ADAM19
Disintegrin and metalloproteinase domain-containing protein 19 precursor (EC 3.4.24.-) (ADAM 19) (Meltrin-beta) (Metalloprotease and disintegrin dendritic antigen marker) (MADDAM) [MLTNB] [FKSG34]
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The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4. We sequenced ADAM19 and its promoter region along with the ≈21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-analysis of common variants in each region identified statistically significant associations (316 tests; P<1.58×10(-4)) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 single-nucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene (ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant (ADAM19 rs13155908, minor allele frequency=0.12; P=1.56×10(-4)). Analysis of rare variants (minor allele frequency <1%) using sequence kernel association test did not identify associations with either region. Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4.
MeSH Terms
- ADAM Proteins
- Aged
- Aged, 80 and over
- Aging
- Cohort Studies
- Female
- Genetic Variation
- Genome-Wide Association Study
- Genomics
- Heart Diseases
- Humans
- Lung
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- Sequence Analysis, DNA
Keywords
- Airway Obstruction
- genome-wide association study
- lung
- polymorphism, genetic
- pulmonary disease, chronic obstructive
- respiratory function tests
- sequence analysis, DNA
More than half of ADAM (a disintegrin and metalloprotease) family members are expressed in mammalian male reproductive organs such as testis and epididymis. The ADAM19 gene identified in mouse is a member of the ADAM family and is highly enriched in testes of a newborn mouse. The present study was performed to determine its expression pattern in whole mouse testes in vivo as well as its in vitro action and regulation in testis cells from 2-day-old mice. Reverse transcriptase polymerase chain reaction (RT-PCR) detected ADAM19 mRNA from 15.5 days postcoitum (dpc) to 21 days postpartum (dpp), with high expression during the perinatal period. Immunohistochemistry demonstrated ADAM19 protein localization to the seminiferous cords at both embryonic and postnatal ages examined (from 15.5-19.5 dpc to 2 dpp). In particular, we obtained new evidence that a neutralizing antibody to ADAM19 had no influence on the proliferation of 2 dpp testis cells cultured in serum-free medium when compared to controls. Interestingly, it inhibited the 2 dpp testis cell proliferation elicited by stimulation with 10% FCS (P<0.01) or FSH (P<0.05). Lastly, using a model of 2 dpp testis cell cultures and RT-PCR procedures, we demonstrated that follicle stimulating-hormone (FSH) reduced the levels of ADAM19 mRNA in a time-dependent manner. Taken together, these results indicate that the expression of ADAM19 may be subject to regulation by FSH during mouse testis development. Furthermore, ADAM19 can act to regulate the proliferation of perinatal testis cells in the perinatal period.
MeSH Terms
- ADAM Proteins
- Aging
- Animals
- DNA Primers
- Gene Expression Regulation, Developmental
- Male
- RNA, Messenger
- Reverse Transcriptase Polymerase Chain Reaction
- Seminiferous Tubules
- Swine
- Testis