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miRNAs, single nucleotide polymorphisms (SNPs) and age-related macular degeneration (AMD).

Abstract Advanced age-related macular degeneration (AAMD) is a complex sight-threating disease of public health significance. Micro RNAs (miRNAs) have been proposed as biomarkers for AAMD. The presence of certain single nucleotide polymorphisms (SNPs) may influence the explanatory value of these biomarkers. Here we present findings from an integrated approach used to determine whether AAMD-associated SNPs have the capacity to influence miRNA-mRNA pairing and, if so, to what extent such pairing may be manifested in a discrete AAMD transcriptome. Using a panel of 8854 SNPs associated with AAMD at p-values ≤5.0E-7 from a cohort of >30,000 elderly people, we identified SNPs in miRNA target-encoding constituents of: (1) regulator of complement activation (RCA) genes (rs390679, CFHR1, p≤2.14E-214 | rs12140421, CFHR3, p≤4.63E-29); (2) genes of major histocompatibility complex (MHC) loci (rs4151672, CFB, p≤8.91E-41 | rs115404146, HLA-C, p≤6.32E-12 | rs1055821, HLA-B, p≤1.93E-9 | rs1063355, HLA-DQB1, p≤6.82E-14); and (3) genes of the 10q26 AAMD locus (rs1045216, PLEKHA1, p≤4.17E-142 | rs2672603, ARMS2, p≤7.14E-46). We used these findings with existing data on AAMD-related retinal miRNA and transcript profiles for the purpose of making inferences on SNP-mRNA-miRNA-AAMD relationships. Four of 12 miRNAs significantly elevated in AAMD retina (hsa-miR-155-5p, hsa-let-7a-5p, hsa-let-7b-5p hsa-let-7d-5p) also showed strong pairing capacity (TarBase 7.1 context++ score <-0.2, miRanda 3.3 pairing score >150) with miRNA target transcripts encoded by AAMD-associated SNPs resident in HLA-DQB1 (rs1063355, hsa-miR-155-5p) and TGFBR1 (rs868, hsa-let-7). Three of the 12 miRNAs overexpressed in AAMD retina are inducible by NFkB and have high affinity targets in the complement factor H (CFH) mRNA 3' UTR. We used ENSEMBL to identify polymorphic regions in the CFH mRNA 3' UTR with the capacity to disrupt miRNA-mRNA pairing. Two variants (rs766666504 and rs459598) existed in DNA sequence encoding the seed region of hsa-miR-146a-5p in the CFH mRNA 3' UTR - as this miRNA is also elevated in both vitreous and serum of people with AAMD, it shows great value as a biomarker. Our findings suggest that knowledge on the nature of DNA sequence variation may increase the explanatory power of miRNA biomarkers in genetically diverse populations, while yielding information with which to develop: (1) mechanistic tests on processes implicated in AMD pathogenesis; and, (2) site-specific small molecules (synthetic mimetics or anti-miRNAs) with preventive or therapeutic efficacy for AAMD.
PMID
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Authors

Mayor MeshTerms

Polymorphism, Single Nucleotide

Keywords

age related macular degeneration

hsa-miR-146a

micro RNA

retina

single nucleotide polymorphism (SNP)

