Apolipoprotein A-I concentrations and risk of coronary artery disease: A Mendelian randomization study

Karjalainen, Minna K.; Holmes, Michael V.; Wang, Qin; Anufrieva, Olga; Kähönen, Mika; Lehtimäki, Terho; Havulinna, Aki S.; Kristiansson, Kati; Salomaa, Veikko; Perola, Markus; Viikari, Jorma; Raitakari, Olli T.; Järvelin, Marjo‐Riitta; Ala‐Korpela, Mika; Kettunen, Johannes

doi:10.1016/j.atherosclerosis.2020.02.002

Cited by 49 publications

(43 citation statements)

References 41 publications

(68 reference statements)

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“…Recent studies suggest that HDL functions and quality characteristics, rather than HDL-C concentration, are the main determinants of HDL anti-atherogenic properties [5]. Our data are consistent with previous evidence, and reflect that HDL-C and ApoA-I levels in the bloodstream are not causally related to CAD [3,11]. However, we observed a decrease in CAD risk when HDL-C was mainly transported in smaller HDLs, but an increase in CAD risk when HDL-C was carried by larger HDL particles (in both main and validation analyses, there is a gradient towards greater CAD risk as more cholesterol is transported in larger HDLs).…”

Section: Discussionsupporting

confidence: 91%

“…However, we observed a decrease in CAD risk when HDL-C was mainly transported in smaller HDLs, but an increase in CAD risk when HDL-C was carried by larger HDL particles (in both main and validation analyses, there is a gradient towards greater CAD risk as more cholesterol is transported in larger HDLs). The protective effect of cholesterol content in medium-sized HDLs and the increase in CAD risk due to cholesterol levels in larger particles observed in our data may contribute to explaining why the overall HDL-C levels are not causally associated with cardiovascular risk [3,11]. Our results could also help explain the therapeutic failure of the pharmacological agents known to increase HDL-C levels.…”

Section: Discussionsupporting

confidence: 49%

“…These studies assess the association between the genetically determined lifelong values of a biomarker and the development of a clinical outcome. MR studies have already raised serious doubts on the causal role of quantitative HDL characteristics, such as HDL-C and apolipoprotein A-I (ApoA-I) levels, in CAD [3,11]. However, to date, the association between qualitative HDL characteristics and CAD has not been tested using a MR approach.…”

Section: Introductionmentioning

confidence: 99%

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High-density lipoprotein characteristics and coronary artery disease: a Mendelian randomization study

et al. 2020

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Background: To assess whether genetically determined quantitative and qualitative HDL characteristics were independently associated with coronary artery disease (CAD). Methods: We designed a two-sample multivariate Mendelian randomization study with available genome-wide association summary data. We identified genetic variants associated with HDL cholesterol and apolipoprotein A-I levels, HDL size, particle levels, and lipid content to define our genetic instrumental variables in one sample (Kettunen et al. study, n = 24,925) and analyzed their association with CAD risk in a different study (CARDIoGRAMplusC4D, n = 184,305). We validated these results by defining our genetic variables in another database (METSIM, n = 8372) and studied their relationship with CAD in the CARDIoGRAMplusC4D dataset. To estimate the effect size of the associations of interest adjusted for other lipoprotein traits and minimize potential pleiotropy, we used the Multi-trait-based Conditional & Joint analysis. Results: Genetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD. HDL mean diameter (β = 0.27 [95%CI = 0.19; 0.35]), cholesterol levels in very large HDLs (β = 0.29 [95%CI = 0.17; 0.40]), and triglyceride content in very large HDLs (β = 0.14 [95%CI = 0.040; 0.25]) were directly associated with CAD risk, whereas the cholesterol content in medium-sized HDLs (β = −0.076 [95%CI =-0.10; −0.052]) was inversely related to this risk. These results were validated in the METSIM-CARDIoGRAMplusC4D data. Conclusions: Some qualitative HDL characteristics (related to size, particle distribution, and cholesterol and triglyceride content) are related to CAD risk while HDL cholesterol levels are not.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 49%

Section: Introductionmentioning

confidence: 99%

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High-density lipoprotein characteristics and coronary artery disease: a Mendelian randomization study

et al. 2020

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“…Conversely, there was a lack of evidence from downstream analyses that any HDL-related measure identified in initial analyses influence CAD risk. These findings therefore corroborate evidence from various studies and trial outcomes which support HDL cholesterol or apolipoprotein A-I as non-causal for CAD (Voight et al, 2012, Marz et al, 2017, Richardson et al, 2020b, Karjalainen et al, 2020); although it may still be useful for risk prediction (Davey Smith and Phillips, 2020, Holmes and Davey Smith, 2019).…”

