4b4f4b001d6ad8b145b5ad4a08f72080 302183.pdf d2ed18db05da31af6d4641b28ed49289971b08d1 302183.pdf b662e8c280a61fed2d5be994d328997e5946df9f8ba63d7e5309440cf54b9759 302183.pdf Title: Genetic Variants at the 9p21.3 Locus Are Associated with Risk for Non-Compressible Artery Disease: Results from the ARTPER Study Subject: Peripheral artery disease (PAD) and non-compressible artery disease (NCAD) constitute predictors of subclinical atherosclerosis easily assessed through the ankle brachial index (ABI). Although both diseases show substantial genetic influences, few genetic association studies have focused on the ABI and PAD, and none have focused on NCAD. To overcome these limitations, we assessed the role of several candidate genes on the ABI, both in its continuous distribution and in the clinical manifestations associated to its extreme values: PAD and NCAD. We examined 13 candidate genomic regions in 1606 participants from the ARTPER study, a prospective population-based cohort, with the ABI assessed through ultrasonography. Association analyses were conducted independently for individuals with PAD (ABI < 0.9) or with NCAD (ABI > 1.4) vs. healthy participants. After including potential covariates and correction for multiple testing, minor alleles in the genetic markers rs10757278 and rs1333049, both in the 9p21.3 region, were significantly associated with a decreased risk of NCAD. Associations with the ABI showed limited support to these results. No significant associations were detected for PAD. The locus 9p21.3 constitutes the first genetic locus associated with NCAD, an assessment of subclinical atherosclerosis feasible for implementation in primary healthcare settings that has been systematically neglected from genetic studies. Keywords: ankle brachial index; non-compressible artery disease; peripheral artery disease; 9p21.3; subclinical atherosclerosis Author: Marc Via, Guillem Pera, Rosa Forés, Anna Costa-Garrido, Antonio Heras, José Miguel Baena-Díez, Edurne Pedrosa, Inmaculada C. Clemente, Noemí Lamonja-Vicente, Maria Mataró, Pere Torán-Montserrat and M. Teresa Alzamora Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Tue Dec 19 07:49:23 2023 CET ModDate: Tue Dec 19 07:57:24 2023 CET Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 11 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 271356 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- JYPLJJ+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 IBTYZX+VnURWPalladioL Type 1 Custom yes yes yes 16 0 RVVBGC+URWPalladioL-Bold Type 1 Custom yes yes yes 21 0 ULORQM+URWPalladioL-Roma Type 1 Custom yes yes yes 27 0 NRQZCR+URWPalladioL-Ital Type 1 Custom yes yes yes 32 0 KONDUX+EuphemiaUCAS-Bold Type 1C WinAnsi yes yes no 48 0 HIZBRM+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 51 0 EILUJF+CMSY10 Type 1 Builtin yes yes yes 68 0 NGOKVJ+EURM10 Type 1 Builtin yes yes yes 79 0 WBVKDJ+URWPalladioL-BoldItal Type 1 Custom yes yes yes 87 0 ZYYJXI+EURB10 Type 1 Builtin yes yes yes 98 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-11-23 05:18:41 CET RepresentationInformation: 302183.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-01-10 14:47:11 CET Size: 271356 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 260 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Subjects Destination: subsection.2.1 Item: Title: Data Collection Destination: subsection.2.2 Item: Title: Genetic Analyses Destination: subsection.2.3 Item: Title: Statistical Analyses Destination: subsection.2.4 Item: Title: Results Destination: section.3 Children: Item: Title: Sample Destination: subsection.3.1 Item: Title: Association Analyses Destination: subsection.3.2 Item: Title: Discussion Destination: section.4 Item: Title: References Destination: appendix.A. Info: Title: Genetic Variants at the 9p21.3 Locus Are Associated