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Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.
Rhodes CJ, Batai K, Bleda M, Haimel M, Southgate L, Germain M, Pauciulo MW, Hadinnapola C, Aman J, Girerd B, Arora A, Knight J, Hanscombe KB, Karnes JH, Kaakinen M, Gall H, Ulrich A, Harbaum L, Cebola I, Ferrer J, Lutz K, Swietlik EM, Ahmad F, Amouyel P, Archer SL, Argula R, Austin ED, Badesch D, Bakshi S, Barnett C, Benza R, Bhatt N, Bogaard HJ, Burger CD, Chakinala M, Church C, Coghlan JG, Condliffe R, Corris PA, Danesino C, Debette S, Elliott CG, Elwing J, Eyries M, Fortin T, Franke A, Frantz RP, Frost A, Garcia JGN, Ghio S, Ghofrani HA, Gibbs JSR, Harley J, He H, Hill NS, Hirsch R, Houweling AC, Howard LS, Ivy D, Kiely DG, Klinger J, Kovacs G, Lahm T, Laudes M, Machado RD, MacKenzie Ross RV, Marsolo K, Martin LJ, Moledina S, Montani D, Nathan SD, Newnham M, Olschewski A, Olschewski H, Oudiz RJ, Ouwehand WH, Peacock AJ, Pepke-Zaba J, Rehman Z, Robbins I, Roden DM, Rosenzweig EB, Saydain G, Scelsi L, Schilz R, Seeger W, Shaffer CM, Simms RW, Simon M, Sitbon O, Suntharalingam J, Tang H, Tchourbanov AY, Thenappan T, Torres F, Toshner MR, Treacy CM, Vonk Noordegraaf A, Waisfisz Q, Walsworth AK, Walter RE, Wharton J, White RJ, Wilt J, Wort SJ, Yung D, Lawrie A, Humbert M, Soubrier F, Trégouët DA, Prokopenko I, Kittles R, Gräf S, Nichols WC, Trembath RC, Desai AA, Morrell NW, Wilkins MR, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium
(2019) Lancet Respir Med 7: 227-238
MeSH Terms: Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotyping Techniques, HLA-DP alpha-Chains, HLA-DP beta-Chains, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Pulmonary Arterial Hypertension, Risk Assessment, SOXF Transcription Factors, Signal Transduction, Survival Analysis
Show Abstract · Added March 8, 2020
BACKGROUND - Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.
METHODS - We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.
FINDINGS - A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity.
INTERPRETATION - This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.
FUNDING - UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
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16 MeSH Terms
Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations.
Seow WJ, Matsuo K, Hsiung CA, Shiraishi K, Song M, Kim HN, Wong MP, Hong YC, Hosgood HD, Wang Z, Chang IS, Wang JC, Chatterjee N, Tucker M, Wei H, Mitsudomi T, Zheng W, Kim JH, Zhou B, Caporaso NE, Albanes D, Shin MH, Chung LP, An SJ, Wang P, Zheng H, Yatabe Y, Zhang XC, Kim YT, Shu XO, Kim YC, Bassig BA, Chang J, Ho JC, Ji BT, Kubo M, Daigo Y, Ito H, Momozawa Y, Ashikawa K, Kamatani Y, Honda T, Sakamoto H, Kunitoh H, Tsuta K, Watanabe SI, Nokihara H, Miyagi Y, Nakayama H, Matsumoto S, Tsuboi M, Goto K, Yin Z, Shi J, Takahashi A, Goto A, Minamiya Y, Shimizu K, Tanaka K, Wu T, Wei F, Wong JY, Matsuda F, Su J, Kim YH, Oh IJ, Song F, Lee VH, Su WC, Chen YM, Chang GC, Chen KY, Huang MS, Yang PC, Lin HC, Xiang YB, Seow A, Park JY, Kweon SS, Chen CJ, Li H, Gao YT, Wu C, Qian B, Lu D, Liu J, Jeon HS, Hsiao CF, Sung JS, Tsai YH, Jung YJ, Guo H, Hu Z, Wang WC, Chung CC, Lawrence C, Burdett L, Yeager M, Jacobs KB, Hutchinson A, Berndt SI, He X, Wu W, Wang J, Li Y, Choi JE, Park KH, Sung SW, Liu L, Kang CH, Hu L, Chen CH, Yang TY, Xu J, Guan P, Tan W, Wang CL, Sihoe AD, Chen Y, Choi YY, Hung JY, Kim JS, Yoon HI, Cai Q, Lin CC, Park IK, Xu P, Dong J, Kim C, He Q, Perng RP, Chen CY, Vermeulen R, Wu J, Lim WY, Chen KC, Chan JK, Chu M, Li YJ, Li J, Chen H, Yu CJ, Jin L, Lo YL, Chen YH, Fraumeni JF, Liu J, Yamaji T, Yang Y, Hicks B, Wyatt K, Li SA, Dai J, Ma H, Jin G, Song B, Wang Z, Cheng S, Li X, Ren Y, Cui P, Iwasaki M, Shimazu T, Tsugane S, Zhu J, Jiang G, Fei K, Wu G, Chien LH, Chen HL, Su YC, Tsai FY, Chen YS, Yu J, Stevens VL, Laird-Offringa IA, Marconett CN, Lin D, Chen K, Wu YL, Landi MT, Shen H, Rothman N, Kohno T, Chanock SJ, Lan Q
(2017) Hum Mol Genet 26: 454-465
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Antigens, Nuclear, Asian Continental Ancestry Group, Butyrophilins, Case-Control Studies, ErbB Receptors, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Germ-Line Mutation, HLA-DP beta-Chains, Humans, Lung Neoplasms, Male, Membrane Proteins, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Sex Characteristics, Smoking, Transcription Factors
Show Abstract · Added April 3, 2018
To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P < 5 × 10-8), namely, rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub-analyses by EGFR status, rs9387478 (ROS1/DCBLD1) and rs2179920 (HLA-DPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non-smoking lung cancer. Our results extend the catalogue of regions associated with lung adenocarcinoma in non-smoking Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications.
Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.
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23 MeSH Terms