Genetically Mediated Lipid Metabolism and Risk of Insulin Resistance: Insights from Mendelian Randomization Studies
2
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Dysregulated lipid metabolism, characterized by higher levels of circulating triglycerides, higher levels of small, low density lipoprotein, and accumulation of intracellular lipids, is linked to insulin resistance and related complications such as type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). Considering that various metabolic, genetic, and environmental factors are involved in the development of T2DM and CVD, the causalities of these diseases are often confounded. In recent years, Mendelian randomization (MR) studies coupling genetic data in population studies have revealed new insights into the risk factors influencing the development of CVD and T2DM. This review briefly conceptualizes MR and summarizes the genetic traits related to lipid metabolism by evaluating their effects on the indicators of insulin resistance based on the results of recent MR studies. The data from the MR study cases referred to in this review indicate that the causal associations between lipid status and insulin resistance in MR studies are not conclusive. Furthermore, available data on Asian ethnicities, including Korean, are very limited. More genome-wide association studies and MR studies on Asian populations should be conducted to identify Asian- or Korean-specific lipid traits in the development of insulin resistance and T2DM. The present review discusses certain studies that investigated genetic variants related to nutrient intake that can modify lipid metabolism outcomes. Up-to-date inferences on the causal association between lipids and insulin resistance using MR should be interpreted with caution because of several limitations, including pleiotropic effects and lack of information on genotype and ethnicity.
Abstract
Dysregulated lipid metabolism, characterized by higher levels of circulating triglycerides, higher levels of small, low density lipoprotein, and accumulation of intracellular lipids, is linked to insulin resistance and related complications such as type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). Considering that various metabolic, genetic, and environmental factors are involved in the development of T2DM and CVD, the causalities of these diseases are often confounded. In recent years, Mendelian randomization (MR) studies coupling genetic data in population studies have revealed new insights into the risk factors influencing the development of CVD and T2DM. This review briefly conceptualizes MR and summarizes the genetic traits related to lipid metabolism by evaluating their effects on the indicators of insulin resistance based on the results of recent MR studies. The data from the MR study cases referred to in this review indicate that the causal associations between lipid status and insulin resistance in MR studies are not conclusive. Furthermore, available data on Asian ethnicities, including Korean, are very limited. More genome-wide association studies and MR studies on Asian populations should be conducted to identify Asian- or Korean-specific lipid traits in the development of insulin resistance and T2DM. The present review discusses certain studies that investigated genetic variants related to nutrient intake that can modify lipid metabolism outcomes. Up-to-date inferences on the causal association between lipids and insulin resistance using MR should be interpreted with caution because of several limitations, including pleiotropic effects and lack of information on genotype and ethnicity.
참고문헌 (49)
- Dehghan A, "Meta-analysis of genome-wide association studies in >80 000 subjects identifies multiple loci for C-reactive protein levels", Circulation, 123, pp.731~738 (2011)
- Hingorani A, "Nature's randomised trials", Lancet, 366, pp.1906~1908 (2005)
- Rainwater DL, "Effects of NIDDM on lipoprotein(a)concentration and apolipoprotein(a) size", Diabetes, 43, pp.942~946 (1994)
- Mora S, "Lipoprotein(a) and risk of type 2diabetes", Clin Chem, 56, pp.1252~1260 (2010)
