6ee8e554f494bce96ca8eb2403f234ce pmc_32942679.pdf 196025a1b9cb858d684d208fcf541c5e7fe1d994 pmc_32942679.pdf 919ae77ed91a4c8fd526cdc901220802b7f35aec48f087537d62362d085ed2dd pmc_32942679.pdf Title: Polygenic Markers in Patients Diagnosed of Autosomal Dominant Hypercholesterolemia in Catalonia: Distribution of Weighted LDL-c-Raising SNP Scores and Refinement of Variant Selection Subject: Familial hypercholesterolemia (FH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes. A pathological variant has not been identified in 30–70% of clinically diagnosed FH patients, and a burden of LDL cholesterol (LDL-c)-raising alleles has been hypothesized as a potential cause of hypercholesterolemia in these patients. Our aim was to study the distribution of weighted LDL-c-raising single-nucleotide polymorphism (SNP) scores (weighted gene scores or wGS) in a population recruited in a clinical setting in Catalonia. The study included 670 consecutive patients with a clinical diagnosis of FH and a prior genetic study involving 250 mutation-positive (FH/M+) and 420 mutation-negative (FH/M-) patients. Three wGSs based on LDL-c-raising variants were calculated to evaluate their distribution among FH patients and compared with 503 European samples from the 1000 Genomes Project. The FH/M- patients had significantly higher wGSs than the FH/M+ and control populations, with sensitivities ranging from 42% to 47%. A wGS based only on the SNPs significantly associated with FH (wGS8) showed a higher area under the receiver operating characteristic curve, and higher diagnostic specificity and sensitivity, with 46.4% of the subjects in the top quartile. wGS8 would allow for the assignment of a genetic cause to 66.4% of the patients if those with polygenic FH are added to the 37.3% of patients with monogenic FH. Our data indicate that a score based on 8 SNPs and the75th percentile cutoff point may identify patients with polygenic FH in Catalonia, although with limited diagnostic sensitivity and specificity. Keywords: familial hypercholesterolemia; atherosclerosis; genetic risk scores; cardiovascular risk; molecular diagnosis Author: Jesús M. Martín-Campos, Sheila Ruiz-Nogales, Daiana Ibarretxe, Emilio Ortega, Elisabet Sánchez-Pujol, Meritxell Royuela-Juncadella, Àlex Vila, Carolina Guerrero, Alberto Zamora, Cristina Soler i Ferrer, Juan Antonio Arroyo, Gemma Carreras, Susana Martínez-Figueroa, Rosa Roig, Núria Plana, Francisco Blanco-Vaca and Xarxa d’Unitats de Lípids i Arteriosclerosi (XULA) Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Tue Sep 15 12:51:14 2020 CEST ModDate: Tue Sep 15 12:51:14 2020 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 14 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1115090 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- KUBKJX+URWPalladioL-Ital Type 1 Custom yes yes no 79 0 MABDDR+URWPalladioL-Bold Type 1 Custom yes yes no 80 0 ZFEYQJ+VnURWPalladioL-Bold Type 1 Custom yes yes no 81 0 CFRSOE+URWPalladioL-Roma Type 1 Custom yes yes no 82 0 APWKLL+VnURWPalladioL Type 1 Custom yes yes no 83 0 OFLXAT+Rpxr Type 1 Builtin yes yes no 84 0 EBFBTV+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 89 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 106 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 107 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 108 0 RINQCR+Pxsy Type 1 Builtin yes yes no 146 0 YICMPF+Rpcxr Type 1 Builtin yes yes no 195 0 XYBOVT+Rpxb Type 1 Builtin yes yes no 213 0 JOHJPG+URWPalladioL-BoldItal Type 1 Custom yes yes no 214 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 228 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 229 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 230 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 231 0 Times New Roman TrueType WinAnsi no no no 232 0 ABCDEE+Palatino Linotype,BoldItalic TrueType WinAnsi yes yes no 233 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 269 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 270 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 271 0 ABCDEE+Palatino Linotype,Bold CID TrueType Identity-H yes yes yes 272 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 273 0 ABCDEE+Palatino Linotype,BoldItalic TrueType WinAnsi yes yes no 274 0 YWGLGW+Rpxi Type 1 Builtin yes yes no 315 0 TMLEUV+EURM10 Type 1 Builtin yes yes no 316 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-27 03:50:04 CEST RepresentationInformation: pmc_32942679.