68fd98d8ce26cc4df1accfd642a05f4c pmc_9139123.pdf a135e942bed5b80646ef8ec7355754eaa627d941 pmc_9139123.pdf 848ad3c8691f2c4b64dfdfccca15d67425f15fae604251065e9f6a75fc2950e8 pmc_9139123.pdf Title: Influence of Type 2 Diabetes in the Association of PNPLA3 rs738409 and TM6SF2 rs58542926 Polymorphisms in NASH Advanced Liver Fibrosis Subject: Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis in western countries. Insulin resistance (IR), type 2 diabetes (T2D), and the polymorphisms patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 and transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 are independent risk factors of NASH. Nevertheless, little is known about the interaction between IR and T2D with these polymorphisms in the pathogenesis of NASH and the development of advanced fibrosis. Thus, our study aimed to investigate this relationship. This is a cross-sectional study including NASH patients diagnosed by liver biopsy, at the Vall d’Hebron University Hospital. A total of 140 patients were included (93 T2D, 47 non-T2D). T2D (OR = 4.67; 95%CI 2.13–10.20; p < 0.001), PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms (OR = 3.94; 95%CI 1.63–9.54; p = 0.002) were independently related with advanced liver fibrosis. T2D increased the risk of advance fibrosis on top of the two polymorphisms (OR = 14.69; 95%CI 3.03–77.35; p = 0.001 for PNPLA3 rs738409 and OR = 11.45; 95%CI 3.16–41.55; p < 0.001 for TM6SF2 rs58542926). In non-T2D patients, the IR (HOMA-IR 5.2, OR = 14.33; 95%CI 2.14–18.66; p = 0.014) increased the risk of advanced fibrosis when the polymorphisms were present (OR = 19.04; 95%CI 1.71–650.84; p = 0.042). The T2D and IR status increase the risk of advanced fibrosis in patients with NASH carrying the PNPLA3 rs738409 and/or TM6SF2 rs58542926 polymorphisms, respectively. Keywords: nonalcoholic steatohepatitis (NASH); advanced fibrosis; PNPLA3 p.I148M; TM6SF2 p.E167K; type 2 diabetes (T2D); homeostatic model assessment for insulin resistance (HOMA-IR) Author: Pablo Gabriel-Medina, Roser Ferrer-Costa, Francisco Rodriguez-Frias, Andreea Ciudin, Salvador Augustin, Jesus Rivera-Esteban, Juan M. Pericàs and David Martinez Selva Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri Apr 29 05:43:13 2022 CEST ModDate: Fri Apr 29 06:03:42 2022 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 12 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 304257 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- CIQLLF+VnURWPalladioL Type 1 Custom yes yes no 10 0 RKUFNW+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 ZAGYSR+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 KLUSUE+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 HRUJQI+URWPalladioL-BoldItal Type 1 Custom yes yes no 28 0 IKKWKP+CMSY10 Type 1 Builtin yes yes no 32 0 WNWTFR+VnURWPalladioL-Bold Type 1 Custom yes yes no 36 0 EBFBTV+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 54 0 CAMXTK+EURM10 Type 1 Builtin yes yes no 79 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-05-18 03:25:03 CEST RepresentationInformation: pmc_9139123.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-05-18 02:37:14 CEST Size: 304257 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 264 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Item: Title: Results Destination: section.3 Children: Item: Title: Characteristics of the Study Cohort Destination: subsection.3.1 Item: Title: Genetic Analysis Destination: subsection.3.2 Item: Title: Risk Factors of Advanced Liver Fibrosis Destination: subsection.3.3 Item: Title: Discussion Destination: section.4 Item: Title: References Destination: section.4 Info: Title: Influence of Type 2 Diabetes in the Association of PNPLA3 rs738409 and TM6SF2 rs58542926 Polymorphisms in NASH Advanced Liver Fibrosis Author: Pablo Gabriel-Medina, Roser Ferrer-Costa, Francisco Rodriguez-Frias, Andreea Ciudin, Salvador Augustin, Jesus Rivera-Esteban, Juan M. Pericàs and David