Genetic Variants Modifying the Triglycerides-Lowering Effect of Fish Oil Supplementation: A Genome-Wide Interaction Study

Abstract Objectives To identify genetic variants that modify the effect of fish oil supplementation on blood lipids, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, and triglycerides. Methods We performed a genome-wide interaction study in 73,962 participants of European ancestry from the UK Biobank. Candidate associations were evaluated in a replication study with 7,284 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Meta-analysis was further performed across the two cohorts. Results Four novel interaction loci were identified at genome-wide significance in meta-analysis. The lead variant in the GJB6-GJB2-GJA3 gene cluster, rs112803755 (A > G; minor allele frequency = 0.041), shows an interaction effect but not the main effect, suggesting that it would not have been discovered in a typical association study. Fish oil supplementation is associated with a decreased blood level of triglycerides in individuals carrying the minor allele, but with an increased level in homozygotes of the major allele. This locus is significantly associated with higher GJB2 expression of connexin 26 in adipose tissue, while connexin activity is known to change upon exposure to omega-3 fatty acids. Significant interaction effects were also found in three other loci in the genes SLC12A3 (HDL-C), ABCA6 (LDL-C), and MLXIPL (LDL-C), but highly significant main effects are also present. Conclusions Our study identifies novel interaction effects for four genetic loci and highlights genetic variants in the GJB6-GJB2-GJA3 gene cluster, which modify the effects of fish oil supplementation on lowering blood triglycerides. These findings highlight the need and possibility for personalized nutrition. Funding Sources The University of Georgia Research Foundation

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Genetic variants in LEKR1 and GALNT10 modulate sex-difference in carotid intima-media thickness: A genome-wide interaction study

Atherosclerosis ◽

10.1016/j.atherosclerosis.2015.04.019 ◽

2015 ◽

Vol 240 (2) ◽

pp. 462-467 ◽

Cited By ~ 14

Author(s):

Chuanhui Dong ◽

David Della-Morte ◽

Ashley Beecham ◽

Liyong Wang ◽

Digna Cabral ◽

...

Keyword(s):

Sex Difference ◽

Genetic Variants ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

Interaction Study ◽

Media Thickness ◽

Genome Wide ◽

A Genome

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Two Weeks of Low Dose Fish Oil Supplementation Followed By A Single Bout of Exercise Increases High Density Lipoprotein Cholesterol in College-Aged and Middle-Aged Men

Journal of Nutrition & Food Sciences ◽

10.4172/2155-9600.1000221 ◽

2013 ◽

Vol 03 (05) ◽

Author(s):

Rachael M Thomas ◽

Edward Meadors

Keyword(s):

High Density Lipoprotein ◽

Fish Oil ◽

High Density Lipoprotein Cholesterol ◽

Low Dose ◽

Density Lipoprotein ◽

High Density ◽

Lipoprotein Cholesterol ◽

Middle Aged ◽

Single Bout ◽

Fish Oil Supplementation

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Genome-Wide Association for HbA1c in Malay Identified Deletion on SLC4A1 that Influences HbA1c Independent of Glycemia

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa658 ◽

2020 ◽

Vol 105 (12) ◽

pp. 3854-3864

Author(s):

Jin-Fang Chai ◽

Shih-Ling Kao ◽

Chaolong Wang ◽

Victor Jun-Yu Lim ◽

Ing Wei Khor ◽

...

