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Article: Pancreatitis polygenic risk score is associated with acute pancreatitis in multifactorial chylomicronemia syndrome.

Guay, Simon-Pierre / Paquette, Martine / Taschereau, Amélie / Desgagné, Véronique / Bouchard, Luigi / Bernard, Sophie / Baass, Alexis

Journal of clinical lipidology

2024

Abstract: Background: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia associated with an increased risk of acute pancreatitis (AP). The risk of AP is heterogenous and is associated with increased level of triglycerides (TG) ... ...

Abstract	Background: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia associated with an increased risk of acute pancreatitis (AP). The risk of AP is heterogenous and is associated with increased level of triglycerides (TG) and presence of rare variants in TG metabolism-related genes. Objective: To determine if the accumulation of common variants in pancreatitis susceptibility genes, measured with a weighted polygenic risk score (PRS), is associated with AP in MCS patients. Methods: A total of 114 patients with MCS underwent genetic testing for eight single nucleotide polymorphisms (SNPs) in known pancreatitis susceptibility genes (ABCG8, CLDN2, CTRB1/2, CTRC, PRSS1, PRSS2, SPINK1 and TWIST2). A weighted PRS was calculated to account for the phenotypic effect of each SNP locus. Results: A high pancreatitis-PRS score (≥ 0.44) was associated with a 2.94-fold increase risk of AP (p = 0.02) among patients with MCS. MCS patients with a high pancreatitis-PRS and a rare variant in TG metabolism-related gene have a 9.50-fold increase risk of acute pancreatitis (p = 0.001), compared to those with a low-PRS and no rare variant. A multivariate analysis including the presence of rare variants, the maximal TG values and a high pancreatitis-PRS explained 26% of the variability in AP in MCS patients. Conclusion: This study shows for the first time that the accumulation of common variants in pancreatitis susceptibility genes is associated with AP in MCS patients. Pancreatitis-PRS could help clinicians to identify MCS patients who may be at higher risk of AP and who may benefit from more aggressive treatment.
Language	English
Publishing date	2024-02-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2365061-8
ISSN	1876-4789 ; 1933-2874
ISSN (online)	1876-4789
ISSN	1933-2874
DOI	10.1016/j.jacl.2024.02.007
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Article ; Online: Acute pancreatitis risk in multifactorial chylomicronemia syndrome depends on the molecular cause of severe hypertriglyceridemia.

Guay, Simon-Pierre / Paquette, Martine / Taschereau, Amélie / Girard, Lysanne / Desgagné, Véronique / Bouchard, Luigi / Bernard, Sophie / Baass, Alexis

Atherosclerosis

2024 , Page(s) 117489

Abstract: Background and aims: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis (AP). Severe hyperTG is mainly polygenic in nature, either caused by the ... ...

Abstract	Background and aims: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis (AP). Severe hyperTG is mainly polygenic in nature, either caused by the presence of heterozygous pathogenic variants (PVs) in TG-related metabolism genes or by accumulation of common variants in hyperTG susceptibility genes. This study aims to determine if the risk of AP is similar amongst MCS patients with different molecular causes of severe hyperTG. Methods: This study included 114 MCS patients who underwent genetic testing for PVs in TG-related metabolism genes and 16 single nucleotide polymorphisms (SNPs) in hyperTG susceptibility genes. A weighted TG-polygenic risk score (TG-PRS) was calculated. A TG-PRS score ≥ 90th percentile was used to define a high TG-PRS. Results: Overall, 66.7% of patients had severe hyperTG of polygenic origin. MCS patients with only a PV and those with both a PV and high TG-PRS were more prone to have maximal TG concentration ≥ 40 mmol/L (OR 5.33 (1.55-18.36); p = 0.008 and OR 5.33 (1.28-22.25); p = 0.02), as well as higher prevalence of AP (OR 3.64 (0.89-14.92); p = 0.07 and OR 11.90 (2.54-55.85); p = 0.002) compared to MCS patients with high TG-PRS alone. Conclusions: This is the first study to show that MCS caused by a high TG-PRS and a PV is associated with higher risk of AP, similar to what is seen in the monogenic form of severe hyperTG. This suggests that determining the molecular cause of severe hyperTG could be useful to stratify the risk of pancreatitis in MCS.
Language	English
Publishing date	2024-02-27
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	80061-2
ISSN	1879-1484 ; 0021-9150
ISSN (online)	1879-1484
ISSN	0021-9150
DOI	10.1016/j.atherosclerosis.2024.117489
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Article ; Online: Epigenetics and fetal metabolic programming: a call for integrated research on larger cohorts.

