Adaptive Human CDKAL1 Variants Underlie Hormonal Response Variations at the Enteroinsular Axis
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{"title"=>"Adaptive human CDKAL1 variants underlie hormonal response variations at the enteroinsular axis", "type"=>"journal", "authors"=>[{"first_name"=>"Chia Lin", "last_name"=>"Chang", "scopus_author_id"=>"56926974800"}, {"first_name"=>"James J.", "last_name"=>"Cai", "scopus_author_id"=>"55498169000"}, {"first_name"=>"Shang Yu", "last_name"=>"Huang", "scopus_author_id"=>"56656712000"}, {"first_name"=>"Po Jen", "last_name"=>"Cheng", "scopus_author_id"=>"7401618873"}, {"first_name"=>"Ho Yen", "last_name"=>"Chueh", "scopus_author_id"=>"7003384290"}, {"first_name"=>"Sheau Yu Teddy", "last_name"=>"Hsu", "scopus_author_id"=>"7403183691"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84907190244", "doi"=>"10.1371/journal.pone.0105410", "pui"=>"600033481", "issn"=>"19326203", "pmid"=>"25222615", "sgr"=>"84907190244"}, "id"=>"22aa1872-ed3e-3f3a-b86b-c58ab67e8d46", "abstract"=>"<p>Recent analyses have identified positively selected loci that explain differences in immune responses, body forms, and adaptations to extreme climates, but variants that describe adaptations in energy-balance regulation remain underexplored. To identify variants that confer adaptations in energy-balance regulation, we explored the evolutionary history and functional associations of candidate variants in 207 genes. We screened single nucleotide polymorphisms in genes that had been associated with energy-balance regulation for unusual genetic patterns in human populations, followed by studying associations among selected variants and serum levels of GIP, insulin, and C-peptide in pregnant women after an oral glucose tolerance test. Our analysis indicated that 5? variants in <italic>CDKAL1, CYB5R4</italic>, <italic>GAD2</italic>, and <italic>PPARG</italic> are marked with statistically significant signals of gene?environment interactions. Importantly, studies of serum hormone levels showed that variants in <italic>CDKAL1</italic> are associated with glucose-induced GIP and insulin responses (<italic>p</italic>&lt;0.05). On the other hand, a <italic>GAD2</italic> variant exhibited a significant association with glucose-induced C-peptide response. In addition, simulation analysis indicated that a type 2 diabetes risk variant in <italic>CDKAL1</italic> (rs7754840) was selected in East Asians ?6,900 years ago. Taken together, these data indicated that variants in <italic>CDKAL1</italic> and <italic>GAD2</italic> were targets of prior environmental selection. Because the selection of the <italic>CDKAL1</italic> variant overlapped with the selection of a cluster of <italic>GIP</italic> variants in the same population ?11,800 to 2,000 years ago, we speculate that these regulatory genes at the human enteroinsular axis could be highly responsive to environmental selection in recent human history.</p>", "link"=>"http://www.mendeley.com/research/adaptive-human-cdkal1-variants-underlie-hormonal-response-variations-enteroinsular-axis", "reader_count"=>9, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Student > Doctoral Student"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>1, "Student > Master"=>2, "Other"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Student > Doctoral Student"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>1, "Student > Master"=>2, "Other"=>1}, "reader_count_by_subject_area"=>{"Nursing and Health Professions"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>2, "Medicine and Dentistry"=>3, "Social Sciences"=>1, "Economics, Econometrics and Finance"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Social Sciences"=>{"Social Sciences"=>1}, "Economics, Econometrics and Finance"=>{"Economics, Econometrics and Finance"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>2}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1676229"], "description"=>"a<p> T2D  =  Type 2 diabetes; GDM  =  Gestational diabetes mellitus; OB  =  obesity.