Choline Dehydrogenase Polymorphism rs12676 Is a Functional Variation and Is Associated with Changes in Human Sperm Cell Function
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{"title"=>"Choline dehydrogenase polymorphism rs12676 is a functional variation and is associated with changes in human sperm cell function", "type"=>"journal", "authors"=>[{"first_name"=>"Amy R.", "last_name"=>"Johnson", "scopus_author_id"=>"7410015945"}, {"first_name"=>"Sai", "last_name"=>"Lao", "scopus_author_id"=>"55203078600"}, {"first_name"=>"Tongwen", "last_name"=>"Wang", "scopus_author_id"=>"55758206400"}, {"first_name"=>"Joseph A.", "last_name"=>"Galanko", "scopus_author_id"=>"6603715132"}, {"first_name"=>"Steven H.", "last_name"=>"Zeisel", "scopus_author_id"=>"7006373416"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"22558321", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)", "doi"=>"10.1371/journal.pone.0036047", "issn"=>"19326203", "scopus"=>"2-s2.0-84860476723", "pui"=>"364720860", "sgr"=>"84860476723"}, "id"=>"12e4a8c0-65f1-36e4-857c-c570cf7e763e", "abstract"=>"Approximately 15% of couples are affected by infertility and up to half of these cases arise from male factor infertility. Unidentified genetic aberrations such as chromosomal deletions, translocations and single nucleotide polymorphisms (SNPs) may be the underlying cause of many cases of idiopathic male infertility. Deletion of the choline dehydrogenase (Chdh) gene in mice results in decreased male fertility due to diminished sperm motility; sperm from Chdh(-/-) males have decreased ATP concentrations likely stemming from abnormal sperm mitochondrial morphology and function in these cells. Several SNPs have been identified in the human CHDH gene that may result in altered CHDH enzymatic activity. rs12676 (G233T), a non-synonymous SNP located in the CHDH coding region, is associated with increased susceptibility to dietary choline deficiency and risk of breast cancer. We now report evidence that this SNP is also associated with altered sperm motility patterns and dysmorphic mitochondrial structure in sperm. Sperm produced by men who are GT or TT for rs12676 have 40% and 73% lower ATP concentrations, respectively, in their sperm. rs12676 is associated with decreased CHDH protein in sperm and hepatocytes. A second SNP located in the coding region of IL17BR, rs1025689, is linked to altered sperm motility characteristics and changes in choline metabolite concentrations in sperm.", "link"=>"http://www.mendeley.com/research/choline-dehydrogenase-polymorphism-rs12676-functional-variation-associated-changes-human-sperm-cell", "reader_count"=>10, "reader_count_by_academic_status"=>{"Researcher"=>3, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>2}, "reader_count_by_user_role"=>{"Researcher"=>3, "Student > Ph. D. Student"=>4, "Student > Postgraduate"=>1, "Student > Master"=>2}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>6, "Medicine and Dentistry"=>1, "Arts and Humanities"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>6}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Arts and Humanities"=>{"Arts and Humanities"=>1}}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/645697"], "description"=>"<p>On Day 1, all subjects gave informed consent, completed a health questionnaire form and blood samples were collected. Plasma was separated from other blood components and reserved for measures of choline metabolites. Genomic DNA was isolated from purified lymphocytes and used to genotype subjects for rs12676 and rs1025689 SNPs. Individuals with the genotypes of interest were invited to complete Day 2 of the study which entailed leaving a semen sample for measures of semen characteristics, sperm motility, ATP concentration and mitochondrial morphology.</p>", "links"=>[], "tags"=>["genetics and genomics", "Computational biology", "cell biology", "developmental biology", "Biochemistry"], "article_id"=>316186, "categories"=>["Biological Sciences", "Biochemistry", "Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Amy R. Johnson", "Sai Lao", "Tongwen Wang", "Joseph A. Galanko", "Steven H. Zeisel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036047.g001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Study_design_/316186", "title"=>"Study design.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-27 01:43:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/646576"], "description"=>"<p>Semen volume, total number of sperm per ejaculate and sperm concentration was determined by measuring the volume of the ejaculate before washing and counting the number of sperm using a hemocytometer. For rs12676 <i>N</i> = 19 (GG), 22 (GT) or 5 (TT). For rs1025689 <i>N</i> = 12 (GG), 22 (GT), 11 (CC). Values are mean ± SEM. Statistical differences among groups were tested on log 10 transformed data using ANOVA and Tukey-Kramer HSD.</p>*<p>indicates P<0.05.</p>†<p>World Health Organization reference values and 5% lower reference limit for human semen characteristics within the general population.</p>", "links"=>[], "tags"=>["parameters", "rs12676", "rs1025689"], "article_id"=>317063, "categories"=>["Biological Sciences", "Biochemistry", "Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Amy R. Johnson", "Sai Lao", "Tongwen Wang", "Joseph A. Galanko", "Steven H. Zeisel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036047.t003", "stats"=>{"downloads"=>9, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Semen_parameters_by_rs12676_and_rs1025689_genotype_/317063", "title"=>"Semen parameters by rs12676 and rs1025689 genotype.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-04-27 01:57:43"}