Bouchard, Luigi

Diabetes

2013 Volume 62, Issue 4, Page(s) 1026–1028

MeSH term(s)	DNA Methylation/physiology ; Diabetes, Gestational/metabolism ; Epigenesis, Genetic/physiology ; Female ; Humans ; Obesity/genetics ; Pregnancy ; Prenatal Exposure Delayed Effects ; Proteins/metabolism
Chemical Substances	Proteins ; mesoderm specific transcript protein
Language	English
Publishing date	2013-03-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db12-1763
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Article: Associations between Cord Blood Leptin Levels and Childhood Adiposity Differ by Sex and Age at Adiposity Assessment.

Blais, Kasandra / Doyon, Myriam / Arguin, Mélina / Bouchard, Luigi / Perron, Patrice / Hivert, Marie-France

Life (Basel, Switzerland)

2022 Volume 12, Issue 12

Abstract: Lower cord blood leptin levels have been associated with lower and higher adiposity in childhood and associations seem to differ according to the child’s age, methods of adiposity assessment and sex. Our aim was to investigate sex-specific associations ... ...

Abstract	Lower cord blood leptin levels have been associated with lower and higher adiposity in childhood and associations seem to differ according to the child’s age, methods of adiposity assessment and sex. Our aim was to investigate sex-specific associations of cord blood leptinemia with childhood adiposity at birth, 3 and 5 years of age. We measured cord blood leptin using Luminex immunoassays in 520 offspring from the Gen3G cohort. We tested associations between cord blood leptin and body mass index (BMI) z-score, skinfolds thicknesses (SFT), and body composition using dual-energy X-ray absorptiometry, adjusted for confounders. At birth, girls had almost twice as much leptin in cord blood as boys (15.5 [8.9; 25.6] vs. 8.6 [4.9; 15.0] ng/mL; p < 0.0001) as well as significantly greater adiposity. Lower levels of cord blood leptin were associated with higher sum of SFT (β = −0.05 ± 0.02; p = 0.03) and higher BMI z-score (β= −0.22 ± 0.08; p = 0.01) in 3-year-old boys only. We did not observe these associations at age 5, or in girls. Our results suggest a sexual dimorphism in the programming of leptin sensitivity and childhood adiposity, but further observational and functional studies are needed to better understand the role of leptin in early life.
Language	English
Publishing date	2022-12-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662250-6
ISSN	2075-1729
ISSN	2075-1729
DOI	10.3390/life12122060
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Article ; Online: Portrait of autosomal recessive diseases in the French-Canadian founder population of Saguenay-Lac-Saint-Jean.

Cruz Marino, Tania / Leblanc, Josianne / Pratte, Annabelle / Tardif, Jessica / Thomas, Marie-Jacqueline / Fortin, Carol-Ann / Girard, Lysanne / Bouchard, Luigi

American journal of medical genetics. Part A

2023 Volume 191, Issue 5, Page(s) 1145–1163

Abstract: The population of the Saguenay-Lac-Saint-Jean (SLSJ) region, located in the province of Quebec, Canada, is recognized as a founder population, where some rare autosomal recessive diseases show a high prevalence. Through the clinical and molecular study ... ...

Abstract	The population of the Saguenay-Lac-Saint-Jean (SLSJ) region, located in the province of Quebec, Canada, is recognized as a founder population, where some rare autosomal recessive diseases show a high prevalence. Through the clinical and molecular study of 82 affected individuals from 60 families, this study outlines 12 diseases identified as recurrent in SLSJ. Their carrier frequency was estimated with the contribution of 1059 healthy individuals, increasing the number of autosomal recessive diseases with known carrier frequency in this region from 14 to 25. We review the main clinical and molecular features previously reported for these disorders. Five of the studied diseases have a potential lethal effect and three are associated with intellectual deficiency. Therefore, we believe that the provincial program for carrier screening should be extended to include these eight disorders. The high-carrier frequency, together with the absence of consanguinity in most of these unrelated families, suggest a founder effect and genetic drift for the 12 recurrent variants. We recommend further studies to validate this hypothesis, as well as to extend the present study to other regions in the province of Quebec, since some of these disorders could also be present in other French-Canadian families.
MeSH term(s)	Humans ; Canada/epidemiology ; Quebec/epidemiology ; Consanguinity ; Genes, Recessive ; Inheritance Patterns
Language	English
Publishing date	2023-02-14
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2108614-X
ISSN	1552-4833 ; 0148-7299 ; 1552-4825
ISSN (online)	1552-4833
ISSN	0148-7299 ; 1552-4825
DOI	10.1002/ajmg.a.63147
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Zs.A 1376/A: Show issues