</p>b<p> Significant F<sub>ST</sub>, which is defined as higher than 95<sup>th</sup> percentile of F<sub>ST</sub> of common SNPs in the HapMap populations.</p>c<p> Significant iHS assessed using coalescent simulations (see <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0105410#s2\" target=\"_blank\">Methods</a>). iHS has not been determined (N.D.) for SNPs with a minor allele frequency <0.10.</p><p>Gene region candidate SNPs that exhibited signs of selection.</p>", "links"=>[], "tags"=>["Adaptive Human CDKAL 1 Variants Underlie Hormonal Response Variations", "5r", "GAD 2 variant", "gip", "glucose tolerance test", "CDKAL 1", "pparg", "gene", "type 2 diabetes risk variant", "CDKAL 1 variant", "cyb", "serum hormone levels"], "article_id"=>1170229, "categories"=>["Uncategorised"], "users"=>["Chia Lin Chang", "James J. Cai", "Shang Yu Huang", "Po Jen Cheng", "Ho Yen Chueh", "Sheau Yu Teddy Hsu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0105410.t001", "stats"=>{"downloads"=>3, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Gene_region_candidate_SNPs_that_exhibited_signs_of_selection_/1170229", "title"=>"Gene region candidate SNPs that exhibited signs of selection.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-09-15 02:42:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/1676228"], "description"=>"<p>Schematic representation of the selection of multiple <i>CDKAL1</i> and <i>GIP</i> variants in ASN population <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0105410#pone.0105410-Chang1\" target=\"_blank\">[5]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0105410#pone.0105410-Chang2\" target=\"_blank\">[6]</a>. The selection of <i>CDKAL1</i> and <i>GIP</i> variants appeared to occur independently within a 1,200-year time window in the last ten thousand years. The effects of these selections on enteroinsular hormonal responses are indicated by red arrows. The actions of hormones are indicated by black arrows.</p>", "links"=>[], "tags"=>["Adaptive Human CDKAL 1 Variants Underlie Hormonal Response Variations", "5r", "GAD 2 variant", "gip", "glucose tolerance test", "CDKAL 1", "pparg", "gene", "type 2 diabetes risk variant", "CDKAL 1 variant", "cyb", "serum hormone levels"], "article_id"=>1170228, "categories"=>["Uncategorised"], "users"=>["Chia Lin Chang", "James J. Cai", "Shang Yu Huang", "Po Jen Cheng", "Ho Yen Chueh", "Sheau Yu Teddy Hsu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0105410.g004", "stats"=>{"downloads"=>1, "page_views"=>24, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_CDKAL1_and_GIP_variants_were_selected_in_recent_human_history_/1170228", "title"=>"<i>CDKAL1</i> and <i>GIP</i> variants were selected in recent human history.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-15 02:42:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/1676223"], "description"=>"<p>The distribution of the F<sub>ST</sub> for common SNPs across the human genome and the F<sub>ST</sub> for rs1325471, rs2236418, and rs2920502. For rs1325471 and rs2236418, F<sub>ST</sub> estimations between YRI and CEU (<b>a-b</b>) are shown on the <i>x</i>-axis. For rs2920502, comparisons between YRI and ASN (<b>c</b>) are shown on the <i>x</i>-axis. The black arrows indicate the corresponding values of F<sub>ST</sub> for the candidate variant. The <i>y</i>-axis represents the frequency of SNPs with a given F<sub>ST</sub> estimate. Significant F<sub>ST</sub>, which is defined as higher than 95<sup>th</sup> percentile of F<sub>ST</sub> of all common SNPs of HapMap populations, is indicated by an asterisk.