jylhävä Sara Hägg Rare functional variants in the CRP and G6PC genes modify the relationship between obesity and serum C‐reactive protein in white British population Molecular Genetics & Genomic Medicine C‐reactive protein loss‐of‐function variants obesity protein‐altering variants rare genetic variants UK Biobank |
| title | Rare functional variants in the CRP and G6PC genes modify the relationship between obesity and serum C‐reactive protein in white British population |
| title_full | Rare functional variants in the CRP and G6PC genes modify the relationship between obesity and serum C‐reactive protein in white British population |
| title_fullStr | Rare functional variants in the CRP and G6PC genes modify the relationship between obesity and serum C‐reactive protein in white British population |
| title_full_unstemmed | Rare functional variants in the CRP and G6PC genes modify the relationship between obesity and serum C‐reactive protein in white British population |
| title_short | Rare functional variants in the CRP and G6PC genes modify the relationship between obesity and serum C‐reactive protein in white British population |
| title_sort | rare functional variants in the crp and g6pc genes modify the relationship between obesity and serum c reactive protein in white british population |
| topic | C‐reactive protein loss‐of‐function variants obesity protein‐altering variants rare genetic variants UK Biobank |
| url | https://doi.org/10.1002/mgg3.2255 |
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