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Article ; Online: Maternal glycemia in pregnancy is longitudinally associated with blood DNAm variation at the FSD1L gene from birth to 5 years of age.

Taschereau, Amélie / Thibeault, Kathrine / Allard, Catherine / Juvinao-Quintero, Diana / Perron, Patrice / Lutz, Sharon M / Bouchard, Luigi / Hivert, Marie-France

Clinical epigenetics

2023 Volume 15, Issue 1, Page(s) 107

Abstract: Background: In utero exposure to maternal hyperglycemia has been associated with an increased risk for the development of chronic diseases in later life. These predispositions may be programmed by fetal DNA methylation (DNAm) changes that persist ... ...

Abstract	Background: In utero exposure to maternal hyperglycemia has been associated with an increased risk for the development of chronic diseases in later life. These predispositions may be programmed by fetal DNA methylation (DNAm) changes that persist postnatally. However, although some studies have associated fetal exposure to gestational hyperglycemia with DNAm variations at birth, and metabolic phenotypes in childhood, no study has yet examined how maternal hyperglycemia during pregnancy may be associated with offspring DNAm from birth to five years of age. Hypothesis: Maternal hyperglycemia is associated with variation in offspring DNAm from birth to 5 years of age. Methods: We estimated maternal hyperglycemia using the area under the curve for glucose (AUC Results: In utero exposure to higher maternal AUC Conclusion: Maternal hyperglycemia is associated with offspring DNAm longitudinally assessed from birth to 5 years of age.
MeSH term(s)	Female ; Humans ; Pregnancy ; Body Mass Index ; Diabetes, Gestational ; DNA Methylation ; Fetal Blood ; Genotype ; Hyperglycemia ; Child, Preschool
Chemical Substances	FSD-1 protein, synthetic
Language	English
Publishing date	2023-06-29
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553921-8
ISSN	1868-7083 ; 1868-7075
ISSN (online)	1868-7083
ISSN	1868-7075
DOI	10.1186/s13148-023-01524-7
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Article ; Online: Placental IGFBP1 levels during early pregnancy and the risk of insulin resistance and gestational diabetes.

Hivert, Marie-France / White, Frédérique / Allard, Catherine / James, Kaitlyn / Majid, Sana / Aguet, François / Ardlie, Kristin G / Florez, Jose C / Edlow, Andrea G / Bouchard, Luigi / Jacques, Pierre-Étienne / Karumanchi, S Ananth / Powe, Camille E

Nature medicine

2024

Abstract: Reduced insulin sensitivity (insulin resistance) is a hallmark of normal physiology in late pregnancy and also underlies gestational diabetes mellitus (GDM). We conducted transcriptomic profiling of 434 human placentas and identified a positive ... ...

Abstract	Reduced insulin sensitivity (insulin resistance) is a hallmark of normal physiology in late pregnancy and also underlies gestational diabetes mellitus (GDM). We conducted transcriptomic profiling of 434 human placentas and identified a positive association between insulin-like growth factor binding protein 1 gene (IGFBP1) expression in the placenta and insulin sensitivity at ~26 weeks gestation. Circulating IGFBP1 protein levels rose over the course of pregnancy and declined postpartum, which, together with high gene expression levels in our placenta samples, suggests a placental or decidual source. Higher circulating IGFBP1 levels were associated with greater insulin sensitivity (lesser insulin resistance) at ~26 weeks gestation in the same cohort and in two additional pregnancy cohorts. In addition, low circulating IGFBP1 levels in early pregnancy predicted subsequent GDM diagnosis in two cohorts of pregnant women. These results implicate IGFBP1 in the glycemic physiology of pregnancy and suggest a role for placental IGFBP1 deficiency in GDM pathogenesis.
Language	English
Publishing date	2024-04-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-024-02936-5
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Zs.A 4212: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Detecting cord blood cell type-specific epigenetic associations with gestational diabetes mellitus and early childhood growth.