</p>", "links"=>[], "tags"=>["Adaptive Human CDKAL 1 Variants Underlie Hormonal Response Variations", "5r", "GAD 2 variant", "gip", "glucose tolerance test", "CDKAL 1", "pparg", "gene", "type 2 diabetes risk variant", "CDKAL 1 variant", "cyb", "serum hormone levels"], "article_id"=>1170223, "categories"=>["Uncategorised"], "users"=>["Chia Lin Chang", "James J. Cai", "Shang Yu Huang", "Po Jen Cheng", "Ho Yen Chueh", "Sheau Yu Teddy Hsu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0105410.g001", "stats"=>{"downloads"=>1, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Differential_distribution_of_CYB5R4_GAD2_and_PPARG_variants_in_human_populations_/1170223", "title"=>"Differential distribution of <i>CYB5R4, GAD2</i>, and <i>PPARG</i> variants in human populations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-15 02:42:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/1676224"], "description"=>"<p>Plots of iHS over the distance between selected variants and neighboring SNPs at increasing distances in YRI, CEU, and ASN populations (rs9368197 [<b>a</b>], rs1325471 [<b>b</b>], rs2236418 [<b>c</b>], rs292502 [<b>d</b>], rs7754840 [<b>e</b>], and rs7756992 [<b>f</b>]). A significant difference in EHH decay between the derived allele and the ancestral allele is indicated by an asterisk. The candidate variant is positioned at the center of the plots.</p>", "links"=>[], "tags"=>["Adaptive Human CDKAL 1 Variants Underlie Hormonal Response Variations", "5r", "GAD 2 variant", "gip", "glucose tolerance test", "CDKAL 1", "pparg", "gene", "type 2 diabetes risk variant", "CDKAL 1 variant", "cyb", "serum hormone levels"], "article_id"=>1170224, "categories"=>["Uncategorised"], "users"=>["Chia Lin Chang", "James J. Cai", "Shang Yu Huang", "Po Jen Cheng", "Ho Yen Chueh", "Sheau Yu Teddy Hsu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0105410.g002", "stats"=>{"downloads"=>2, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Haplotype_diversity_surrounding_CDKAL1_CYB5R4_and_GAD2_variants_is_allele_dependent_in_select_populations_/1170224", "title"=>"Haplotype diversity surrounding <i>CDKAL1, CYB5R4</i>, and <i>GAD2</i> variants is allele-dependent in select populations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-15 02:42:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/1676236"], "description"=>"<div><p>Recent analyses have identified positively selected loci that explain differences in immune responses, body forms, and adaptations to extreme climates, but variants that describe adaptations in energy-balance regulation remain underexplored. To identify variants that confer adaptations in energy-balance regulation, we explored the evolutionary history and functional associations of candidate variants in 207 genes. We screened single nucleotide polymorphisms in genes that had been associated with energy-balance regulation for unusual genetic patterns in human populations, followed by studying associations among selected variants and serum levels of GIP, insulin, and C-peptide in pregnant women after an oral glucose tolerance test. Our analysis indicated that 5′ variants in <i>CDKAL1, CYB5R4</i>, <i>GAD2</i>, and <i>PPARG</i> are marked with statistically significant signals of gene–environment interactions. Importantly, studies of serum hormone levels showed that variants in <i>CDKAL1</i> are associated with glucose-induced GIP and insulin responses (<i>p</i><0.05). On the other hand, a <i>GAD2</i> variant exhibited a significant association with glucose-induced C-peptide response. In addition, simulation analysis indicated that a type 2 diabetes risk variant in <i>CDKAL1</i> (rs7754840) was selected in East Asians ∼6,900 years ago. Taken together, these data indicated that variants in <i>CDKAL1</i> and <i>GAD2</i> were targets of prior environmental selection. Because the selection of the <i>CDKAL1</i> variant overlapped with the selection of a cluster of <i>GIP</i> variants in the same population ∼11,800 to 2,000 years ago, we speculate that these regulatory genes at the human enteroinsular axis could be highly responsive to environmental selection in recent human history.