Martinez Selva Subject: Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis in western countries. Insulin resistance (IR), type 2 diabetes (T2D), and the polymorphisms patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 and transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 are independent risk factors of NASH. Nevertheless, little is known about the interaction between IR and T2D with these polymorphisms in the pathogenesis of NASH and the development of advanced fibrosis. Thus, our study aimed to investigate this relationship. This is a cross-sectional study including NASH patients diagnosed by liver biopsy, at the Vall d’Hebron University Hospital. A total of 140 patients were included (93 T2D, 47 non-T2D). T2D (OR = 4.67; 95%CI 2.13 10.20; p < 0.001), PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphisms (OR = 3.94; 95%CI 1.63 9.54; p = 0.002) were independently related with advanced liver fibrosis. T2D increased the risk of advance fibrosis on top of the two polymorphisms (OR = 14.69; 95%CI 3.03 77.35; p = 0.001 for PNPLA3 rs738409 and OR = 11.45; 95%CI 3.16 41.55; p < 0.001 for TM6SF2 rs58542926). In non-T2D patients, the IR (HOMA-IR 5.2, OR = 14.33; 95%CI 2.14 18.66; p = 0.014) increased the risk of advanced fibrosis when the polymorphisms were present (OR = 19.04; 95%CI 1.71 650.84; p = 0.042). The T2D and IR status increase the risk of advanced fibrosis in patients with NASH carrying the PNPLA3 rs738409 and/or TM6SF2 rs58542926 polymorphisms, respectively. Keywords: nonalcoholic steatohepatitis (NASH); advanced fibrosis; PNPLA3 p.I148M; TM6SF2 p.E167K; type 2 diabetes (T2D); homeostatic model assessment for insulin resistance (HOMA-IR) Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri Apr 29 05:43:13 CEST 2022 ModDate: Fri Apr 29 06:03:42 CEST 2022 ID: 0xa3724f2bc5af18c237a72ee78822362e, 0xa3724f2bc5af18c237a72ee78822362e Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: IKKWKP+CMSY10 FontSubset: true FirstChar: 20 LastChar: 21 FontDescriptor: FontName: IKKWKP+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: WNWTFR+VnURWPalladioL-Bold FontSubset: true FirstChar: 160 LastChar: 160 FontDescriptor: FontName: WNWTFR+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: ZAGYSR+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: ZAGYSR+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: KLUSUE+URWPalladioL-Ital FontSubset: true FirstChar: 46 LastChar: 121 FontDescriptor: FontName: KLUSUE+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: CIQLLF+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 226 FontDescriptor: FontName: CIQLLF+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: HRUJQI+URWPalladioL-BoldItal FontSubset: true FirstChar: 50 LastChar: 112 FontDescriptor: FontName: HRUJQI+URWPalladioL-BoldItal Flags: Symbolic FontBBox: -170, -300, 1073, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: RKUFNW+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 122 FontDescriptor: FontName: RKUFNW+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: CAMXTK+EURM10 FontSubset: true FirstChar: 12 LastChar: 22 FontDescriptor: FontName: CAMXTK+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 34, 335, 152, 344 Annotation: Subtype: Link Rect: 34, 325, 105, 332 Annotation: Subtype: Link Rect: 34, 164, 96, 186 Annotation: Subtype: Link Rect: 126, 90, 154, 99 Annotation: Subtype: Link Rect: 34, 78, 147, 87 Annotation: Subtype: Link Rect: 34, 756, 197, 792 Annotation: Subtype: Link Rect: 515, 756, 560, 792 Annotation: Subtype: Link Rect: 266, 644, 277, 657 Annotation: Subtype: Link Rect: 425, 644, 436, 657 Annotation: Subtype: Link Rect: 532, 644, 543, 657 Annotation: Subtype: Link Rect: 336, 631, 347, 645 Annotation: Subtype: Link Rect: 373, 80, 380, 89 ActionDest: 101 Annotation: Subtype: Link Rect: 130, 17, 302, 28 Annotation: Subtype: Link Rect: 389, 17, 560, 28 Annotation: Subtype: Link Rect: 34, 468, 87, 487 