Keyword(s):

Genetic Variants ◽

Hba1c Level ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Genome Wide Association ◽

Specific Reference ◽

Genetic Determinants ◽

Genome Wide ◽

Whole Exome ◽

A Genome

Abstract Context Glycated hemoglobin A1c (HbA1c) level is used to screen and diagnose diabetes. Genetic determinants of HbA1c can vary across populations and many of the genetic variants influencing HbA1c level were specific to populations. Objective To discover genetic variants associated with HbA1c level in nondiabetic Malay individuals. Design and Participants We conducted a genome-wide association study (GWAS) analysis for HbA1c using 2 Malay studies, the Singapore Malay Eye Study (SiMES, N = 1721 on GWAS array) and the Living Biobank study (N = 983 on GWAS array and whole-exome sequenced). We built a Malay-specific reference panel to impute ethnic-specific variants and validate the associations with HbA1c at ethnic-specific variants. Results Meta-analysis of the 1000 Genomes imputed array data identified 4 loci at genome-wide significance (P < 5 × 10-8). Of the 4 loci, 3 (ADAM15, LINC02226, JUP) were novel for HbA1c associations. At the previously reported HbA1c locus ATXN7L3-G6PC3, association analysis using the exome data fine-mapped the HbA1c associations to a 27-bp deletion (rs769664228) at SLC4A1 that reduced HbA1c by 0.38 ± 0.06% (P = 3.5 × 10-10). Further imputation of this variant in SiMES confirmed the association with HbA1c at SLC4A1. We also showed that these genetic variants influence HbA1c level independent of glucose level. Conclusion We identified a deletion at SLC4A1 associated with HbA1c in Malay. The nonglycemic lowering of HbA1c at rs769664228 might cause individuals carrying this variant to be underdiagnosed for diabetes or prediabetes when HbA1c is used as the only diagnostic test for diabetes.

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Elevation of Low-Density Lipoprotein Cholesterol Concentration with Over-the-Counter Fish Oil Supplementation

Annals of Pharmacotherapy ◽

10.1345/aph.1h695 ◽

2007 ◽

Vol 41 (7-8) ◽

pp. 1296-1300 ◽

Cited By ~ 5

Author(s):

Jennifer M Malinowski ◽

Kimberly Metka

Keyword(s):

Fish Oil ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Cholesterol Concentration ◽

Low Density ◽

Low Density Lipoprotein Cholesterol ◽

Over The Counter ◽

Epa And Dha ◽

Fish Oil Supplementation

Objective: To report a case of elevated low-density lipoprotein cholesterol (LDL-C) concentration in a patient taking fish oil supplements for hypertriglyceridemia. Case Summary: A 63-year-old white woman had been taking 2.7 g of eico-sapentaenotc acid (EPA) and docosahexaenoic acid (DHA) daily in 9 g of over-the-counter (OTC) fish oil capsules for triglyceride lowering. Prior to the adverse event, she had baseline fasting triglyceride (TG) and LDL-C concentrations of 278 mg/dL and 106 mg/dL, respectively. After 6 weeks of treatment with fish oil, fasting TG levels decreased by 47.5% (-132 mg/dL) and the LDL-C increased by 75% (+80 mg/dL). Discontinuation of therapy for 6 weeks resulted in TG returning to high concentrations (334 mg/dL; +56 mg/dL change from baseline) and LDL-C decreasing toward baseline (143 mg/dL; +37 mg/dL change from baseline). Discussion: Fish oil, an omega-3 polyunsaturated fatty acid, consists of EPA and DHA. EPA and DHA are thought to inhibit the synthesis of triglycerides in the liver. Type IV dyslipidemic patients may develop increased LDL-C levels while taking fish oil to lower triglycerides due to possible down-regulation of the LDL-C receptor in hepatic cells and formation of larger LDL particles. Use of the Naranjo probability scale indicates a probable relationship between elevations in LDL-C from baseline and initiation of fish oil treatment for hypertriglyceridemia. It is unknown whether any component within this particular product could have contributed to such an unusual elevation in LDL-C. Conclusions: This case documents a much higher LDL-C elevation associated with OTC fish oil supplementation than has been previously identified in the literature. Healthcare providers should be advised that LDL-C levels may increase with use of OTC fish oil and should monitor patients periodically for such elevations. The significance of this Increase on clinical outcomes is not known.