</p></div>", "links"=>[], "tags"=>["Adaptive Human CDKAL 1 Variants Underlie Hormonal Response Variations", "5r", "GAD 2 variant", "gip", "glucose tolerance test", "CDKAL 1", "pparg", "gene", "type 2 diabetes risk variant", "CDKAL 1 variant", "cyb", "serum hormone levels"], "article_id"=>1170236, "categories"=>["Uncategorised"], "users"=>["Chia Lin Chang", "James J. Cai", "Shang Yu Huang", "Po Jen Cheng", "Ho Yen Chueh", "Sheau Yu Teddy Hsu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0105410", "stats"=>{"downloads"=>1, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Adaptive_Human_CDKAL1_Variants_Underlie_Hormonal_Response_Variations_at_the_Enteroinsular_Axis/1170236", "title"=>"Adaptive Human <i>CDKAL1</i> Variants Underlie Hormonal Response Variations at the Enteroinsular Axis", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-09-15 02:42:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/1676230"], "description"=>"a<p> <i>p</i> values of comparisons between a homozygous genotype, and those with a heterozygous or an opposite homozygous genotype (Student's <i>t</i>-test).</p>b<p> Significantly different from the averages of those with a heterozygous or a homozygous ancestral genotype. (<i>p</i><0.05).</p>c<p> Significantly different from the averages of those with a heterozygous or a homozygous derived genotype (<i>p</i><0.05).</p><p>Association between selected SNPs and hormonal responses after glucose challenge tests in pregnant women.</p>", "links"=>[], "tags"=>["Adaptive Human CDKAL 1 Variants Underlie Hormonal Response Variations", "5r", "GAD 2 variant", "gip", "glucose tolerance test", "CDKAL 1", "pparg", "gene", "type 2 diabetes risk variant", "CDKAL 1 variant", "cyb", "serum hormone levels"], "article_id"=>1170230, "categories"=>["Uncategorised"], "users"=>["Chia Lin Chang", "James J. Cai", "Shang Yu Huang", "Po Jen Cheng", "Ho Yen Chueh", "Sheau Yu Teddy Hsu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0105410.t002", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Association_between_selected_SNPs_and_hormonal_responses_after_glucose_challenge_tests_in_pregnant_women_/1170230", "title"=>"Association between selected SNPs and hormonal responses after glucose challenge tests in pregnant women.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-09-15 02:42:16"}
  • {"files"=>["https://ndownloader.figshare.com/files/1676226"], "description"=>"<p><b>a</b>) Measurements of serum insulin levels in patients during the 23<sup>rd</sup> to the 29<sup>th</sup> weeks of pregnancy at 1 hr after the 50-gram glucose challenge test. Levels of insulin in patients who were homozygous for the derived T allele of rs9368197 (28.8±3.1 mU/L, <i>N</i> = 36) were significantly lower than those of patients carrying the ancestral G allele (i.e., heterozygotes and ancestral allele homozygotes, 42.8±3.7 mU/L, <i>N</i> = 89). <b>b</b>) Measurements of serum GIP levels in patients during the 23<sup>rd</sup> to the 29<sup>th</sup> weeks of pregnancy at 1 hr after the 50-gram glucose challenge test. Circulating levels of GIP in patients who were homozygous for the ancestral G allele of rs7754840 (68.9±4.5 pg/ml, <i>N</i>  = 54) were significantly lower than were those of patients carrying a derived C allele (i.e., heterozygotes and derived allele homozygotes, 82.8±4.5 pg/ml, <i>N</i> = 65). Serum hormone levels are presented as mean ± SEM.</p>", "links"=>[], "tags"=>["Adaptive Human CDKAL 1 Variants Underlie Hormonal Response Variations", "5r", "GAD 2 variant", "gip", "glucose tolerance test", "CDKAL 1", "pparg", "gene", "type 2 diabetes risk variant", "CDKAL 1 variant", "cyb", "serum hormone levels"], "article_id"=>1170226, "categories"=>["Uncategorised"], "users"=>["Chia Lin Chang", "James J. Cai", "Shang Yu Huang", "Po Jen Cheng", "Ho Yen Chueh", "Sheau Yu Teddy Hsu"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0105410.g003", "stats"=>{"downloads"=>2, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genotypes_of_rs9368197_and_rs7754840_in_CDKAL1_impart_a_difference_in_glucose_induced_insulin_and_GIP_response_respectively_after_glucose_challenge_tests_/1170226", "title"=>"Genotypes of rs9368197 and rs7754840 in <i>CDKAL1</i> impart a difference in glucose-induced insulin and GIP response, respectively, after glucose challenge tests.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-15 02:42:16"}

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