with Risk for Non-Compressible Artery Disease: Results from the ARTPER Study Author: Marc Via, Guillem Pera, Rosa Forés, Anna Costa-Garrido, Antonio Heras, José Miguel Baena-Díez, Edurne Pedrosa, Inmaculada C. Clemente, Noemí Lamonja-Vicente, Maria Mataró, Pere Torán-Montserrat and M. Teresa Alzamora Subject: Peripheral artery disease (PAD) and non-compressible artery disease (NCAD) constitute predictors of subclinical atherosclerosis easily assessed through the ankle brachial index (ABI). Although both diseases show substantial genetic influences, few genetic association studies have focused on the ABI and PAD, and none have focused on NCAD. To overcome these limitations, we assessed the role of several candidate genes on the ABI, both in its continuous distribution and in the clinical manifestations associated to its extreme values: PAD and NCAD. We examined 13 candidate genomic regions in 1606 participants from the ARTPER study, a prospective population-based cohort, with the ABI assessed through ultrasonography. Association analyses were conducted independently for individuals with PAD (ABI < 0.9) or with NCAD (ABI > 1.4) vs. healthy participants. After including potential covariates and correction for multiple testing, minor alleles in the genetic markers rs10757278 and rs1333049, both in the 9p21.3 region, were significantly associated with a decreased risk of NCAD. Associations with the ABI showed limited support to these results. No significant associations were detected for PAD. The locus 9p21.3 constitutes the first genetic locus associated with NCAD, an assessment of subclinical atherosclerosis feasible for implementation in primary healthcare settings that has been systematically neglected from genetic studies. Keywords: ankle brachial index; non-compressible artery disease; peripheral artery disease; 9p21.3; subclinical atherosclerosis Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Tue Dec 19 07:49:23 CET 2023 ModDate: Tue Dec 19 07:57:24 CET 2023 ID: 0x4acbfe50d6e012244b7b744ff8f4beef, 0x4acbfe50d6e012244b7b744ff8f4beef Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: NRQZCR+URWPalladioL-Ital FontSubset: true FirstChar: 45 LastChar: 121 FontDescriptor: FontName: NRQZCR+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: IBTYZX+VnURWPalladioL FontSubset: true FirstChar: 160 LastChar: 226 FontDescriptor: FontName: IBTYZX+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: ZYYJXI+EURB10 FontSubset: true FirstChar: 12 LastChar: 12 FontDescriptor: FontName: ZYYJXI+EURB10 Flags: Symbolic FontBBox: -30, -247, 1178, 723 FontFile: true ToUnicode: true Font: BaseFont: EILUJF+CMSY10 FontSubset: true FirstChar: 0 LastChar: 21 FontDescriptor: FontName: EILUJF+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true ToUnicode: true Font: BaseFont: RVVBGC+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: RVVBGC+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: WBVKDJ+URWPalladioL-BoldItal FontSubset: true FirstChar: 112 LastChar: 112 FontDescriptor: FontName: WBVKDJ+URWPalladioL-BoldItal Flags: Symbolic FontBBox: -170, -300, 1073, 935 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: JYPLJJ+VnURWPalladioL-Bold FontSubset: true FirstChar: 161 LastChar: 226 FontDescriptor: FontName: JYPLJJ+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: ULORQM+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: ULORQM+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true ToUnicode: true Font: BaseFont: NGOKVJ+EURM10 FontSubset: true FirstChar: 12 LastChar: 21 FontDescriptor: FontName: NGOKVJ+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true ToUnicode: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 112, 279, 152, 288 Annotation: Subtype: Link Rect: 34, 267, 135, 276 Annotation: Subtype: Link Rect: 34, 164, 96, 186 Annotation: Subtype: Link