Rare functional variants in the CRP and G6PC genes modify the relationship between obesity and serum C-reactive protein in white British population

Li, Xia1,2,3; Ploner, Alexander3; Wang, Yunzhang3; Mak, Jonathan K. L.3; Lu, Yi3; Magnusson, Patrik K. E.3; Jylhava, Juulia3,4; Hagg, Sara3

2023-07-01

10.1002/mgg3.2255

MOLECULAR GENETICS & GENOMIC MEDICINE   影响因子和分区

2324-9269

2324-9269

BackgroundC-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. MethodsWe 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. ResultsAt the gene level, PA mutation burdens of the CRP (& beta; = -0.685, p = 2.87e-28) and G6PC genes (& beta; = 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 (p(interaction) = 0.008) and G6PC gene (p(interaction) = 0.034) compared to the corresponding non-carriers. ConclusionPA 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.

C-reactive protein loss-of-function variants obesity protein-altering variants rare genetic variants UK Biobank

SCI

英语

第一

Swedish Research Council["2018-05973","2017-00641","2018-02077","2015-03255"] ; FORTE[2013-2292]

Genetics & Heredity

Genetics & Heredity

WOS:001035575400001

WILEY

2-s2.0-85165683196

Web of Science

1.Southern Univ Sci & Technol, Sch Publ Hlth & Emergency Management, Shenzhen, Peoples R China
2.Southern Univ Sci & Technol, Shenzhen Key Lab Cardiovasc Hlth & Precis Med, Shenzhen, Peoples R China
3.Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden
4.Univ Tampere, Social Sci Hlth Sci & Gerontol Res Ctr GEREC, Tampere, Finland

Li, Xia,Ploner, Alexander,Wang, Yunzhang,et al. Rare functional variants in the CRP and G6PC genes modify the relationship between obesity and serum C-reactive protein in white British population[J]. MOLECULAR GENETICS & GENOMIC MEDICINE,2023,11(12).

Li, Xia.,Ploner, Alexander.,Wang, Yunzhang.,Mak, Jonathan K. L..,Lu, Yi.,...&Hagg, Sara.(2023).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,11(12).

Li, Xia,et al."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 11.12(2023).