Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study

被引：20

作者：

Kocarnik, Jonathan M. ^{[1
,2
]}

Richard, Melissa ^{[3
]}

Graff, Misa ^{[4
]}

Haessler, Jeffrey ^{[1
]}

Bien, Stephanie ^{[1
]}

Carlson, Chris ^{[1
]}

Carty, Cara L. ^{[5
]}

Reiner, Alexander P. ^{[1
]}

Avery, Christy L. ^{[4
]}

Ballantyne, Christie M. ^{[6
]}

LaCroix, Andrea Z. ^{[7
]}

Assimes, Themistocles L. ^{[8
]}

Barbalic, Maja ^{[9
]}

Pankratz, Nathan ^{[10
]}

Tang, Weihong ^{[11
]}

Tao, Ran ^{[12
]}

Chen, Dongquan ^{[13
]}

Talavera, Gregory A. ^{[14
]}

Daviglus, Martha L. ^{[15
]}

Chirinos-Medina, Diana A. ^{[16
]}

Pereira, Rocio ^{[17
]}

Nishimura, Katie ^{[1
]}

Buzkova, Petra ^{[18
]}

Best, Lyle G. ^{[19
]}

Ambite, Jose Luis ^{[20
]}

Cheng, Iona ^{[21
]}

Crawford, Dana C. ^{[22
]}

Hindorff, Lucia A. ^{[23
]}

Fornage, Myriam ^{[3
,24
]}

Heiss, Gerardo ^{[4
]}

North, Kari E. ^{[4
]}

Haiman, Christopher A. ^{[25
]}

Peters, Ulrike ^{[1
]}

Le Marchand, Loic ^{[26
]}

Kooperberg, Charles ^{[1
]}

机构：

[1] Fred Hutchinson Canc Res Ctr, Publ Hlth Sci, 1100 Fairview Ave N,Mailstop M4-B402, Seattle, WA 98109 USA

[2] Univ Washington, Inst Translat Hlth Sci, Seattle, WA 98195 USA

[3] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX 77030 USA

[4] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27515 USA

[5] PATH, Seattle, WA USA

[6] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[7] Univ San Diego, Dept Epidemiol, San Diego, CA 92110 USA

[8] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA

[9] Univ Texas Houston, Div Epidemiol Human Genet & Environm Sci, Houston, TX USA

[10] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA

[11] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA

[12] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN USA

[13] Univ Alabama Birmingham, Div Prevent Med, Birmingham, AL USA

[14] San Diego State Univ, Div Hlth Promot & Behav Sci, San Diego, CA 92182 USA

[15] Univ Illinois, Coll Med, Inst Minor Hlth Res, Chicago, IL USA

[16] Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA

[17] Univ Colorado, Div Endocrinol, Anschutz Med Campus, Aurora, CO USA

[18] Univ Washington, Dept Biostat, Seattle, WA 98195 USA

[19] Missouri Breaks Ind Res Inc, Eagle Butte, SD USA

[20] Univ Southern Calif, Inst Informat Sci, Marina Del Rey, CA USA

[21] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA

[22] Case Western Reserve Univ, Populat & Quantitat Hlth Sci, Cleveland, OH 44106 USA

[23] NHGRI, Div Genom Med, NIH, Bethesda, MD 20892 USA

[24] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA

[25] Univ Southern Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA

[26] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA

来源：

HUMAN MOLECULAR GENETICS | 2018年 / 27卷 / 16期

基金：

美国国家卫生研究院;

关键词：

CORONARY-HEART-DISEASE; MIDDLE-AGED MEN; WIDE ASSOCIATION; CARDIOVASCULAR RISK; PHOSPHOLIPASE A(2); METABOLIC-SYNDROME; ISCHEMIC-STROKE; CANDIDATE GENE; BLOOD-PRESSURE; POLYMORPHISMS;

D O I：

10.1093/hmg/ddy211

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and-200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E 7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicityspecific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.

引用

页码：2940 / 2953

页数：14

共 23 条

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Hu, Yao
Bien, Stephanie A.
Nishimura, Katherine K.
Haessler, Jeffrey
Hodonsky, Chani J.
Baldassari, Antoine R.
Highland, Heather M.
Wang, Zhe
Preuss, Michael
Sitlani, Colleen M.
Wojcik, Genevieve L.
Tao, Ran
Graff, Mariaelisa
Huckins, Laura M.
Sun, Quan
Chen, Ming-Huei
Mousas, Abdou
Auer, Paul L.
Lettre, Guillaume
Tang, Weihong
Qi, Lihong
Thyagarajan, Bharat
Buyske, Steve
Fornage, Myriam
Hindorff, Lucia A.
Li, Yun
Lin, Danyu
Reiner, Alexander P.
North, Kari E.
Loos, Ruth J. F.
Raffield, Laura M.
Peters, Ulrike
Avery, Christy L.
Kooperberg, Charles
BMC GENOMICS, 2021, 22 (01)
[22] The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis
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Jeff, Janina M.
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Setiawan, V. Wendy
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Haiman, Christopher
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Heiss, Gerardo
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Buzkova, Petra
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Abul-Husn, Noura S.
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Yao, Jie
Guo, Xiuqing
Bielinski, Suzette J.
Rotter, Jerome I.
Vaidya, Dhananjay
Chen, Yii-Der Ida
Castaneda, Sheila F.
Daviglus, Martha
Kaplan, Robert
Talavera, Gregory A.
Ryckman, Kelli K.
Peters, Ulrike
Ambite, Jose Luis
Buyske, Steven
Hindorff, Lucia
Kooperberg, Charles
Matise, Tara
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PLOS ONE, 2018, 13 (07):
[23] A Systematic Mapping Approach of 16q12.2/FTO and BMI in More Than 20,000 African Americans Narrows in on the Underlying Functional Variation: Results from the Population Architecture using Genomics and Epidemiology (PAGE) Study
Peters, Ulrike
North, Kari E.
Sethupathy, Praveen
Buyske, Steve
Haessler, Jeff
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Fesinmeyer, Megan D.
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Kuller, Lew H.
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Ehret, Georg
Nguyen, Khanh-Dung H.
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PLOS GENETICS, 2013, 9 (01):

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