Rect: 125, 90, 154, 99 Annotation: Subtype: Link Rect: 34, 78, 149, 87 Annotation: Subtype: Link Rect: 34, 756, 135, 792 Annotation: Subtype: Link Rect: 515, 756, 560, 792 Annotation: Subtype: Link Rect: 96, 642, 107, 655 Annotation: Subtype: Link Rect: 177, 642, 188, 655 Annotation: Subtype: Link Rect: 436, 642, 447, 655 Annotation: Subtype: Link Rect: 240, 629, 252, 643 Annotation: Subtype: Link Rect: 110, 617, 121, 630 Annotation: Subtype: Link Rect: 233, 617, 244, 630 Annotation: Subtype: Link Rect: 351, 70, 358, 79 ActionDest: 109 Annotation: Subtype: Link Rect: 96, 17, 240, 28 Annotation: Subtype: Link Rect: 416, 17, 560, 28 Annotation: Subtype: Link Rect: 34, 388, 87, 407 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 449, 744, 456, 752 ActionDest: 109 Annotation: Subtype: Link Rect: 296, 706, 303, 715 ActionDest: 109 Annotation: Subtype: Link Rect: 473, 681, 480, 690 ActionDest: 109 Annotation: Subtype: Link Rect: 480, 681, 487, 690 ActionDest: 109 Annotation: Subtype: Link Rect: 352, 655, 358, 665 ActionDest: 109 Annotation: Subtype: Link Rect: 304, 631, 311, 639 ActionDest: 109 Annotation: Subtype: Link Rect: 213, 618, 220, 627 ActionDest: 109 Annotation: Subtype: Link Rect: 223, 618, 235, 627 ActionDest: 109 Annotation: Subtype: Link Rect: 262, 605, 274, 614 ActionDest: 109 Annotation: Subtype: Link Rect: 411, 518, 423, 526 ActionDest: 109 Annotation: Subtype: Link Rect: 424, 517, 435, 526 ActionDest: 112 Annotation: Subtype: Link Rect: 269, 480, 281, 489 ActionDest: 112 Annotation: Subtype: Link Rect: 282, 480, 294, 489 ActionDest: 112 Annotation: Subtype: Link Rect: 510, 442, 522, 451 ActionDest: 112 Annotation: Subtype: Link Rect: 281, 329, 293, 338 ActionDest: 112 Annotation: Subtype: Link Rect: 512, 291, 524, 301 ActionDest: 112 Annotation: Subtype: Link Rect: 475, 241, 487, 250 ActionDest: 112 Annotation: Subtype: Link Rect: 344, 216, 356, 225 ActionDest: 112 Annotation: Subtype: Link Rect: 262, 191, 274, 200 ActionDest: 112 Annotation: Subtype: Link Rect: 345, 154, 357, 162 ActionDest: 112 Annotation: Subtype: Link Rect: 360, 153, 371, 162 ActionDest: 112 Annotation: Subtype: Link Rect: 448, 116, 460, 125 ActionDest: 112 Annotation: Subtype: Link Rect: 439, 78, 451, 87 ActionDest: 112 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 536, 617, 543, 626 ActionDest: 109 Annotation: Subtype: Link Rect: 544, 617, 556, 626 ActionDest: 112 Annotation: Subtype: Link Rect: 478, 416, 485, 425 ActionDest: 109 Annotation: Subtype: Link Rect: 398, 390, 410, 399 ActionDest: 112 Annotation: Subtype: Link Rect: 410, 391, 422, 399 ActionDest: 112 Annotation: Subtype: Link Rect: 508, 378, 515, 387 ActionDest: 109 Annotation: Subtype: Link Rect: 446, 300, 453, 312 ActionDest: 73 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 200, 539, 212, 549 ActionDest: 112 Annotation: Subtype: Link Rect: 526, 513, 533, 524 ActionDest: 84 Annotation: Subtype: Link Rect: 168, 223, 369, 235 Annotation: Subtype: Link Rect: 503, 225, 515, 234 ActionDest: 112 Annotation: Subtype: Link Rect: 409, 188, 421, 197 ActionDest: 112 Annotation: Subtype: Link Rect: 430, 185, 560, 197 Annotation: Subtype: Link Rect: 165, 173, 295, 185 Page: Sequence: 5 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 362, 599, 369, 611 ActionDest: 73 Annotation: Subtype: Link Rect: 237, 473, 244, 485 ActionDest: 84 Annotation: Subtype: Link Rect: 521, 463, 533, 472 ActionDest: 112 Annotation: Subtype: Link Rect: 195, 423, 202, 435 ActionDest: 95 Annotation: Subtype: Link Rect: 343, 385, 350, 397 ActionDest: 73 Annotation: Subtype: Link Rect: 190, 297, 197, 309 ActionDest: 95 Page: Sequence: 7 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 520, 578, 527, 590 ActionDest: 95 Annotation: Subtype: Link Rect: 448, 392, 455, 401 ActionDest: 109 Annotation: Subtype: Link Rect: 270, 354, 282, 363 