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-03-31 11:43:25 CEST Size: 1115090 Format: PDF Version: 1.5 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 0 FreeObjects: 2 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: ぉのぴひはつふっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸲ Item: Title: ぅへばづひどねづのぴちぬぜ〴ぜ〰こづっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮ㄩ‾㸊⡜㌷㙜㌷㝜〰こふぢなづっぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰こぎぐぜ〴ぜ〰ぇづのはぴべばどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Children: Item: Title: こふぢなづっぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰こぎぐぜ〴ぜ〰ぇづのはぴべばどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: こぎぐぜ〴ぜ〰ぇづのはぴべばどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: げづびふぬぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぃとちひちっぴづひどびぴどっびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぐはばふぬちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ぇづのはぴべばどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰しづどでとぴづつぜ〴ぜ〰ぇづのづぜ〴ぜ〰こっはひづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸳⸱ Children: Item: Title: ぃとちひちっぴづひどびぴどっびぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぐはばふぬちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ぇづのはぴべばどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰しづどでとぴづつぜ〴ぜ〰ぇづのづぜ〴ぜ〰こっはひづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸳⸱ Item: Title: ぇづのはぴべばどのでぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰しづどでとぴづつぜ〴ぜ〰ぇづのづぜ〴ぜ〰こっはひづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸳⸱ Item: Title: しづどでとぴづつぜ〴ぜ〰ぇづのづぜ〴ぜ〰こっはひづびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸳⸱ Children: Item: Title: ぅびぴどねちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぎふねぢづひぜ〴ぜ〰はてぜ〴ぜ〰ぐはぬべでづのどっぜ〴ぜ〰うえぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獵扳散瑩潮⸳⸳⸲ Item: Title: ぁびびはっどちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぷぇこぜ〴ぜ〰ぷどぴとぜ〴ぜ〰ぐとづのはぴべばづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: いどびっふびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: ぃはのっぬふびどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: げづてづひづのっづび Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: MABDDR+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 150 FontDescriptor: FontName: MABDDR+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: ZFEYQJ+VnURWPalladioL-Bold FontSubset: true FirstChar: 128 LastChar: 243 FontDescriptor: FontName: ZFEYQJ+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: CFRSOE+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 246 FontDescriptor: FontName: CFRSOE+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: RINQCR+Pxsy FontSubset: true FirstChar: 0 LastChar: 122 FontDescriptor: FontName: RINQCR+Pxsy Flags: Symbolic FontBBox: -21, -994, 1292, 912 FontFile: true Font: BaseFont: APWKLL+VnURWPalladioL FontSubset: true FirstChar: 128 LastChar: 243 FontDescriptor: FontName: APWKLL+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: YICMPF+Rpcxr FontSubset: true FirstChar: 151 LastChar: 174 FontDescriptor: FontName: YICMPF+Rpcxr Flags: Symbolic FontBBox: -212, -286, 1344, 973 FontFile: true Font: BaseFont: OFLXAT+Rpxr FontSubset: true FirstChar: 11 LastChar: 62 FontDescriptor: FontName: OFLXAT+Rpxr Flags: Symbolic FontBBox: -40, -283, 904, 728 FontFile: true Font: BaseFont: XYBOVT+Rpxb FontSubset: