Pulmonary Hypertension Associated Genetic Variants in Sarcoidosis Associated Pulmonary Hypertension
Abstract
:1. Introduction
2. Materials and Methods
2.1. Patients and Samples
2.2. Whole Exome Sequencing and Variant Filtering
2.3. Diagnostic PH Gene Panel
2.4. Exploratory Analysis in Genes Biologically Involved in PH Pathways
2.5. Statistical Analysis
3. Results
3.1. Patient Cohorts
3.2. Diagnostic Gene Panel
3.3. Genes of Biological Relevance in PH
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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SAPH (n = 39) | SA (n = 39) | p-Value | ||
---|---|---|---|---|
Male, n (%) | 19 (48.7) | 19 (48.7) | 1.00 | |
Age mean (SD), y | 59.2 (11.3) | 60.9 (10.9) | 0.50 | |
Ancestry | White, n (%) | 27 (69.2) | 27 (69.2) | 1.00 |
Black, n (%) | 9 (23.1) | 9 (23.1) | ||
Hindustan, n (%) | 3 (7.7) | 3 (7.7) | ||
Scadding stage (n = 38; n = 39) | 0, n (%) | 2 (5.3) | 8 (20.5) | 0.016 |
1, n (%) | 4 (10.5) | 3 (7.7) | ||
2, n (%) | 4 (10.5) | 9 (23.1) | ||
3, n (%) | 2 (5.3) | 6 (15.4) | ||
4, n (%) | 26 (68.4) | 13 (33.3) | ||
Lung fibrosis score (n = 38; n = 39) | <5%, n (%) | 9 (23.7) | 22 (56.4) | <0.001 |
5–20%, n (%) | 1 (2.6) | 7 (17.9) | ||
>20%, n (%) | 28 (73.7) | 10 (25.6) | ||
FVC % predicted, mean (SD) (n = 37; n = 36) | 66.6 (19.4) | 94.2 (23.1) | <0.001 | |
DLCO SB% predicted, mean, mean (SD) (n = 32; n = 32) | 47.8 (18.5) | 68.4 (15.2) | <0.001 | |
Mean PAP mmHg, mean (SD) | 37.4 (10.9) | ND | ||
PVR Wood units, mean (SD) (n = 36; ND) | 5.6 (3.1) | ND | ||
Cardiac output L·min-1, mean (SD) (n = 38; ND) | 5.7 (1.8) | ND | ||
PCWP mmHg, mean (SD) (n = 37; ND) | 9.7 (3.6) | ND |
Gene | Transcript | Nucleotide Change | Amino Acid Change | dbSNP | gnomAD Frequency | CADD | SIFT a | PPh2 b | Mutation Taster c | Mutation Assessor d | Variant Classification e | SAPH Carrier ID(s) | SA Carrier ID(s) |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
KCNK3 | NM_002246.3 | c.418C>A | p.(L140M) | rs755486166 | 0.0000 | 25.5 | D | PrD | D | M | VUS | - | SA67 |
BMPR2 | NM_001204.7 | c.86A>G | p.(N29S) | rs112862820 | 0.0007 | 16.2 | T | B | B | N | LB | SAPH5 | - |
KDR | NM_002253.4 | c.3762+8C>A | NA | rs78801899 | 0.0003 | 17.0 | NA | NA | B | NA | VUS | - | SA71 |
KDR | NM_002253.4 | c.2854G>A | p.(V952I) | rs13129474 | 0.0000 | 20.0 | T | B | B | N | VUS | - | SA41 |
KDR | NM_002253.4 | c.2837G>A | p.(R946H) | rs140041720 | 0.0002 | 28.7 | D | PrD | B | N | VUS | SAPH1 | - |
KDR | NM_002253.4 | c.406G>A | p.(V136M) | rs35636987 | 0.0007 | 24.1 | D | PrD | B | M | VUS | SAPH6 | - |
KDR | NM_002253.4 | c.170G>C | p.(R57T) | rs139047809 | 0.0012 | 19.3 | T | PoD | B | M | VUS | - | SA41 |
ENG | NM_000118.3 | c.1844C>T | p.(S615L) | rs148002300 | 0.0015 | 21.1 | T | B | B | M | LB | SAPH10 | - |
ENG | NM_000118.3 | c.583G>A | p.(E195K) | rs1255912441 | 0.0000 | 17.6 | T | B | B | M | VUS | SAPH15 | - |
ENG | NM_000118.3 | c.572G>A | p.(G191D) | rs41322046 | 0.0091 | 24.2 | D | PrD | B | M | B | SAPH11 | - |