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A Genome-wide Association and Admixture Mapping Study of Bronchodilator Drug Response in African Americans with Asthma

10.1101/157198 ◽

2017 ◽

Cited By ~ 1

Author(s):

Melissa L. Spear ◽

Donglei Hu ◽

Maria Pino-Yanes ◽

Scott Huntsman ◽

Anton S. M. Sonnenberg ◽

...

Keyword(s):

African Americans ◽

Genetic Variants ◽

Drug Response ◽

Meta Analysis ◽

Genome Wide ◽

A Genome ◽

Children With Asthma ◽

American Children ◽

Racial Ethnic ◽

Shared Genetic

AbstractBackgroundShort-acting B2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the U.S 1, 2. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma3ObjectiveTo identify genetic variants that may contribute to differences in BDR in African Americans with asthma.MethodsWe performed a genome-wide association study of BDR in 949 African American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase 3 genotypes. We used linear regression models adjusting for age, sex, body mass index and genetic ancestry to test for an association between BDR and genotype at single nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1,830 Latinos (Total=2,779). Lastly, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. Two additional populations of 416 Latinos and 1,325 African Americans were used to replicate significant associations.ResultsWe identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p=7.69 × 10−9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958, and rs7081864, p≤5 × 10−8).ConclusionsOur findings indicate that both population specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.Key messagesA GWAS for BDR in African American children with asthma identified an intergenic population specific variant at 9q21 to be associated with increased bronchodilator drug response (BDR).A meta-analysis of GWAS across African Americans and Latinos identified shared genetic variants at 10q21 in the intron of PRKG1 to be associated with differences in BDR.Further genetic studies need to be performed in diverse populations to identify the full set of genetic variants that contribute to BDR.

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Abstract 141: APOA1, CETP, and CILP2 Variants Modify the Lipid Response to Fenofibrate: Genetics of Lipid Lowering and Diet Network

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.32.suppl_1.a141 ◽

2012 ◽

Vol 32 (suppl_1) ◽

Author(s):

Stella Aslibekyan ◽

Marguerite M Irvin ◽

Alexis C Frazier-Wood ◽

Robert J Straka ◽

Ingrid B Borecki ◽

...

Keyword(s):

Blood Lipids ◽

Association Studies ◽

Meta Analysis ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Lipid Lowering ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Lipid Response ◽

Induced Changes

Introduction: Despite the widespread use of fibrates in treatment of dyslipidemia, the observed response is highly heterogeneous, suggesting a role for genetic determinants. Whether replicated variants associated with blood lipids identified by genome wide association studies (GWAS) are also associated with lipid response to fenofibrate is unknown. Objectives: To test if 95 genome-wide significant loci identified in a recent meta-analysis of blood lipids are associated with changes in high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, and triglycerides (TG) following 3 weeks of therapy with 160 mg of micronized fenofibrate. Methods: Using data from 861 European American Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) participants, we fit mixed linear models with baseline blood lipids and the post-to-pre fenofibrate treatment ratio of blood lipid levels as outcomes, the corresponding genetic markers from the published meta-analysis as predictors, and age, sex, pedigree, and ancestry as assessed by principal components as covariates. A Bonferroni correction was applied to adjust for multiple comparisons. Least square means were used to report the direction of fenofibrate-induced changes by genotype. Results: We observed statistically significant associations between rs964184 , a variant near the APOA1 gene, and baseline HDL-C (P<0.0001) and baseline TG (P<0.0001), as well as with diminished response to fenofibrate as evidenced by a smaller increase in HDL-C (P<0.0001) and a smaller decrease in TG (P=0.0001) per each copy of the variant allele. Additionally, we report suggestive associations of rs3764261 locus in the CETP gene and the rs10401969 locus in the CILP2 gene with decreased fenofibrate response as measured by changes in LDL-C (P=0.0003 and 0.02, respectively) and non-HDL-C (P=0.004 and 0.005, respectively). Conclusions: We have identified several novel biologically relevant loci associated with baseline blood lipids and fenofibrate-induced changes in blood lipids.