  • {"files"=>["https://ndownloader.figshare.com/files/332953", "https://ndownloader.figshare.com/files/332999", "https://ndownloader.figshare.com/files/333060", "https://ndownloader.figshare.com/files/333104"], "description"=>"<div><p>Approximately 15% of couples are affected by infertility and up to half of these cases arise from male factor infertility. Unidentified genetic aberrations such as chromosomal deletions, translocations and single nucleotide polymorphisms (SNPs) may be the underlying cause of many cases of idiopathic male infertility. Deletion of the choline dehydrogenase (<em>Chdh</em>) gene in mice results in decreased male fertility due to diminished sperm motility; sperm from <em>Chdh<sup>−/−</sup></em> males have decreased ATP concentrations likely stemming from abnormal sperm mitochondrial morphology and function in these cells. Several SNPs have been identified in the human <em>CHDH</em> gene that may result in altered CHDH enzymatic activity. rs12676 (G233T), a non-synonymous SNP located in the <em>CHDH</em> coding region, is associated with increased susceptibility to dietary choline deficiency and risk of breast cancer. We now report evidence that this SNP is also associated with altered sperm motility patterns and dysmorphic mitochondrial structure in sperm. Sperm produced by men who are GT or TT for rs12676 have 40% and 73% lower ATP concentrations, respectively, in their sperm. rs12676 is associated with decreased CHDH protein in sperm and hepatocytes. A second SNP located in the coding region of <em>IL17BR</em>, rs1025689, is linked to altered sperm motility characteristics and changes in choline metabolite concentrations in sperm.</p> </div>", "links"=>[], "tags"=>["choline", "dehydrogenase", "polymorphism", "rs12676", "changes", "sperm"], "article_id"=>125749, "categories"=>["Biological Sciences", "Biochemistry", "Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Amy R. Johnson", "Sai Lao", "Tongwen Wang", "Joseph A. Galanko", "Steven H. Zeisel"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0036047.s001", "https://dx.doi.org/10.1371/journal.pone.0036047.s002", "https://dx.doi.org/10.1371/journal.pone.0036047.s003", "https://dx.doi.org/10.1371/journal.pone.0036047.s004"], "stats"=>{"downloads"=>10, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Choline_Dehydrogenase_Polymorphism_rs12676_Is_a_Functional_Variation_and_Is_Associated_with_Changes_in_Human_Sperm_Cell_Function/125749", "title"=>"Choline Dehydrogenase Polymorphism rs12676 Is a Functional Variation and Is Associated with Changes in Human Sperm Cell Function", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-04-27 01:35:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/646539"], "description"=>"<p>Average age, average number of biological children per subject and occurrence of abnormal semen characteristics or infertility were calculated from self-reported information. N = 79, except for average number of biological children, which was calculated only in men who answered this question (N = 71).</p>", "links"=>[], "tags"=>["genetics and genomics", "Computational biology", "cell biology", "developmental biology", "Biochemistry"], "article_id"=>317026, "categories"=>["Biological Sciences", "Biochemistry", "Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Amy R. Johnson", "Sai Lao", "Tongwen Wang", "Joseph A. Galanko", "Steven H. Zeisel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036047.t002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Characteristics_of_the_study_population_/317026", "title"=>"Characteristics of the study population.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-04-27 01:57:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/645763"], "description"=>"<p>Mean velocity (MVUS, <i>A</i>), curvilinear velocity (VCL, <i>B</i>), straight line velocity (VSL, <i>C</i>) and mean tortuosity (MT, <i>D</i>) were determined for sperm. Sperm were prepared and motility characteristics measured as described in the <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036047#s2\" target=\"_blank\">Methods</a> section. N = 2756 (GG), 2553 (GT), 827 (TT) sperm. Statistical analyses were performed as described in the <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036047#s2\" target=\"_blank\">Methods</a> section; refer to <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036047#pone-0036047-t004\" target=\"_blank\">Table 4</a> for p-values. X-axis values indicate the upper limit of each quartile; the line at 25% represents values for sperm from GG subjects.</p>", "links"=>[], "tags"=>["characteristics", "sperm", "rs12676"], "article_id"=>316253, "categories"=>["Biological Sciences", "Biochemistry", "Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Amy R. Johnson", "Sai Lao", "Tongwen Wang", "Joseph A. Galanko", "Steven H. Zeisel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036047.g002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Motility_characteristics_of_sperm_change_with_rs12676_genotype_/316253", "title"=>"Motility characteristics of sperm change with rs12676 genotype.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-27 01:44:13"}