KCNA5 | NM_002234.4 | c.188G>T | p.(G63V) | rs768062067 | 0.0000 | 20.1 | - | B | B | N | VUS | SAPH34 | - |
KCNA5 | NM_002234.4 | c.929C>T | p.(P310L) | rs17215402 | 0.0040 | 18.2 | T | B | B | L | LB | SAPH12 | - |
KCNA5 | NM_002234.4 | c.1733G>A | p.(R578K) | rs12720445 | 0.0054 | 17.2 | T | B | B | M | LB | SAPH24; SAPH13; SAPH11 | - |
ACVRL1 | NM_001077401.2 | c.-159C>T | NA | rs542225698 | 0.0009 | 17.3 | NA | NA | B | NA | VUS | SAPH23; SAPH8 | - |
ACVRL1 | NM_000020.3 | c.1445C>T | p.(A482V) | rs139142865 | 0.0016 | 23.2 | D | PrD | B | M | LB | SAPH26 | - |
SMAD9 | NM_005905.6 | c.677G>A | p.(R226Q) | rs78249575 | 0.0012 | 17.9 | A | B | B | N | VUS | - | SA77 |
EIF2AK4 | NM_001013703.4 | c.13C>T | p.(R5C) | rs746773845 | 0.0000 | 23.3 | NA | B | B | L | VUS | SAPH10 | - |
EIF2AK4 | NM_001013703.4 | c.4792G>A | p.(A1598T) | rs1045326564 | 21.0 | T | B | B | N | VUS | - | SA71 | |
TBX4 | NM_018488.3 | c.104C>T | p.(A35V) | rs148424252 | 0.0089 | 16.5 | T | B | B | N | LB | - | SA58 |
TBX4 | NM_018488.3 | c.1094A>G | p.(H365R) | rs1443274012 | 0.0000 | 25.5 | T | PrD | D | M | VUS | SAPH17 | - |
Gene | Transcript | Nucleotide Change | Amino Acid Change | dbSNP | gnomAD Frequency | CADD | SIFT a | PPh2 b | Mutation Taster c | Mutation Assessor d | Variant Classification e | SAPH Carrier ID(s) | SA Carrier ID(s) |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
PDE6B | NM_001145291.2 | c.35T>C | p.(L12P) | - | - | 24.1 | - | PrD | D | M | VUS | SAPH20 | - |
PDE6B | NM_001145291.2 | c.143G>A | p.(R48Q) | rs113842820 | 0.0082 | 15.4 | - | B | B | L | B | SAPH1; SAPH38 | - |
PDE6B | NM_001145291.2 | c.373C>G | p.(P125A) | rs28414606 | 0.0078 | 15.6 | - | B | B | N | B | SAPH38 | - |
PDE6B | NM_001145291.2 | c.496G>A | p.(E166K) | rs115775983 | 0.0090 | 15.6 | - | B | B | N | LB | SAPH1 | SA68 |
PDE6B | NM_001145291.2 | c.706G>A | p.(G236S) | rs75543439 | 0.0002 | 20.4 | - | B | B | N | VUS | SAPH14 | - |
PDE6B | NM_001145291.2 | c.794G>A | p.(R265Q) | rs144562730 | 0.0011 | 26.1 | - | PrD | B | L | VUS | SAPH12 | - |
PDE6B | NM_001145291.2 | c.1295C>T | p.(T432I) | rs775120495 | 0.0000 | 23.7 | - | PoD | B * | M | VUS | SAPH34 | - |
PDE6B | NM_001145291.2 | c.2344G>A | p.(V782M) | rs145124626 | 0.0003 | 26.9 | - | PrD | D | M | VUS | - | SA41 |
PDE6B | NM_001145291.2 | c.2524G>A | p.(G842S) | rs367709559 | 0.0000 | 22.3 | - | B | B | L | VUS | - | SA41 |
COL5A1 | NM_001278074.1 | c.278C>T | p.(A93V) | rs41306397 | 0.0087 | 22.2 | D | B | B | L | LB | SAPH28; SAPH16 | SA61 |
COL5A1 | NM_001278074.1 | c.2695G>A | p.(G899S) | rs149964491 | 0.0016 | 23.3 | T | PoD | B | N | LB | SAPH38 | - |
COL5A1 | NM_001278074.1 | c.4906G>A | p.(A1636T) | rs113452150 | 0.0073 | 29.1 | D | PoD | D | H | VUS | SAPH40 | - |
COL5A1 | NM_001278074.1 | c.5407G>A | p.(D1803N) | rs61729495 | 0.0061 | 19.0 | A | B | B | N | LB | SAPH30; SAPH5 | - |
MMP21 | NM_147191.1 | c.1361C>T | p.(A454V) | rs28381319 | 0.0002 | 22.3 | T | B | B | M | B | SAPH31; SAPH35; SAPH39 | SA80 |