Lu, Tianyuan / Cardenas, Andres / Perron, Patrice / Hivert, Marie-France / Bouchard, Luigi / Greenwood, Celia M T

Clinical epigenetics

2021 Volume 13, Issue 1, Page(s) 131

Abstract: Background: Epigenome-wide association studies (EWAS) have provided opportunities to understand the role of epigenetic mechanisms in development and pathophysiology of many chronic diseases. However, an important limitation of conventional EWAS is that ... ...

Abstract	Background: Epigenome-wide association studies (EWAS) have provided opportunities to understand the role of epigenetic mechanisms in development and pathophysiology of many chronic diseases. However, an important limitation of conventional EWAS is that profiles of epigenetic variability are often obtained in samples of mixed cell types. Here, we aim to assess whether changes in cord blood DNA methylation (DNAm) associated with gestational diabetes mellitus (GDM) exposure and early childhood growth markers occur in a cell type-specific manner. Results: We analyzed 275 cord blood samples collected at delivery from a prospective pre-birth cohort with genome-wide DNAm profiled by the Illumina MethylationEPIC array. We estimated proportions of seven common cell types in each sample using a cord blood-specific DNAm reference panel. Leveraging a recently developed approach named CellDMC, we performed cell type-specific EWAS to identify CpG loci significantly associated with GDM, or 3-year-old body mass index (BMI) z-score. A total of 1410 CpG loci displayed significant cell type-specific differences in methylation level between 23 GDM cases and 252 controls with a false discovery rate < 0.05. Gene Ontology enrichment analysis indicated that LDL transportation emerged from CpG specifically identified from B-cells DNAm analyses and the mitogen-activated protein kinase pathway emerged from CpG specifically identified from natural killer cells DNAm analyses. In addition, we identified four and six loci associated with 3-year-old BMI z-score that were specific to CD8+ T-cells and monocytes, respectively. By performing genome-wide permutation tests, we validated that most of our detected signals had low false positive rates. Conclusion: Compared to conventional EWAS adjusting for the effects of cell type heterogeneity, the proposed approach based on cell type-specific EWAS could provide additional biologically meaningful associations between CpG methylation, prenatal maternal GDM or 3-year-old BMI. With careful validation, these findings may provide new insights into the pathogenesis, programming, and consequences of related childhood metabolic dysregulation. Therefore, we propose that cell type-specific analyses are worth cautious explorations.
MeSH term(s)	Adult ; Biomarkers/blood ; Birth Cohort ; Body Height ; Body Mass Index ; Body Weight ; Canada ; Child Development ; Child, Preschool ; Diabetes, Gestational/genetics ; Epigenesis, Genetic/genetics ; Epigenome/genetics ; Epigenomics/methods ; Female ; Fetal Blood/chemistry ; Genome-Wide Association Study/methods ; Humans ; Infant, Newborn ; Male ; Pregnancy ; Prospective Studies
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-06-26
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553921-8
ISSN	1868-7083 ; 1868-7075
ISSN (online)	1868-7083
ISSN	1868-7075
DOI	10.1186/s13148-021-01114-5
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Article ; Online: Associations of maternal insulin resistance during pregnancy and offspring inflammation at birth and at 5 years of age: A prospective study in the Gen3G cohort.

Faleschini, Sabrina / Doyon, Myriam / Arguin, Mélina / Perron, Patrice / Bouchard, Luigi / Hivert, Marie-France

Cytokine

2021 Volume 146, Page(s) 155636

Abstract: Background: Maternal insulin resistance is associated with greater maternal inflammation during pregnancy, but its relation to inflammation in offspring remains unclear. The goal of this study was to assess the relationship of gestational insulin ... ...