  • {"files"=>["https://ndownloader.figshare.com/files/646641"], "description"=>"<p>Statistical analyses were conducted as described in the Methods section. N.S, not significant.</p>", "links"=>[], "tags"=>["sperm", "motility"], "article_id"=>317134, "categories"=>["Biological Sciences", "Biochemistry", "Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Amy R. Johnson", "Sai Lao", "Tongwen Wang", "Joseph A. Galanko", "Steven H. Zeisel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036047.t004", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Significance_values_for_sperm_motility_analyses_/317134", "title"=>"Significance values for sperm motility analyses.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-04-27 01:58:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/646610"], "description"=>"<p>Allele distribution frequency was calculated as a percentage of the total screened population following genotyping by direct sequencing (rs12676) or TaqMan assay (rs1025689). N = 79.</p>", "links"=>[], "tags"=>["rs1025689", "snp", "frequencies", "screened"], "article_id"=>317099, "categories"=>["Biological Sciences", "Biochemistry", "Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Amy R. Johnson", "Sai Lao", "Tongwen Wang", "Joseph A. Galanko", "Steven H. Zeisel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036047.t001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_rs12676_and_rs1025689_SNP_distribution_frequencies_in_the_screened_population_/317099", "title"=>"rs12676 and rs1025689 SNP distribution frequencies in the screened population.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-04-27 01:58:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/646101"], "description"=>"<p>Sperm were fixed and processed for transmission electron microscopy as described in the <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036047#s2\" target=\"_blank\">Methods</a> section. Longitudinal and cross-sectional sections of sperm were examined for mitochondria structure anomalies. Representative images for rs12676 genotypes (GG, panel <i>A</i> and <i>D</i>; GT, panel <i>B</i> and <i>E</i>; TT, panel <i>C</i> and <i>F</i>) are shown. N = 5 per genotype. Micrographs shown are at 80,000× magnification and arrows indicate mitochondria.</p>", "links"=>[], "tags"=>["tt", "genotype", "dysmorphic", "mitochondrial"], "article_id"=>316594, "categories"=>["Biological Sciences", "Biochemistry", "Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Amy R. Johnson", "Sai Lao", "Tongwen Wang", "Joseph A. Galanko", "Steven H. Zeisel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036047.g004", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_rs12676_TT_genotype_is_associated_with_dysmorphic_mitochondrial_structure_in_sperm_/316594", "title"=>"rs12676 TT genotype is associated with dysmorphic mitochondrial structure in sperm.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-27 01:49:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/645906"], "description"=>"<p>Mean velocity (MVUS, <i>A</i>), curvilinear velocity (VCL, <i>B</i>), straight-line velocity (VSL, <i>C</i>) and mean tortuosity (MT, <i>D</i>) were determined for sperm. Sperm were prepared and motility characteristics measured as described in the <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036047#s2\" target=\"_blank\">Methods</a> section. N = 1708 (GG), 2709 (GC), 1719 (CC) sperm. Statistical analyses were performed as described in the <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036047#s2\" target=\"_blank\">Methods</a> section; refer to <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036047#pone-0036047-t004\" target=\"_blank\">Table 4</a> for p-values. X-axis values indicate the upper limit of each quartile except for last label, which indicates the lower limit of the fourth quartile; the line at 25% represents values for sperm from GG subjects.</p>", "links"=>[], "tags"=>["characteristics", "rs1025689"], "article_id"=>316394, "categories"=>["Biological Sciences", "Biochemistry", "Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Amy R. Johnson", "Sai Lao", "Tongwen Wang", "Joseph A. Galanko", "Steven H. Zeisel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036047.g003", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Motility_characteristics_change_with_rs1025689_genotype_/316394", "title"=>"Motility characteristics change with rs1025689 genotype.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-27 01:46:34"}