MMP21 | NM_147191.1 | c.1046A>G | p.(E349G) | rs28381302 | 0.0021 | 23.2 | D | PoD | B | M | LB | SAPH21; SAPH12 | SA54 |
MMP21 | NM_147191.1 | c.290C>T | p.(A97V) | rs554501102 | 0.0006 | 17.4 | D | B | B | M | VUS | SAPH27 | - |
NOTCH3 | NM_000435.3 | c.6221C>T | p.(P2074L) | rs114447350 | 0.0003 | 21.9 | T | B | B | N | B | SAPH33; SAPH30 | - |
NOTCH3 | NM_000435.3 | c.5900T>C | p.(M1967T) | rs377589088 | 0.0012 | 26.9 | D | PrD | D | N | VUS | SAPH28 | - |
NOTCH3 | NM_000435.3 | c.5854G>A | p.(V1952M) | rs115582213 | 0.0088 | 27.3 | D | PrD | B | L | B | - | SA48; SA68 |
NOTCH3 | NM_000435.3 | c.5284G>A | p.(V1762M) | rs756495084 | 0.0030 | 15.5 | T | B | B | N | LB | SAPH27 | - |
NOTCH3 | NM_000435.3 | c.4762A>C | p.(N1588H) | - | 0.0009 | 26.3 | D | PrD | B | M | VUS | SAPH11 | - |
NOTCH3 | NM_000435.3 | c.4679G>C | p.(R1560P) | rs78501403 | 0.0097 | 24.7 | T | PrD | B | L | LB | SAPH35 | - |
NOTCH3 | NM_000435.3 | c.3352A>T | p.(N1118Y) | rs376950447 | 0.0001 | 22.3 | D | PrD | B | L | VUS | SAPH24 | - |
NOTCH3 | NM_000435.3 | c.3088G>A | p.(G1030R) | rs1179899018 | 0.0082 | 23.8 | D | PrD | D | H | VUS | SAPH21 | - |
NOTCH3 | NM_000435.3 | c.2039G>A | p.(R680H) | rs10406745 | 0.0002 | 17.3 | T | B | B | L | LB | SAPH30 | - |
NOTCH3 | NM_000435.3 | c.1490C>T | p.(S497L) | rs114207045 | - | 24.9 | T | B | B | L | B | SAPH9 | - |
NOTCH3 | NM_000435.3 | c.182G>A | p.(R61Q) | rs1222763947 | 0.0015 | 18.0 | T | B | B | N | VUS | SAPH12 | - |
GUCY2F | NM_001522.3 | c.2380G>A | p.(E794K) | rs35726803 | 0.0001 | 28.5 | D | PrD | B | M | VUS | SAPH24 | SA68 |
GUCY2F | NM_001522.3 | c.1883G>A | p.(R628Q) | rs7883913 | 0.0000 | 24.1 | D | PrD | B | M | VUS | SAPH12 | - |
GUCY2F | NM_001522.3 | c.1720A>C | p.(K574Q) | rs139586665 | 0.0048 | 25.2 | D | PrD | B | M | VUS | SAPH29 | - |
GUCY2F | NM_001522.3 | c.1483A>C | p.(N495H) | rs148768857 | 0.0067 | 20.2 | T | B | B | L | LB | SAPH40; SAPH39 | - |
GUCY2F | NM_001522.3 | c.688C>T | p.(R230W) | rs33973457 | 0.0000 | 22.7 | D | PoD | B | L | LB | SAPH33 | - |
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Groen, K.; Huitema, M.P.; van der Vis, J.J.; Post, M.C.; Grutters, J.C.; Baughman, R.P.; van Moorsel, C.H.M. Pulmonary Hypertension Associated Genetic Variants in Sarcoidosis Associated Pulmonary Hypertension. Diagnostics 2022, 12, 2564. https://doi.org/10.3390/diagnostics12102564
Groen K, Huitema MP, van der Vis JJ, Post MC, Grutters JC, Baughman RP, van Moorsel CHM. Pulmonary Hypertension Associated Genetic Variants in Sarcoidosis Associated Pulmonary Hypertension. Diagnostics. 2022; 12(10):2564. https://doi.org/10.3390/diagnostics12102564
Chicago/Turabian StyleGroen, Karlijn, Marloes P. Huitema, Joanne J. van der Vis, Marco C. Post, Jan C. Grutters, Robert P. Baughman, and Coline H. M. van Moorsel. 2022. "Pulmonary Hypertension Associated Genetic Variants in Sarcoidosis Associated Pulmonary Hypertension" Diagnostics 12, no. 10: 2564. https://doi.org/10.3390/diagnostics12102564