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A Genome-Wide Association Study of Monozygotic Twin-Pairs Suggests a Locus Related to Variability of Serum High-Density Lipoprotein Cholesterol

Twin Research and Human Genetics ◽

10.1017/thg.2012.63 ◽

2012 ◽

Vol 15 (6) ◽

pp. 691-699 ◽

Cited By ~ 18

Author(s):

Ida Surakka ◽

John B. Whitfield ◽

Markus Perola ◽

Peter M. Visscher ◽

Grant W. Montgomery ◽

...

Keyword(s):

High Density Lipoprotein ◽

High Density Lipoprotein Cholesterol ◽

Serum Lipid ◽

Density Lipoprotein ◽

Monozygotic Twin ◽

High Density ◽

Genome Wide Association ◽

Lipoprotein Cholesterol ◽

Genome Wide ◽

A Genome

Genome-wide association analysis on monozygotic twin-pairs offers a route to discovery of gene–environment interactions through testing for variability loci associated with sensitivity to individual environment/lifestyle. We present a genome-wide scan of loci associated with intra-pair differences in serum lipid and apolipoprotein levels. We report data for 1,720 monozygotic female twin-pairs from GenomEUtwin project with 2.5 million SNPs, imputed or genotyped, and measured serum lipid fractions for both twins. We found one locus associated with intra-pair differences in high-density lipoprotein cholesterol, rs2483058 in an intron of SRGAP2, where twins carrying the C allele are more sensitive to environmental factors (P = 3.98 × 10−8). We followed up the association in further genotyped monozygotic twins (N = 1,261), which showed a moderate association for the variant (P = 0.200, same direction of an effect). In addition, we report a new association on the level of apolipoprotein A-II (P = 4.03 × 10−8).

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A Genome-Wide Association Study and Polygenic Risk Score Analysis of Posttraumatic Stress Disorder and Metabolic Syndrome in a South African Population

Frontiers in Neuroscience ◽

10.3389/fnins.2021.677800 ◽

2021 ◽

Vol 15 ◽

Author(s):

Patricia C. Swart ◽

Leigh L. van den Heuvel ◽

Cathryn M. Lewis ◽

Soraya Seedat ◽

Sian M. J. Hemmings

Keyword(s):

Metabolic Syndrome ◽

South African ◽

Genetic Variants ◽

Genome Wide Association Study ◽

Stress Disorder ◽

Meta Analysis ◽

Genome Wide Association ◽

Polygenic Risk ◽

Genome Wide ◽

A Genome

Posttraumatic stress disorder (PTSD) is a trauma-related disorder that frequently co-occurs with metabolic syndrome (MetS). MetS is characterized by obesity, dyslipidemia, and insulin resistance. To provide insight into these co-morbidities, we performed a genome-wide association study (GWAS) meta-analysis to identify genetic variants associated with PTSD, and determined if PTSD polygenic risk scores (PRS) could predict PTSD and MetS in a South African mixed-ancestry sample. The GWAS meta-analysis of PTSD participants (n = 260) and controls (n = 343) revealed no SNPs of genome-wide significance. However, several independent loci, as well as five SNPs in the PARK2 gene, were suggestively associated with PTSD (p < 5 × 10–6). PTSD-PRS was associated with PTSD diagnosis (Nagelkerke’s pseudo R2 = 0.0131, p = 0.00786), PTSD symptom severity [as measured by CAPS-5 total score (R2 = 0.00856, p = 0.0367) and PCL-5 score (R2 = 0.00737, p = 0.0353)], and MetS (Nagelkerke’s pseudo R2 = 0.00969, p = 0.0217). These findings suggest an association between PTSD and PARK2, corresponding with results from the largest PTSD-GWAS conducted to date. PRS analysis suggests that genetic variants associated with PTSD are also involved in the development of MetS. Overall, the results contribute to a broader goal of increasing diversity in psychiatric genetics.

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