Abstract	Background: Maternal insulin resistance is associated with greater maternal inflammation during pregnancy, but its relation to inflammation in offspring remains unclear. The goal of this study was to assess the relationship of gestational insulin resistance and other glycemic markers with offspring inflammation at birth and at 5 years of age. Methods: We included 653 mother-child pairs from the prospective pre-birth Gen3G cohort. We examined maternal insulin and glucose levels measured during the second trimester of pregnancy, from which we derived the homeostatic model of assessment of insulin resistance (HOMA-IR) and the Matsuda index. We assessed offspring inflammation at birth and at 5 years of age by measuring plasma tumor necrosis factor-α (TNFα) concentrations. We conducted multivariable regression models to evaluate associations of each insulin and glucose marker with offspring inflammation adjusting for confounding variables. Results: Higher levels of fasting insulin were associated with lower TNFα levels at birth (-0.78, 95% CI [-1.45, -0.11]), in the fully adjusted model. We observed similar associations with the HOMA-IR and opposite direction with the Matsuda index. We did not find persistence of the association between maternal fasting insulin and offspring TNFα at 5 years of age. Conclusions: Greater maternal insulin resistance during pregnancy was associated with lower cord blood TNFα levels in newborns. The mechanisms by which maternal insulin resistance may promote lower inflammatory levels in newborns are not fully understood and more research is needed to deepen our understanding of these mechanisms.
MeSH term(s)	Biomarkers/metabolism ; Blood Glucose/metabolism ; Child, Preschool ; Female ; Humans ; Infant, Newborn ; Inflammation/blood ; Inflammation/pathology ; Insulin/metabolism ; Insulin Resistance ; Male ; Multivariate Analysis ; Pregnancy ; Prospective Studies ; Regression Analysis ; Tumor Necrosis Factor-alpha/blood
Chemical Substances	Biomarkers ; Blood Glucose ; Insulin ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2021-07-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1018055-2
ISSN	1096-0023 ; 1043-4666
ISSN (online)	1096-0023
ISSN	1043-4666
DOI	10.1016/j.cyto.2021.155636
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Zs.A 2840: Show issues

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Article ; Online: miR profile in pagetic osteoclasts: from large-scale sequencing to gene expression study.

Nguyen, Hoang Dong / Bisson, Martine / Scott, Michelle / Boire, Gilles / Bouchard, Luigi / Roux, Sophie

Journal of molecular medicine (Berlin, Germany)

2021 Volume 99, Issue 12, Page(s) 1771–1781

Abstract: Paget's disease of bone (PDB) is characterized by excessive and disorganized bone remodeling, in which bone-resorbing osteoclasts play a key role. We investigated microRNA (miR) expression in osteoclasts derived from the blood of 40 PDB patients and 30 ... ...

Abstract	Paget's disease of bone (PDB) is characterized by excessive and disorganized bone remodeling, in which bone-resorbing osteoclasts play a key role. We investigated microRNA (miR) expression in osteoclasts derived from the blood of 40 PDB patients and 30 healthy controls. By deep sequencing, a preliminary analysis identified differentially expressed miRs in a discovery cohort of 9 PDB patients and 9 age and sex-matched healthy controls. Six mature miRs, miR-29b1-3p, miR-15b-5p, miR-181a-5p, let-7i-3p, miR-500b-5p, and miR-1246, were found to be significantly decreased in pagetic overactive osteoclasts. The differential expression of the miRs was confirmed by the analysis of a larger independent cohort using qPCR. In an integrative network biology analysis of the miR candidates, we identified strong validated interactions between the miRs and some pathways, primarily apoptosis, and major osteoclast signaling pathways including PI3K/Akt, IFNγ, or TGFβ, as well as c-Fos, a transcription factor, and MMP-9, a metalloprotease. In addition, other genes like CCND2, CCND1, WEE1, SAMHD1, and AXIN2 were revealed in this network of interactions. Our results enhance the understanding of osteoclast biology in PDB; our work may also provide fresh perspectives on the research or therapeutic development of other bone diseases. KEY MESSAGES: miR profile in overactive osteoclasts from patients with Paget's disease of bone. Six mature miRs were significantly decreased in pagetic osteoclasts vs controls. miRs of interest: let7i-3p, miR-15b-5p, -29b1-3p, -181a-5p, -500b-5p, and -1246. Target genes and enriched pathways highlight the importance of apoptotic pathways.
MeSH term(s)	Aged ; Aged, 80 and over ; Female ; Gene Expression Profiling ; Humans ; Male ; MicroRNAs ; Middle Aged ; Osteitis Deformans/genetics ; Osteoclasts/metabolism ; RNA-Seq
Chemical Substances	MicroRNAs
Language	English
Publishing date	2021-10-05
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1223802-8
ISSN	1432-1440 ; 0946-2716
ISSN (online)	1432-1440
ISSN	0946-2716
DOI	10.1007/s00109-021-02128-5
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