ActionDest: 112 Annotation: Subtype: Link Rect: 282, 354, 294, 363 ActionDest: 112 Annotation: Subtype: Link Rect: 317, 166, 329, 175 ActionDest: 112 Annotation: Subtype: Link Rect: 195, 128, 207, 137 ActionDest: 112 Annotation: Subtype: Link Rect: 469, 78, 481, 87 ActionDest: 112 Annotation: Subtype: Link Rect: 481, 78, 493, 87 ActionDest: 112 Annotation: Subtype: Link Rect: 544, 78, 556, 87 ActionDest: 112 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 191, 681, 203, 690 ActionDest: 112 Annotation: Subtype: Link Rect: 206, 681, 218, 690 ActionDest: 112 Annotation: Subtype: Link Rect: 398, 643, 410, 652 ActionDest: 112 Annotation: Subtype: Link Rect: 411, 643, 423, 652 ActionDest: 112 Annotation: Subtype: Link Rect: 323, 505, 335, 514 ActionDest: 112 Annotation: Subtype: Link Rect: 408, 480, 420, 489 ActionDest: 112 Annotation: Subtype: Link Rect: 544, 229, 556, 238 ActionDest: 112 Annotation: Subtype: Link Rect: 299, 191, 311, 200 ActionDest: 112 Annotation: Subtype: Link Rect: 311, 191, 323, 200 ActionDest: 112 Annotation: Subtype: Link Rect: 536, 165, 560, 176 Annotation: Subtype: Link Rect: 165, 153, 387, 164 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 423, 422, 460, 433 Annotation: Subtype: Link Rect: 467, 422, 503, 433 Annotation: Subtype: Link Rect: 285, 399, 323, 410 Annotation: Subtype: Link Rect: 329, 399, 365, 410 Annotation: Subtype: Link Rect: 59, 377, 96, 387 Annotation: Subtype: Link Rect: 102, 377, 138, 387 Annotation: Subtype: Link Rect: 160, 343, 198, 353 Annotation: Subtype: Link Rect: 184, 297, 221, 307 Annotation: Subtype: Link Rect: 59, 262, 96, 272 Annotation: Subtype: Link Rect: 239, 228, 276, 238 Annotation: Subtype: Link Rect: 135, 193, 173, 203 Annotation: Subtype: Link Rect: 215, 158, 252, 169 Annotation: Subtype: Link Rect: 183, 136, 221, 146 Annotation: Subtype: Link Rect: 519, 112, 557, 123 Annotation: Subtype: Link Rect: 59, 101, 95, 111 Annotation: Subtype: Link Rect: 113, 78, 150, 88 Annotation: Subtype: Link Rect: 156, 78, 192, 88 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 95, 730, 131, 741 Annotation: Subtype: Link Rect: 113, 696, 150, 706 Annotation: Subtype: Link Rect: 156, 696, 192, 706 Annotation: Subtype: Link Rect: 172, 673, 209, 683 Annotation: Subtype: Link Rect: 215, 673, 252, 683 Annotation: Subtype: Link Rect: 113, 650, 150, 660 Annotation: Subtype: Link Rect: 156, 650, 192, 660 Annotation: Subtype: Link Rect: 499, 615, 536, 625 Annotation: Subtype: Link Rect: 301, 581, 338, 591 Annotation: Subtype: Link Rect: 59, 546, 96, 556 Annotation: Subtype: Link Rect: 59, 512, 96, 522 Annotation: Subtype: Link Rect: 185, 477, 223, 487 Annotation: Subtype: Link Rect: 463, 442, 501, 453 Annotation: Subtype: Link Rect: 507, 442, 543, 453 Annotation: Subtype: Link Rect: 421, 419, 459, 430 Annotation: Subtype: Link Rect: 465, 419, 501, 430 Annotation: Subtype: Link Rect: 479, 373, 516, 384 Annotation: Subtype: Link Rect: 521, 373, 557, 384 Annotation: Subtype: Link Rect: 258, 350, 296, 361 Annotation: Subtype: Link Rect: 302, 350, 338, 361 Annotation: Subtype: Link Rect: 99, 328, 137, 338 Annotation: Subtype: Link Rect: 454, 292, 492, 303 Annotation: Subtype: Link Rect: 409, 258, 447, 269 Annotation: Subtype: Link Rect: 485, 236, 522, 246 Annotation: Subtype: Link Rect: 117, 213, 155, 223 Annotation: Subtype: Link Rect: 477, 200, 515, 211 Annotation: Subtype: Link Rect: 521, 200, 557, 211 Annotation: Subtype: Link Rect: 160, 178, 198, 188 Annotation: Subtype: Link Rect: 204, 178, 240, 188 Annotation: Subtype: Link Rect: 220, 154, 258, 165 Annotation: Subtype: Link Rect: 264, 154, 300, 165 Checksum: 37067002 Type: CRC32 Checksum: 4b4f4b001d6ad8b145b5ad4a08f72080 Type: MD5 Checksum: d2ed18db05da31af6d4641b28ed49289971b08d1 Type: SHA-1 Checksum: b662e8c280a61fed2d5be994d328997e5946df9f8ba63d7e5309440cf54b9759 Type: SHA-256