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 541, 723, 548, 732 ActionDest: 101 Annotation: Subtype: Link Rect: 549, 723, 556, 732 ActionDest: 101 Annotation: Subtype: Link Rect: 381, 698, 388, 707 ActionDest: 101 Annotation: Subtype: Link Rect: 391, 698, 398, 707 ActionDest: 101 Annotation: Subtype: Link Rect: 445, 660, 452, 669 ActionDest: 101 Annotation: Subtype: Link Rect: 319, 647, 326, 657 ActionDest: 101 Annotation: Subtype: Link Rect: 549, 635, 556, 644 ActionDest: 101 Annotation: Subtype: Link Rect: 275, 610, 287, 619 ActionDest: 101 Annotation: Subtype: Link Rect: 448, 585, 460, 594 ActionDest: 101 Annotation: Subtype: Link Rect: 463, 585, 475, 594 ActionDest: 101 Annotation: Subtype: Link Rect: 459, 572, 466, 581 ActionDest: 101 Annotation: Subtype: Link Rect: 538, 547, 550, 556 ActionDest: 101 Annotation: Subtype: Link Rect: 463, 522, 475, 531 ActionDest: 101 Annotation: Subtype: Link Rect: 476, 522, 488, 531 ActionDest: 101 Annotation: Subtype: Link Rect: 335, 497, 347, 506 ActionDest: 101 Annotation: Subtype: Link Rect: 347, 497, 359, 506 ActionDest: 101 Annotation: Subtype: Link Rect: 408, 484, 420, 493 ActionDest: 101 Annotation: Subtype: Link Rect: 235, 459, 247, 468 ActionDest: 104 Annotation: Subtype: Link Rect: 436, 397, 448, 406 ActionDest: 104 Annotation: Subtype: Link Rect: 494, 372, 506, 380 ActionDest: 104 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 460, 735, 472, 744 ActionDest: 104 Annotation: Subtype: Link Rect: 496, 660, 508, 669 ActionDest: 104 Annotation: Subtype: Link Rect: 375, 635, 387, 644 ActionDest: 104 Annotation: Subtype: Link Rect: 340, 622, 352, 631 ActionDest: 104 Annotation: Subtype: Link Rect: 390, 547, 402, 556 ActionDest: 104 Annotation: Subtype: Link Rect: 168, 444, 349, 456 Annotation: Subtype: Link Rect: 267, 307, 274, 317 ActionDest: 76 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 370, 670, 377, 682 ActionDest: 83 Annotation: Subtype: Link Rect: 549, 361, 556, 373 ActionDest: 83 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 290, 619, 297, 631 ActionDest: 89 Annotation: Subtype: Link Rect: 237, 557, 244, 569 ActionDest: 92 Annotation: Subtype: Link Rect: 372, 356, 379, 368 ActionDest: 92 Page: Sequence: 6 Page: Sequence: 7 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 202, 678, 214, 687 ActionDest: 104 Annotation: Subtype: Link Rect: 217, 678, 229, 687 ActionDest: 104 Annotation: Subtype: Link Rect: 449, 665, 461, 674 ActionDest: 104 Annotation: Subtype: Link Rect: 516, 640, 528, 649 ActionDest: 104 Annotation: Subtype: Link Rect: 531, 640, 543, 649 ActionDest: 104 Annotation: Subtype: Link Rect: 544, 640, 556, 649 ActionDest: 104 Annotation: Subtype: Link Rect: 294, 577, 306, 586 ActionDest: 104 Annotation: Subtype: Link Rect: 309, 577, 321, 586 ActionDest: 104 Annotation: Subtype: Link Rect: 375, 552, 387, 561 ActionDest: 104 Annotation: Subtype: Link Rect: 360, 527, 372, 536 ActionDest: 104 Annotation: Subtype: Link Rect: 373, 527, 385, 536 ActionDest: 104 Annotation: Subtype: Link Rect: 385, 527, 397, 536 ActionDest: 104 Annotation: Subtype: Link Rect: 373, 502, 385, 511 ActionDest: 104 Annotation: Subtype: Link Rect: 385, 502, 397, 511 ActionDest: 104 Annotation: Subtype: Link Rect: 338, 489, 350, 498 ActionDest: 104 Annotation: Subtype: Link Rect: 532, 477, 544, 486 ActionDest: 108 Annotation: Subtype: Link Rect: 436, 452, 448, 461 ActionDest: 101 Annotation: Subtype: Link Rect: 449, 452, 461, 461 ActionDest: 108 Annotation: Subtype: Link Rect: 464, 452, 476, 461 ActionDest: 108 Annotation: Subtype: Link Rect: 506, 389, 518, 398 ActionDest: 101 Annotation: Subtype: Link Rect: 519, 389, 531, 398 ActionDest: 104 Annotation: Subtype: Link Rect: 531, 389, 543, 398 ActionDest: 104 Annotation: Subtype: Link Rect: 544, 389, 556, 398 ActionDest: 108 Annotation: Subtype: Link Rect: 455, 276, 467, 285 ActionDest: 104 Annotation: Subtype: Link Rect: 468, 276, 480, 285 ActionDest: 108 Annotation: Subtype: Link