Section: Discussionsupporting

confidence: 86%

Evaluating the direct effects of childhood adiposity on adult systemic-metabolism: A multivariable Mendelian randomization analysis

Richardson

Mykkänen

Pahkala

et al. 2020

Preprint

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Background: Individuals who are obese in childhood have an elevated risk of cardiometabolic disease in adulthood. However, whether childhood adiposity directly impacts intermediate markers of this risk, independent of adult adiposity, is unclear. Methods and Results: We conducted a multivariable Mendelian randomization (MR) study to simultaneously evaluate the effects of childhood and adulthood body size on over 100 systemic molecular biomarkers representing multiple metabolic pathways. We first validated UK Biobank-derived genetic risk scores using data on body mass index (BMI) measured during childhood (n=2,427, age: 3-18 years) and adulthood (n=1,762, age: 34-49 years) from the Young Finns Study (YFS). Results indicated that the childhood score is a stronger predictor of childhood BMI (0.74 vs 0.62 area under the curve (AUC) for the childhood and adult scores respectively), whereas the adult score was a stronger predictor of adulthood BMI (0.57 vs 0.62 AUC). Two-sample MR analyses in a univariable setting using summary genome-wide association study (GWAS) data in up to 24,925 adults provided evidence of an effect of childhood body size on 42 of the 123 metabolic markers assessed (based on P<4.07x10-04). Undertaking multivariable MR analyses suggested that the effects for the majority of these metabolic biomarkers (35/42) substantially attenuated when accounting for adult body size. In further analyses, the biomarkers with the strongest evidence of mediating a long-term effect of adiposity on coronary artery disease (CAD) risk were those related to triglyceride-rich very-low-density lipoprotein particles. In contrast, the biomarkers which showed the strongest evidence of being directly influenced by childhood body size (amino acids leucine, isoleucine and tyrosine) provided little evidence that they mediate this effect on adult disease risk. Conclusions: The effects of childhood adiposity on the majority of biomarkers investigated in this study were greatly attenuated when accounting for adult body size. This suggests that the detrimental impact of genetically predicted childhood adiposity on systemic metabolism, as well as subsequent later life risk of CAD, can likely be mitigated through lifestyle modifications during adolescence and early adulthood.

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“…APOA1 is the major protein component of HDL-C particles, and a Mendelian randomization analysis in Finnish individuals reported that ApoA1 was not associated with risk of CAD. 76 A multivariable Mendelian randomization study examining serum lipid and apolipoprotein levels reported that only ApoB retained a robust relationship with the risk of CAD, 77 and recent Mendelian randomization studies suggest that ApoB is the primary lipid determinant of cardiovascular disease risk. 78; 79 Thus, the association of SIDT2 /Val636Ile with decreased cardiovascular risk could be mediated by its effect on ApoB levels.…”

Section: Discussionmentioning

confidence: 99%

A functional variant of the SIDT2 gene involved in cholesterol transport is associated with HDL-C levels and premature coronary artery disease

León-Mimila

Villamil‐Ramírez

Macías-Kauffer

et al. 2020

Preprint

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Low HDL-C is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Moreover, few lipid-associated variants have been tested for coronary artery disease (CAD) in Hispanic populations. Here, we performed a GWAS for HDL-C levels in 2,183 Mexican individuals, identifying 7 loci, including three with genome-wide significance and containing the candidate genes CETP, ABCA1 and SIDT2. The SIDT2 missense Val636Ile variant was associated with HDL-C levels for the first time, and this association was replicated in 3 independent cohorts (P=5.5x10-21 in the conjoint analysis). The SIDT2/Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C and ApoB levels and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant is functional. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel (HMDP) are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism. In conclusion, this is the first study assessing genetic variants contributing to HDL-C levels and coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans.

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Apolipoprotein A-I concentrations and risk of coronary artery disease: A Mendelian randomization study

Cited by 49 publications

References 41 publications

High-density lipoprotein characteristics and coronary artery disease: a Mendelian randomization study

High-density lipoprotein characteristics and coronary artery disease: a Mendelian randomization study

Evaluating the direct effects of childhood adiposity on adult systemic-metabolism: A multivariable Mendelian randomization analysis

A functional variant of the SIDT2 gene involved in cholesterol transport is associated with HDL-C levels and premature coronary artery disease

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