  • {"files"=>["https://ndownloader.figshare.com/files/646678"], "description"=>"<p>Concentrations of choline and its metabolites were measured in plasma collected during the Day 1 clinic visit as described in <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0036047#s2\" target=\"_blank\">Methods</a>. For rs12676 <i>N</i> = 40 (GG), 30 (GT) and 6 (TT). For rs1025689 <i>N</i> = 15 (GG), 37 (GC) and 24 (CC). Data are expressed nmol/L and are presented as mean ± SEM. ANOVA and Tukey-Kramer HSD were used to detect statistical differences among groups.</p>*<p>indicate p<0.05. Choline metabolite concentrations were measured in 3 million sperm from each subject who provided a semen sample on Day 2. For rs12676 <i>N</i> = 17 (GG), 18 (GT) and 4 (TT). For rs1025689 <i>N</i> = 11 (GG), 17 (GC) and 11 (CC). Data are expressed as nmol/3million sperm and are presented as mean ± SEM. ANOVA and Tukey-Kramer HSD were used to detect statistical differences among groups.</p>†<p>indicates different from rs1025689 GC genotype, p<0.05.</p>", "links"=>[], "tags"=>["metabolite", "concentrations", "plasma"], "article_id"=>317175, "categories"=>["Biological Sciences", "Biochemistry", "Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Amy R. Johnson", "Sai Lao", "Tongwen Wang", "Joseph A. Galanko", "Steven H. Zeisel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036047.t005", "stats"=>{"downloads"=>0, "page_views"=>30, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Choline_metabolite_concentrations_in_plasma_and_sperm_/317175", "title"=>"Choline metabolite concentrations in plasma and sperm.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-04-27 01:59:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/646252"], "description"=>"<p>ATP concentrations were determined in sperm using a commercially available bioluminescent assay kit and ATP concentration was normalized to number of sperm assayed. <i>A</i>, Men who were heterozygous or homozygous for the rs12676 variant T allele have reduced ATP concentrations in their sperm. N = 17 (GG), 18 (GT) and 5 (TT). * indicates difference from GG by ANOVA and Tukey-Kramer HSD, p-value <0.05. <i>B</i>, ATP concentrations are not different with rs1025689 genotype. N = 10 (GG), 21 (GC) and 9 (CC). Data presented are mean ± SEM.</p>", "links"=>[], "tags"=>["rs12676", "allele", "atp", "concentrations"], "article_id"=>316741, "categories"=>["Biological Sciences", "Biochemistry", "Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Amy R. Johnson", "Sai Lao", "Tongwen Wang", "Joseph A. Galanko", "Steven H. Zeisel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036047.g005", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_rs12676_minor_T_allele_is_associated_with_decreased_ATP_concentrations_in_sperm_/316741", "title"=>"The rs12676 minor T allele is associated with decreased ATP concentrations in sperm.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-27 01:52:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/646340"], "description"=>"<p><i>A.</i> Representative longitudinal section of sperm midpiece. <i>B.</i> Representative cross-sectional section of sperm midpiece. Arrows indicate mitochondria. <i>C.</i> ATP concentrations as measured previously; “CC\" group only contains data from men who are CC for rs1025689 and not TT for rs12676. Data presented are mean ± SEM. N = 9 (GG), 22 (GC) and 5 (CC).</p>", "links"=>[], "tags"=>["mitochondrial", "morphology", "atp", "concentrations", "changed", "samples", "men", "homozygous"], "article_id"=>316819, "categories"=>["Biological Sciences", "Biochemistry", "Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Amy R. Johnson", "Sai Lao", "Tongwen Wang", "Joseph A. Galanko", "Steven H. Zeisel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036047.g006", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sperm_mitochondrial_morphology_and_ATP_concentrations_are_not_changed_in_samples_from_men_who_are_homozygous_for_rs1025689_but_not_rs12676_/316819", "title"=>"Sperm mitochondrial morphology and ATP concentrations are not changed in samples from men who are homozygous for rs1025689, but not rs12676.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-27 01:53:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/646463"], "description"=>"<p>The abundance of CHDH protein in sperm (A) and primary hepatocyte (B) lysates was measured by western blot. Blots were probed for ∝-TUBULIN (sperm) or β-ACTIN (hepatocytes) and data presented are the mean ± SEM of the ratio of CHDH: ∝-TUBULIN or CHDH:β-ACTIN protein. Statistical differences were tested by ANOVA and Student's <i>t</i> test. * indicates different from GG, p-value <0.05. ** indicates different from GG, p-value <0.01. N = 3 per genotype.</p>", "links"=>[], "tags"=>["chdh", "sperm", "hepatocytes", "humans", "heterozygous", "homozygous", "rs12676"], "article_id"=>316946, "categories"=>["Biological Sciences", "Biochemistry", "Cell Biology", "Genetics", "Developmental Biology"], "users"=>["Amy R. Johnson", "Sai Lao", "Tongwen Wang", "Joseph A. Galanko", "Steven H. Zeisel"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0036047.g007", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_CHDH_protein_is_decreased_in_sperm_and_primary_hepatocytes_from_humans_who_are_heterozygous_or_homozygous_for_the_rs12676_SNP_/316946", "title"=>"Expression of CHDH protein is decreased in sperm and primary hepatocytes from humans who are heterozygous or homozygous for the rs12676 SNP.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-27 01:55:46"}

PMC Usage Stats | Further Information

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