Rect: 480, 276, 492, 285 ActionDest: 108 Annotation: Subtype: Link Rect: 504, 175, 516, 185 ActionDest: 108 Annotation: Subtype: Link Rect: 516, 175, 528, 185 ActionDest: 108 Annotation: Subtype: Link Rect: 446, 150, 458, 159 ActionDest: 108 Annotation: Subtype: Link Rect: 398, 125, 410, 134 ActionDest: 104 Annotation: Subtype: Link Rect: 271, 113, 282, 122 ActionDest: 108 Annotation: Subtype: Link Rect: 423, 88, 435, 97 ActionDest: 104 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 531, 712, 543, 721 ActionDest: 101 Annotation: Subtype: Link Rect: 544, 712, 556, 721 ActionDest: 108 Annotation: Subtype: Link Rect: 435, 687, 447, 696 ActionDest: 108 Annotation: Subtype: Link Rect: 450, 687, 462, 696 ActionDest: 108 Annotation: Subtype: Link Rect: 399, 612, 411, 621 ActionDest: 108 Annotation: Subtype: Link Rect: 543, 612, 555, 621 ActionDest: 104 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 511, 569, 548, 580 Annotation: Subtype: Link Rect: 294, 547, 332, 557 Annotation: Subtype: Link Rect: 422, 488, 460, 499 Annotation: Subtype: Link Rect: 140, 455, 177, 465 Annotation: Subtype: Link Rect: 310, 420, 348, 430 Annotation: Subtype: Link Rect: 258, 385, 296, 396 Annotation: Subtype: Link Rect: 453, 373, 491, 384 Annotation: Subtype: Link Rect: 108, 340, 145, 350 Annotation: Subtype: Link Rect: 510, 327, 548, 338 Annotation: Subtype: Link Rect: 280, 304, 317, 315 Annotation: Subtype: Link Rect: 187, 270, 225, 281 Annotation: Subtype: Link Rect: 122, 247, 160, 258 Annotation: Subtype: Link Rect: 470, 224, 508, 235 Annotation: Subtype: Link Rect: 113, 190, 150, 200 Annotation: Subtype: Link Rect: 59, 155, 96, 166 Annotation: Subtype: Link Rect: 311, 120, 349, 131 Annotation: Subtype: Link Rect: 214, 97, 252, 108 Annotation: Subtype: Link Rect: 269, 63, 306, 73 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 174, 712, 212, 723 Annotation: Subtype: Link Rect: 226, 690, 263, 700 Annotation: Subtype: Link Rect: 302, 654, 340, 665 Annotation: Subtype: Link Rect: 117, 621, 155, 631 Annotation: Subtype: Link Rect: 150, 598, 188, 608 Annotation: Subtype: Link Rect: 59, 563, 96, 573 Annotation: Subtype: Link Rect: 460, 539, 497, 550 Annotation: Subtype: Link Rect: 118, 517, 155, 527 Annotation: Subtype: Link Rect: 219, 482, 256, 493 Annotation: Subtype: Link Rect: 295, 447, 332, 458 Annotation: Subtype: Link Rect: 259, 413, 297, 424 Annotation: Subtype: Link Rect: 127, 379, 164, 389 Annotation: Subtype: Link Rect: 131, 345, 168, 355 Annotation: Subtype: Link Rect: 192, 310, 229, 320 Annotation: Subtype: Link Rect: 227, 275, 265, 286 Annotation: Subtype: Link Rect: 402, 240, 439, 251 Annotation: Subtype: Link Rect: 491, 217, 529, 228 Annotation: Subtype: Link Rect: 202, 195, 240, 205 Annotation: Subtype: Link Rect: 310, 171, 347, 182 Annotation: Subtype: Link Rect: 493, 148, 531, 159 Annotation: Subtype: Link Rect: 238, 126, 275, 136 Annotation: Subtype: Link Rect: 176, 91, 380, 102 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 86, 713, 123, 723 Annotation: Subtype: Link Rect: 186, 690, 224, 700 Annotation: Subtype: Link Rect: 59, 655, 96, 665 Annotation: Subtype: Link Rect: 59, 632, 96, 642 Annotation: Subtype: Link Rect: 360, 597, 398, 608 Annotation: Subtype: Link Rect: 143, 575, 180, 585 Annotation: Subtype: Link Rect: 59, 540, 96, 550 Annotation: Subtype: Link Rect: 186, 505, 223, 516 Annotation: Subtype: Link Rect: 351, 470, 389, 481 Annotation: Subtype: Link Rect: 278, 436, 315, 447 Annotation: Subtype: Link Rect: 272, 401, 310, 412 Annotation: Subtype: Link Rect: 157, 368, 195, 378 Annotation: Subtype: Link Rect: 379, 344, 417, 355 Annotation: Subtype: Link Rect: 456, 321, 493, 332 Annotation: Subtype: Link Rect: 118, 287, 155, 297 Checksum: d1c01b34 Type: CRC32 Checksum: 68fd98d8ce26cc4df1accfd642a05f4c Type: MD5 Checksum: a135e942bed5b80646ef8ec7355754eaa627d941 Type: SHA-1 Checksum: 848ad3c8691f2c4b64dfdfccca15d67425f15fae604251065e9f6a75fc2950e8 Type: SHA-256