Journal Title clinical chemistry and laboratory medicine
Publication Year Start




PMID- 28343170
OWN - NLM
STAT- MEDLINE
DA  - 20170326
DCOM- 20170411
LR  - 20170411
IS  - 1437-4331 (Electronic)
IS  - 1434-6621 (Linking)
VI  - 55
IP  - 5
DP  - 2017 May 01
TI  - miRNAs, single nucleotide polymorphisms (SNPs) and age-related macular
      degeneration (AMD).
PG  - 763-775
LID - 10.1515/cclm-2016-0898 [doi]
LID - /j/cclm.2017.55.issue-5/cclm-2016-0898/cclm-2016-0898.xml [pii]
AB  - Advanced age-related macular degeneration (AAMD) is a complex sight-threating
      disease of public health significance. Micro RNAs (miRNAs) have been proposed as 
      biomarkers for AAMD. The presence of certain single nucleotide polymorphisms
      (SNPs) may influence the explanatory value of these biomarkers. Here we present
      findings from an integrated approach used to determine whether AAMD-associated
      SNPs have the capacity to influence miRNA-mRNA pairing and, if so, to what extent
      such pairing may be manifested in a discrete AAMD transcriptome. Using a panel of
      8854 SNPs associated with AAMD at p-values &lt;/=5.0E-7 from a cohort of &gt;30,000
      elderly people, we identified SNPs in miRNA target-encoding constituents of: (1) 
      regulator of complement activation (RCA) genes (rs390679, CFHR1, p&lt;/=2.14E-214 | 
      rs12140421, CFHR3, p&lt;/=4.63E-29); (2) genes of major histocompatibility complex
      (MHC) loci (rs4151672, CFB, p&lt;/=8.91E-41 | rs115404146, HLA-C, p&lt;/=6.32E-12 |
      rs1055821, HLA-B, p&lt;/=1.93E-9 | rs1063355, HLA-DQB1, p&lt;/=6.82E-14); and (3) genes
      of the 10q26 AAMD locus (rs1045216, PLEKHA1, p&lt;/=4.17E-142 | rs2672603, ARMS2,
      p&lt;/=7.14E-46). We used these findings with existing data on AAMD-related retinal 
      miRNA and transcript profiles for the purpose of making inferences on
      SNP-mRNA-miRNA-AAMD relationships. Four of 12 miRNAs significantly elevated in
      AAMD retina (hsa-miR-155-5p, hsa-let-7a-5p, hsa-let-7b-5p hsa-let-7d-5p) also
      showed strong pairing capacity (TarBase 7.1 context++ score &lt;-0.2, miRanda 3.3
      pairing score &gt;150) with miRNA target transcripts encoded by AAMD-associated SNPs
      resident in HLA-DQB1 (rs1063355, hsa-miR-155-5p) and TGFBR1 (rs868, hsa-let-7).
      Three of the 12 miRNAs overexpressed in AAMD retina are inducible by NFkB and
      have high affinity targets in the complement factor H (CFH) mRNA 3' UTR. We used 
      ENSEMBL to identify polymorphic regions in the CFH mRNA 3' UTR with the capacity 
      to disrupt miRNA-mRNA pairing. Two variants (rs766666504 and rs459598) existed in
      DNA sequence encoding the seed region of hsa-miR-146a-5p in the CFH mRNA 3' UTR -
      as this miRNA is also elevated in both vitreous and serum of people with AAMD, it
      shows great value as a biomarker. Our findings suggest that knowledge on the
      nature of DNA sequence variation may increase the explanatory power of miRNA
      biomarkers in genetically diverse populations, while yielding information with
      which to develop: (1) mechanistic tests on processes implicated in AMD
      pathogenesis; and, (2) site-specific small molecules (synthetic mimetics or
      anti-miRNAs) with preventive or therapeutic efficacy for AAMD.
FAU - SanGiovanni, John Paul
AU  - SanGiovanni JP
AD  - Laboratory of Membrane Biochemistry and Biophysics, Section on Nutritional
      Neuroscience, NIAAA/NIH, Bethesda, MD.
FAU - SanGiovanni, Peter M
AU  - SanGiovanni PM
AD  - Black Duck Software, Burlington, MA.
FAU - Sapieha, Przemyslaw
AU  - Sapieha P
AD  - Departments of Biochemistry and Ophthalmology, Maisonneuve-Rosemont Hospital
      Research Centre, University of Montreal, Montreal, Quebec.
FAU - De Guire, Vincent
AU  - De Guire V
AD  - Division of Clinical Biochemistry, Maisonneuve-Rosemont Hospital, University of
      Montreal, Department of Biochemistry and Molecular Medicine, Montreal, Quebec.
LA  - eng
PT  - Journal Article
PT  - Review
PL  - Germany
TA  - Clin Chem Lab Med
JT  - Clinical chemistry and laboratory medicine
JID - 9806306
RN  - 0 (MicroRNAs)
SB  - IM
MH  - Gene Expression Regulation
MH  - Humans
MH  - Macular Degeneration/etiology/*genetics/physiopathology
MH  - MicroRNAs/*genetics
MH  - *Polymorphism, Single Nucleotide
MH  - Retina/metabolism
MH  - Vitreous Body/metabolism
OTO - NOTNLM
OT  - *age related macular degeneration
OT  - *hsa-miR-146a
OT  - *micro RNA
OT  - *retina
OT  - *single nucleotide polymorphism (SNP)
EDAT- 2017/03/28 06:00
MHDA- 2017/04/12 06:00
CRDT- 2017/03/27 06:00
PHST- 2016/10/06 [received]
PHST- 2017/02/27 [accepted]
AID - 10.1515/cclm-2016-0898 [doi]
AID - /j/cclm.ahead-of-print/cclm-2016-0898/cclm-2016-0898.xml [pii]
PST - ppublish
SO  - Clin Chem Lab Med. 2017 May 1;55(5):763-775. doi: 10.1515/cclm-2016-0898.

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