Construction and evaluation of the functional polygenic risk score for gastric cancer in a prospective cohort of the European population

被引：0

作者：

Gu, Yuanliang ^{[1
,2
]}

Yan, Caiwang ^{[2
,3
,4
]}

Wang, Tianpei ^{[2
]}

Hu, Beiping ^{[2
]}

Zhu, Meng ^{[2
,3
,4
,5
]}

Jin, Guangfu ^{[1
,2
,3
,4
,5
,6
]}

机构：

[1] Southeast Univ, Sch Publ Hlth, Dept Epidemiol, Nanjing 210009, Jiangsu, Peoples R China

[2] Nanjing Med Univ, Ctr Global Hlth, Sch Publ Hlth, Dept Epidemiol, Nanjing 211166, Jiangsu, Peoples R China

[3] Nanjing Med Univ, Collaborat Innovat Ctr Canc Personalized Med, Jiangsu Key Lab Canc Biomarkers Prevent & Treatmen, Nanjing 211166, Jiangsu, Peoples R China

[4] Nanjing Med Univ, Collaborat Innovat Ctr Canc Personalized Med, Nanjing 211166, Jiangsu, Peoples R China

[5] Nanjing Med Univ, Jiangsu Canc Hosp, Jiangsu Inst Canc Res, Jiangsu Key Lab Mol & Translat Canc Res,Affiliated, Nanjing 210009, Jiangsu, Peoples R China

[6] Nanjing Med Univ, Sch Publ Hlth, Dept Epidemiol, 101 Longmian Ave, Nanjing 211166, Jiangsu, Peoples R China

来源：

CHINESE MEDICAL JOURNAL | 2023年 / 136卷 / 14期

基金：

中国国家自然科学基金;

关键词：

Polygenic risk score; Gastric cancer; Polymorphism; single nucleotide; Cross ancestry; GENOME-WIDE ASSOCIATION; COMPLEX TRAITS; GENETIC RISK; PREDICTION; VARIANTS; ANNOTATION; MUTATIONS; FRAMEWORK;

D O I：

10.1097/CM9.0000000000002716

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background:A polygenic risk score (PRS) derived from 112 single-nucleotide polymorphisms (SNPs) for gastric cancer has been reported in Chinese populations (PRS-112). However, its performance in other populations is unknown. A functional PRS (fPRS) using functional SNPs (fSNPs) may improve the generalizability of the PRS across populations with distinct ethnicities. Methods:We performed functional annotations on SNPs in strong linkage disequilibrium (LD) with the 112 previously reported SNPs to identify fSNPs that affect protein-coding or transcriptional regulation. Subsequently, we constructed an fPRS based on the fSNPs by using the LDpred2-infinitesimal model and then analyzed the performance of the PRS-112 and fPRS in the risk prediction of gastric cancer in 457,521 European participants of the UK Biobank cohort. Finally, the performance of the fPRS in combination with lifestyle factors were evaluated in predicting the risk of gastric cancer. Results:During 4,582,045 person-years of follow-up with a total of 623 incident gastric cancer cases, we found no significant association between the PRS-112 and gastric cancer risk in the European population (hazard ratio [HR] = 1.00 [95% confidence interval (CI) 0.93-1.09], P = 0.846). We identified 125 fSNPs, including seven deleterious protein-coding SNPs and 118 regulatory non-coding SNPs, and used them to construct the fPRS-125. Our result showed that the fPRS-125 was significantly associated with gastric cancer risk (HR = 1.11 [95% CI, 1.03-1.20], P = 0.009). Compared to participants with a low fPRS-125 (bottom quintile), those with a high fPRS-125 (top quintile) had a higher risk of incident gastric cancer (HR = 1.43 [95% CI, 1.12-1.84], P = 0.005). Moreover, we observed that participants with both an unfavorable lifestyle and a high genetic risk had the highest risk of incident gastric cancer (HR = 4.99 [95% CI, 1.55-16.10], P = 0.007) compared to those with both a favorable lifestyle and a low genetic risk. Conclusion:These results indicate that the fPRS-125 derived from fSNPs may act as an indicator to measure the genetic risk of gastric cancer in the European population.

引用

页码：1671 / 1679

页数：9

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