true FirstChar: 43 LastChar: 47 FontDescriptor: FontName: XYBOVT+Rpxb Flags: Symbolic FontBBox: -57, -266, 932, 729 FontFile: true Font: BaseFont: JOHJPG+URWPalladioL-BoldItal FontSubset: true FirstChar: 65 LastChar: 112 FontDescriptor: FontName: JOHJPG+URWPalladioL-BoldItal Flags: Symbolic FontBBox: -170, -300, 1073, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: YWGLGW+Rpxi FontSubset: true FirstChar: 47 LastChar: 47 FontDescriptor: FontName: YWGLGW+Rpxi Flags: Symbolic FontBBox: -162, -280, 856, 733 FontFile: true Font: BaseFont: TMLEUV+EURM10 FontSubset: true FirstChar: 34 LastChar: 34 FontDescriptor: FontName: TMLEUV+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: KUBKJX+URWPalladioL-Ital FontSubset: true FirstChar: 40 LastChar: 121 FontDescriptor: FontName: KUBKJX+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 75, 757, 238, 793 Annotation: Subtype: Link Rect: 474, 757, 519, 793 Annotation: Subtype: Link Rect: 208, 621, 219, 634 Annotation: Subtype: Link Rect: 499, 621, 510, 634 Annotation: Subtype: Link Rect: 274, 580, 285, 594 Annotation: Subtype: Link Rect: 356, 580, 367, 594 Annotation: Subtype: Link Rect: 466, 162, 518, 181 Annotation: Subtype: Link Rect: 176, 38, 281, 50 Annotation: Subtype: Link Rect: 384, 38, 519, 50 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 211, 457, 218, 467 ActionDest: 414 Annotation: Subtype: Link Rect: 427, 403, 434, 413 ActionDest: 414 Annotation: Subtype: Link Rect: 331, 376, 338, 386 ActionDest: 414 Annotation: Subtype: Link Rect: 338, 376, 345, 386 ActionDest: 414 Annotation: Subtype: Link Rect: 154, 349, 161, 359 ActionDest: 414 Annotation: Subtype: Link Rect: 133, 336, 140, 345 ActionDest: 414 Annotation: Subtype: Link Rect: 116, 309, 123, 318 ActionDest: 414 Annotation: Subtype: Link Rect: 348, 309, 355, 318 ActionDest: 414 Annotation: Subtype: Link Rect: 137, 295, 144, 304 ActionDest: 414 Annotation: Subtype: Link Rect: 508, 241, 515, 250 ActionDest: 414 Annotation: Subtype: Link Rect: 275, 228, 282, 237 ActionDest: 414 Annotation: Subtype: Link Rect: 282, 228, 294, 237 ActionDest: 414 Annotation: Subtype: Link Rect: 265, 214, 272, 223 ActionDest: 414 Annotation: Subtype: Link Rect: 273, 214, 279, 223 ActionDest: 414 Annotation: Subtype: Link Rect: 345, 174, 356, 183 ActionDest: 414 Annotation: Subtype: Link Rect: 256, 160, 268, 169 ActionDest: 414 Annotation: Subtype: Link Rect: 191, 133, 203, 142 ActionDest: 414 Annotation: Subtype: Link Rect: 503, 120, 515, 129 ActionDest: 414 Annotation: Subtype: Link Rect: 492, 106, 504, 115 ActionDest: 414 Annotation: Subtype: Link Rect: 341, 79, 353, 88 ActionDest: 414 Annotation: Subtype: Link Rect: 356, 79, 368, 88 ActionDest: 442 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 145, 715, 157, 725 ActionDest: 442 Annotation: Subtype: Link Rect: 450, 702, 462, 711 ActionDest: 442 Annotation: Subtype: Link Rect: 318, 526, 330, 535 ActionDest: 414 Annotation: Subtype: Link Rect: 330, 526, 342, 535 ActionDest: 442 Annotation: Subtype: Link Rect: 503, 379, 515, 388 ActionDest: 442 Annotation: Subtype: Link Rect: 356, 325, 363, 334 ActionDest: 414 Annotation: Subtype: Link Rect: 363, 325, 370, 334 ActionDest: 414 Annotation: Subtype: Link Rect: 111, 187, 248, 199 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 503, 682, 515, 692 ActionDest: 414 Annotation: Subtype: Link Rect: 171, 561, 183, 570 ActionDest: 442 Annotation: Subtype: Link Rect: 299, 561, 311, 570 ActionDest: 414 Annotation: Subtype: Link Rect: 312, 561, 324, 570 ActionDest: 442 Annotation: Subtype: Link Rect: 306, 491, 313, 500 ActionDest: 414 Annotation: Subtype: Link Rect: 189, 397, 200, 406 ActionDest: 442 Annotation: Subtype: Link Rect: 125, 383, 137, 392 ActionDest: 442 Annotation: Subtype: Link Rect: 253, 383, 265, 392 ActionDest: 442 Annotation: Subtype: Link Rect: 418, 317, 430, 326 ActionDest: 442 Annotation: Subtype: Link