Browsing by Subject "Human genetics"

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  • Gregson, John M.; Freitag, Daniel F.; Surendran, Praveen; Stitziel, Nathan O.; Chowdhury, Rajiv; Burgess, Stephen; Kaptoge, Stephen; Gao, Pei; Staley, James R.; Willeit, Peter; Nielsen, Sune F.; Caslake, Muriel; Trompet, Stella; Polfus, Linda M.; Kuulasmaa, Kari; Kontto, Jukka; Perola, Markus; Blankenberg, Stefan; Veronesi, Giovanni; Gianfagna, Francesco; Mannisto, Satu; Kimura, Akinori; Lin, Honghuang; Reilly, Dermot F.; Gorski, Mathias; Mijatovic, Vladan; Munroe, Patricia B.; Ehret, Georg B.; Thompson, Alex; Uria-Nickelsen, Maria; Malarstig, Anders; Dehghan, Abbas; Vogt, Thomas F.; Sasaoka, Taishi; Takeuchi, Fumihiko; Kato, Norihiro; Yamada, Yoshiji; Kee, Frank; Mueller-Nurasyid, Martina; Ferrieres, Jean; Arveiler, Dominique; Amouyel, Philippe; Salomaa, Veikko; Boerwinkle, Eric; Thompson, Simon G.; Ford, Ian; Jukema, J. Wouter; Sattar, Naveed; Packard, Chris J.; Majumder, Abdulla al Shafi; CKDGen Consortium; Int Consortium Blood Pressure; CHARGE Inflammation Working Grp; MICAD Exome Consortium; EPIC-CVD Consortium; CHD Exome Consortium (2017)
    Aims: Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA(2) enzyme activity is causally relevant to coronary heart disease. Methods: In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c. 109+2T> C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7, the gene encoding Lp-PLA(2). We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA(2) activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA(2)-lowering alleles. Results: Lp-PLA(2) activity was decreased by 64% (p = 2.4 x 10 (-25)) with carriage of any of the four loss-of-function variants, by 45% (p<10 (-300)) for every allele inherited at Val279Phe, and by 2.7% (p = 1.9 x 10 (-12)) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA(2) activity by 65% (p<10 (-300)). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA(2) activity were: 0.95 (0.88-1.03) with Val279Phe; 0.92 (0.74-1.16) with carriage of any loss-of-function variant; 1.01 (0.68-1.51) with Val379Ala; and 0.95 (0.89-1.02) with darapladib treatment. Conclusions: In a large-scale human genetic study, none of a series of Lp-PLA(2)-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA(2) is unlikely to be a causal risk factor.
  • Ganel, Liron; Chen, Lei; Christ, Ryan; Vangipurapu, Jagadish; Young, Erica; Das, Indraniel; Kanchi, Krishna; Larson, David; Regier, Allison; Abel, Haley; Kang, Chul J.; Scott, Alexandra; Havulinna, Aki; Chiang, Charleston W. K.; Service, Susan; Freimer, Nelson; Palotie, Aarno; Ripatti, Samuli; Kuusisto, Johanna; Boehnke, Michael; Laakso, Markku; Locke, Adam; Stitziel, Nathan O.; Hall, Ira M. (BioMed Central, 2021)
    Abstract Background Mitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell-type composition. Here, we studied MT-CN variation in blood-derived DNA from 19184 Finnish individuals using a combination of genome (N = 4163) and exome sequencing (N = 19034) data as well as imputed genotypes (N = 17718). Results We identified two loci significantly associated with MT-CN variation: a common variant at the MYB-HBS1L locus (P = 1.6 × 10−8), which has previously been associated with numerous hematological parameters; and a burden of rare variants in the TMBIM1 gene (P = 3.0 × 10−8), which has been reported to protect against non-alcoholic fatty liver disease. We also found that MT-CN is strongly associated with insulin levels (P = 2.0 × 10−21) and other metabolic syndrome (metS)-related traits. Using a Mendelian randomization framework, we show evidence that MT-CN measured in blood is causally related to insulin levels. We then applied an MT-CN polygenic risk score (PRS) derived from Finnish data to the UK Biobank, where the association between the PRS and metS traits was replicated. Adjusting for cell counts largely eliminated these signals, suggesting that MT-CN affects metS via cell-type composition. Conclusion These results suggest that measurements of MT-CN in blood-derived DNA partially reflect differences in cell-type composition and that these differences are causally linked to insulin and related traits.
  • Ganel, Liron; Chen, Lei; Christ, Ryan; Vangipurapu, Jagadish; Young, Erica; Das, Indraniel; Kanchi, Krishna; Larson, David; Regier, Allison; Abel, Haley; Kang, Chul Joo; Scott, Alexandra; Havulinna, Aki; Chiang, Charleston W. K.; Service, Susan; Freimer, Nelson; Palotie, Aarno; Ripatti, Samuli; Kuusisto, Johanna; Boehnke, Michael; Laakso, Markku; Locke, Adam; Stitziel, Nathan O.; Hall, Ira M. (2021)
    Background Mitochondrial genome copy number (MT-CN) varies among humans and across tissues and is highly heritable, but its causes and consequences are not well understood. When measured by bulk DNA sequencing in blood, MT-CN may reflect a combination of the number of mitochondria per cell and cell-type composition. Here, we studied MT-CN variation in blood-derived DNA from 19184 Finnish individuals using a combination of genome (N = 4163) and exome sequencing (N = 19034) data as well as imputed genotypes (N = 17718). Results We identified two loci significantly associated with MT-CN variation: a common variant at the MYB-HBS1L locus (P = 1.6 x 10(-8)), which has previously been associated with numerous hematological parameters; and a burden of rare variants in the TMBIM1 gene (P = 3.0 x 10(-8)), which has been reported to protect against non-alcoholic fatty liver disease. We also found that MT-CN is strongly associated with insulin levels (P = 2.0 x 10(-21)) and other metabolic syndrome (metS)-related traits. Using a Mendelian randomization framework, we show evidence that MT-CN measured in blood is causally related to insulin levels. We then applied an MT-CN polygenic risk score (PRS) derived from Finnish data to the UK Biobank, where the association between the PRS and metS traits was replicated. Adjusting for cell counts largely eliminated these signals, suggesting that MT-CN affects metS via cell-type composition. Conclusion These results suggest that measurements of MT-CN in blood-derived DNA partially reflect differences in cell-type composition and that these differences are causally linked to insulin and related traits.