Desaturase Activity and the Risk of Type 2 Diabetes and Coronary Artery Disease: A Mendelian Randomization Study

Jäger, Susanne; Cuadrat, Rafael R. C.; Hoffmann, Per; Wittenbecher, Clemens; Schulze, Matthias B.

doi:10.3390/nu12082261

Cited by 16 publications

(17 citation statements)

References 56 publications

(88 reference statements)

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“…The strengths of the present studies include the use of genome-wide summary results for objectively measured physical activity and sedentary time, which avoided misreporting bias evident for self-reported measures, as well as the use of newly developed Mendelian randomization method that utilizes full genome-wide summary results to improve statistical power, correct for sample overlap, and assess horizontal pleiotropy, successfully applied in recent Mendelian randomization studies (Jager et al, 2020, Mitchell et al, 2020. The limitations are that we cannot exclude other sources of bias in the measurement of physical activity and sedentary time that could influence the observed causal estimates, including the observer effect and the limited 7-day period of the measurement, which may not be representative of long-term activity habits.…”

Section: Discussionmentioning

confidence: 99%

Mendelian randomization suggests a bidirectional, causal relationship between physical inactivity and adiposity

Carrasquilla

García-Ureña

Fall

et al. 2022

eLife

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Physical inactivity and increased sedentary time are associated with excess weight gain in observational studies. However, some longitudinal studies indicate reverse causality where weight gain leads to physical inactivity and increased sedentary time. As observational studies suffer from reverse causality, it is challenging to assess the true causal directions. Here, we assess the bidirectional causality between physical inactivity, sedentary time and adiposity by bidirectional Mendelian randomization analysis. We assessed genetic liability using results from genome-wide association studies for accelerometer-based physical activity and sedentary time in 91,105 individuals and for body mass index (BMI) in 806,834 individuals. We implemented Mendelian randomization using CAUSE method that accounts for pleiotropy and sample overlap using full genome-wide data. We also applied inverse variance-weighted, MR-Egger, weighted median, and weighted mode methods using genome-wide significant variants only. We found evidence of bidirectional causality between sedentary time and BMI: longer sedentary time was causal for higher BMI [beta (95%CI) from CAUSE method: 0.11 (0.02, 0.2), P=0.02], and higher BMI was causal for longer sedentary time (0.13 (0.08, 0.17), P=6.3.x10-4). Our analyses suggest that higher moderate and vigorous physical activity are causal for lower BMI (moderate: -0.18 (-0.3,-0.05), P=0.006; vigorous: -0.16 (-0.24,-0.08), P=3.8x10-4), but indicate that the association between higher BMI and lower levels of physical activity is due to horizontal pleiotropy. The bidirectional, causal relationship between sedentary time and BMI suggests that decreasing sedentary time is beneficial for weight management, but also that targeting adiposity may lead to additional health benefits by reducing sedentary time.

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Section: Discussionmentioning

confidence: 99%

Mendelian randomization suggests a bidirectional, causal relationship between physical inactivity and adiposity

Carrasquilla

García-Ureña

Fall

et al. 2022

eLife

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“…Several GWAS have reported that SNPs within the FADS1/2 locus are associated with cardiovascular risk factors (e.g. LDL-cholesterol and triglycerides) (19, 76, 77) and previous Mendelian randomization studies have reported that longer and shorter chain PUFA are related to risk of cardiovascular diseases in contrasting directions among Europeans, including coronary artery disease in CARDIoGRAMplusC4D and UK Biobank (26, 27, 78), ischemic stroke in MEGASTROKE and UK Biobank (28, 29), and venous thromboembolism in UK Biobank (29). Our findings expand on previous Mendelian randomization studies by implicating higher FADS1 /D5D activity in the development of a wide range of cardiovascular diseases among Europeans in the largest available samples to date (up to 1,153,768 individuals).…”

Section: Discussionmentioning

confidence: 99%

The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: A Mendelian randomization study

Borges

Haycock

Zheng

et al. 2022

Preprint

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Despite early interest, the evidence linking fatty acids to cardiovascular diseases remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the aetiology of several cardiovascular disease endpoints in up to 1,153,768 European and 212,453 East Asian ancestry individuals. As instruments, we selected single nucleotide polymorphisms (SNP) mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple cardiovascular diseases, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low- density lipoprotein (LDL)-cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that genetically-determined PUFA and MUFA biosynthesis are involved in the aetiology of cardiovascular diseases and suggest LDL-cholesterol as a potential mediating trait between PUFA biosynthesis and cardiovascular diseases risk.

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“…Recent Mendelian Randomization studies have linked FADS variants and desaturase activities with cardiometabolic risk and cardiovascular disease. [ 49,50 ]…”

Section: Discussionmentioning

confidence: 99%

The FADS1 Genotype Modifies Metabolic Responses to the Linoleic Acid and Alpha‐linolenic Acid Containing Plant Oils–Genotype Based Randomized Trial FADSDIET2

Lankinen

Mello

Meuronen

et al. 2021

Molecular Nutrition Food Res

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Scope The article investigates the FADS1 rs174550 genotype interaction with dietary intakes of high linoleic acid (LA) and high alpha‐linolenic acid (ALA) on the response of fatty acid composition of plasma phospholipids (PLs), and of markers of low‐grade inflammation and glucose‐insulin homeostasis. Methods and results One‐hundred thirty homozygotes men for FADS1 rs174550 SNP (TT and CC genotypes) were randomized to an 8‐week intervention with either LA‐ or ALA‐enriched diet (13 E% PUFA). The source of LA and ALA are 30–50 mL of sunflower oil (SFO, 62–63% LA) and Camelina sativa oil (CSO, 30– are randomized to an 35% ALA), respectively. In the SFO arm, there is a significant genotype x diet interaction for the proportion of arachidonic acid in plasma phospholipids (p < 0.001), disposition index (DI30) (p = 0.039), and for serum high‐sensitive c‐reactive protein (hs‐CRP, p = 0.029) after excluding the participants with hs‐CRP concentration of >10 mg L‐1 and users of statins or anti‐inflammatory therapy. In the CSO arm, there are significant genotype x diet interactions for n‐3 polyunsaturated fatty acids, but not for the clinical characteristics. Conclusions The FADS1 genotype modifies the response to high PUFA diets, especially to high‐LA diet. These findings suggest that approaches considering FADS variation may be useful in personalized dietary counseling.

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Desaturase Activity and the Risk of Type 2 Diabetes and Coronary Artery Disease: A Mendelian Randomization Study

Cited by 16 publications

References 56 publications

Mendelian randomization suggests a bidirectional, causal relationship between physical inactivity and adiposity

Mendelian randomization suggests a bidirectional, causal relationship between physical inactivity and adiposity

The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: A Mendelian randomization study

The FADS1 Genotype Modifies Metabolic Responses to the Linoleic Acid and Alpha‐linolenic Acid Containing Plant Oils–Genotype Based Randomized Trial FADSDIET2

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