Rect: 110, 301, 117, 313 ActionDest: 210 Annotation: Subtype: Link Rect: 390, 260, 397, 274 ActionDest: 210 Annotation: Subtype: Link Rect: 417, 250, 429, 259 ActionDest: 442 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 110, 243, 117, 255 ActionDest: 221 Annotation: Subtype: Link Rect: 187, 216, 194, 228 ActionDest: 221 Annotation: Subtype: Link Rect: 468, 165, 479, 174 ActionDest: 442 Annotation: Subtype: Link Rect: 250, 135, 257, 147 ActionDest: 221 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 153, 405, 164, 414 ActionDest: 442 Annotation: Subtype: Link Rect: 316, 199, 323, 211 ActionDest: 260 Annotation: Subtype: Link Rect: 209, 172, 216, 184 ActionDest: 260 Annotation: Subtype: Link Rect: 288, 145, 295, 157 ActionDest: 260 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 419, 391, 431, 400 ActionDest: 442 Annotation: Subtype: Link Rect: 508, 389, 515, 400 ActionDest: 260 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 433, 467, 439, 479 ActionDest: 210 Annotation: Subtype: Link Rect: 298, 346, 310, 356 ActionDest: 442 Annotation: Subtype: Link Rect: 242, 306, 254, 315 ActionDest: 442 Annotation: Subtype: Link Rect: 149, 195, 156, 207 ActionDest: 221 Annotation: Subtype: Link Rect: 206, 195, 213, 207 ActionDest: 221 Annotation: Subtype: Link Rect: 166, 171, 178, 180 ActionDest: 442 Annotation: Subtype: Link Rect: 179, 171, 191, 180 ActionDest: 442 Annotation: Subtype: Link Rect: 310, 117, 322, 126 ActionDest: 442 Annotation: Subtype: Link Rect: 322, 117, 334, 126 ActionDest: 442 Annotation: Subtype: Link Rect: 400, 76, 412, 85 ActionDest: 442 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 338, 526, 350, 535 ActionDest: 442 Annotation: Subtype: Link Rect: 333, 486, 345, 495 ActionDest: 442 Annotation: Subtype: Link Rect: 192, 243, 204, 252 ActionDest: 442 Annotation: Subtype: Link Rect: 503, 229, 515, 238 ActionDest: 442 Annotation: Subtype: Link Rect: 311, 202, 322, 211 ActionDest: 442 Annotation: Subtype: Link Rect: 248, 175, 260, 184 ActionDest: 414 Annotation: Subtype: Link Rect: 260, 175, 272, 184 ActionDest: 442 Annotation: Subtype: Link Rect: 207, 161, 219, 171 ActionDest: 442 Annotation: Subtype: Link Rect: 348, 121, 360, 130 ActionDest: 414 Annotation: Subtype: Link Rect: 207, 94, 219, 103 ActionDest: 442 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 339, 699, 346, 711 ActionDest: 210 Annotation: Subtype: Link Rect: 450, 675, 462, 684 ActionDest: 414 Annotation: Subtype: Link Rect: 463, 675, 475, 684 ActionDest: 414 Annotation: Subtype: Link Rect: 475, 675, 487, 684 ActionDest: 442 Annotation: Subtype: Link Rect: 488, 675, 500, 684 ActionDest: 468 Annotation: Subtype: Link Rect: 503, 675, 515, 684 ActionDest: 468 Annotation: Subtype: Link Rect: 478, 661, 490, 671 ActionDest: 468 Annotation: Subtype: Link Rect: 490, 661, 502, 671 ActionDest: 468 Annotation: Subtype: Link Rect: 503, 661, 515, 671 ActionDest: 468 Annotation: Subtype: Link Rect: 357, 648, 369, 657 ActionDest: 468 Annotation: Subtype: Link Rect: 422, 607, 434, 617 ActionDest: 468 Annotation: Subtype: Link Rect: 227, 540, 239, 549 ActionDest: 468 Annotation: Subtype: Link Rect: 221, 513, 233, 522 ActionDest: 468 Annotation: Subtype: Link Rect: 233, 513, 245, 522 ActionDest: 468 Annotation: Subtype: Link Rect: 464, 445, 476, 454 ActionDest: 468 Annotation: Subtype: Link Rect: 106, 391, 118, 400 ActionDest: 468 Annotation: Subtype: Link Rect: 372, 364, 384, 373 ActionDest: 468 Annotation: Subtype: Link Rect: 260, 283, 272, 292 ActionDest: 442 Annotation: Subtype: Link Rect: 342, 256, 354, 265 ActionDest: 414 Annotation: Subtype: Link Rect: 182, 242, 194, 252 ActionDest: 442 Annotation: Subtype: Link Rect: 359, 216, 371, 225 ActionDest: 442 Annotation: Subtype: Link Rect: 405, 188, 417, 198 ActionDest: 468 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 272, 634, 284, 644 ActionDest: 468 Annotation: Subtype: Link Rect: 130, 607, 142, 617 ActionDest: 468 Annotation: Subtype: Link Rect: 330, 553, 342, 562 ActionDest: 468 Annotation: Subtype: Link Rect: 341, 432, 518, 443 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 230, 683, 268, 693 Annotation: Subtype: Link Rect: 145, 632, 182, 642 Annotation: Subtype: Link Rect: 145, 580, 182, 590 Annotation: Subtype: Link Rect: 390, 553, 425, 564 Annotation: Subtype: Link Rect: 431, 553, 466, 564 Annotation: Subtype: Link Rect: 350, 515, 388, 525 Annotation: Subtype: Link Rect: 177, 464, 214, 474 Annotation: Subtype: Link Rect: 220, 464, 256, 474 Annotation: Subtype: Link Rect: 479, 437, 516, 448 Annotation: Subtype: Link Rect: 100, 425, 136, 435 Annotation: Subtype: Link Rect: 168, 386, 205, 396 Annotation: Subtype: Link Rect: 479, 347, 516, 358 Annotation: Subtype: Link Rect: 100, 335, 136, 345 Annotation: Subtype: Link Rect: 250, 308, 287, 319 Annotation: Subtype: Link Rect: 293, 308, 329, 319 Annotation: Subtype: Link Rect: 136, 283, 173, 293 Annotation: Subtype: Link Rect: 141, 244, 178, 254 Annotation: Subtype: Link Rect: 184, 244, 220, 254 Annotation: Subtype: Link Rect: 328, 205, 366, 216 Annotation: Subtype: Link Rect: 372, 205, 408, 216 Annotation: Subtype: Link Rect: 196, 166, 234, 177 Annotation: Subtype: Link Rect: 240, 166, 276, 177 Annotation: Subtype: Link Rect: 100, 115, 137, 125 Annotation: Subtype: Link Rect: 143, 115, 179, 125 Annotation: Subtype: Link Rect: 480, 75, 516, 86 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 220, 702, 257, 712 Annotation: Subtype: Link Rect: 304, 663, 342, 673 Annotation: Subtype: Link Rect: 456, 637, 494, 648 Annotation: Subtype: Link Rect: 145, 599, 183, 609 Annotation: Subtype: Link Rect: 233, 560, 271, 570 Annotation: Subtype: Link Rect: 277, 560, 313, 570 Annotation: Subtype: Link Rect: 411, 521, 448, 531 Annotation: Subtype: Link Rect: 454, 521, 490, 531 Annotation: Subtype: Link Rect: 214, 495, 251, 506 Annotation: Subtype: Link Rect: 257, 495, 294, 506 Annotation: Subtype: Link Rect: 240, 443, 277, 454 Annotation: Subtype: Link Rect: 233, 404, 270, 415 Annotation: Subtype: Link Rect: 421, 366, 458, 376 Annotation: Subtype: Link Rect: 370, 353, 408, 364 Annotation: Subtype: Link Rect: 362, 327, 467, 338 Annotation: Subtype: Link Rect: 166, 288, 266, 299 Annotation: Subtype: Link Rect: 479, 249, 516, 260 Annotation: Subtype: Link Rect: 458, 211, 496, 222 Annotation: Subtype: Link Rect: 302, 172, 340, 183 Annotation: Subtype: Link Rect: 364, 133, 402, 144 Annotation: Subtype: Link Rect: 377, 82, 415, 92 Annotation: Subtype: Link Rect: 421, 82, 457, 92 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 291, 715, 328, 725 Annotation: Subtype: Link Rect: 335, 715, 371, 725 Annotation: Subtype: Link Rect: 127, 663, 165, 673 Annotation: Subtype: Link Rect: 171, 663, 207, 673 Annotation: Subtype: Link Rect: 100, 625, 137, 635 Annotation: Subtype: Link Rect: 143, 625, 179, 635 Annotation: Subtype: Link Rect: 296, 572, 334, 583 Annotation: Subtype: Link Rect: 231, 533, 268, 544 Annotation: Subtype: Link Rect: 437, 495, 474, 506 Annotation: Subtype: Link Rect: 479, 443, 516, 454 Annotation: Subtype: Link Rect: 422, 417, 459, 428 Annotation: Subtype: Link Rect: 136, 379, 174, 389 Annotation: Subtype: Link Rect: 180, 379, 216, 389 Annotation: Subtype: Link Rect: 264, 341, 301, 351 Annotation: Subtype: Link Rect: 307, 341, 343, 351 Annotation: Subtype: Link Rect: 100, 302, 137, 312 Annotation: Subtype: Link Rect: 143, 302, 179, 312 Annotation: Subtype: Link Rect: 205, 276, 242, 286 Annotation: Subtype: Link Rect: 249, 276, 285, 286 Annotation: Subtype: Link Rect: 352, 236, 390, 247 Annotation: Subtype: Link Rect: 76, 194, 166, 225 Annotation: Subtype: Link Rect: 234, 189, 407, 200 Checksum: 59461a6e Type: CRC32 Checksum: 6ee8e554f494bce96ca8eb2403f234ce Type: MD5 Checksum: 196025a1b9cb858d684d208fcf541c5e7fe1d994 Type: SHA-1