- Koschinsky ML, "The relationship between lipoprotein(a) and the complications of diabetes mellitus", Acta Diabetol, 40, pp.65~76 (2003)
- Swerdlow DI, "Blood lipids and type 2 diabetes risk: can genetics help untangle the web?", Diabetes, 64, pp.2344~2345 (2015)
- Burgess S, "Multivariable Mendelian randomization: the use of pleiotropic genetic variants to estimate causal effects", Am J Epidemiol, 181, pp.251~260 (2015)
- Burgess S, "Use of allele scores as instrumental variables for Mendelian randomization", Int J Epidemiol, 42, pp.1134~1144 (2013)
- Davey Smith G, "Mendelian randomization: genetic anchors for causal inference in epidemiological studies", Hum Mol Genet, 23, pp.R89~R98 (2014)
- Ebrahim S, "Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology?", Hum Genet, 123, pp.15~33 (2008)
- Danesh J, "Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies", Circulation, 102, pp.1082~1085 (2000)
- Holmes MV, "Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis", Am J Hum Genet, 94, pp.198~208 (2014)
- Craig WY, "Lipoprotein(a) as a risk factor for ischemic heart disease: metaanalysis of prospective studies", Clin Chem, 44, pp.2301~2306 (1998)
- Burgess S, "Mendelian randomization: where are we now and where are we going?", Int J Epidemiol, 44, pp.379~388 (2015)
- Dubé JB, "Lipoprotein(a): more interesting than ever after 50 years", Curr Opin Lipidol, 23, pp.133~140 (2012)
- Kamstrup PR, "Lipoprotein(a) concentrations, isoform size, and risk of type 2 diabetes:a Mendelian randomisation study", Lancet Diabetes Endocrinol, 1, pp.220~227 (2013)
- Ye Z, "The association between circulating lipoprotein(a) and type 2 diabetes: is it causal?", Diabetes, 63, pp.332~342 (2014)
- Do R, "Common variants associated with plasma triglycerides and risk for coronary artery disease", Nat Genet, 45, pp.1345~1352 (2013)
- Fall T, "Using genetic variants to assess the relationship between circulating lipids and type 2 diabetes", Diabetes, 64, pp.2676~2684 (2015)
- Buchmann N, "Association between lipoprotein(a) level and type 2 diabetes: no evidence for a causal role of lipoprotein(a) and insulin", Acta Diabetol, 54, pp.1031~1038 (2017)
- Swerdlow DI, "HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials", Lancet, 385, pp.351~361 (2015)
- Schmidt AF, "PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study", Lancet Diabetes Endocrinol, 5, pp.97~105 (2017)
- Savage DB, "Recent insights into fatty liver, metabolic dyslipidaemia and their links to insulin resistance", Curr Opin Lipidol, 21, pp.329~336 (2010)
- Gupta AK, "Determinants of new-onset diabetes among 19,257 hypertensive patients randomized in the Anglo-Scandinavian Cardiac Outcomes Trial--Blood Pressure Lowering Arm and the relative influence of antihypertensive medication", Diabetes Care, 31, pp.982~988 (2008)
- Schmidt MI, "Identifying individuals at high risk for diabetes: the Atherosclerosis Risk in Communities study", Diabetes Care, 28, pp.2013~2018 (2005)
- Semple RK, "Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis", J Clin Invest, 119, pp.315~322 (2009)
- Nolan CJ, "Fatty acid signaling in the beta-cell and insulin secretion", Diabetes, 55(Suppl 2), pp.S16~S23 (2006)
- De Silva NM, "Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance", Diabetes, 60, pp.1008~1018 (2011)
- Drew BG, "The emerging role of HDL in glucose metabolism", Nat Rev Endocrinol, 8, pp.237~245 (2012)
- Wilson PW, "Prediction of incident diabetes mellitus in middle-aged adults: the Framingham Offspring Study", Arch Intern Med, 167, pp.1068~1074 (2007)
- Drew BG, "High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus", Circulation, 119, pp.2103~2111 (2009)
- Fryirs MA, "Effects of high-density lipoproteins on pancreatic beta-cell insulin secretion", Arterioscler Thromb Vasc Biol, 30, pp.1642~1648 (2010)
- Moriyama K, "HDL2-cholesterol", HDL3-cholesterol ratio was associated with insulin resistance, high-molecular-weight adiponectin, and components for metabolic syndrome in Japanese, 2014, pp.106, 360~365
- Haase CL, "HDL Cholesterol and risk of type 2diabetes: a Mendelian randomization study", Diabetes, 64, pp.3328~3333 (2015)
- Tabara Y, "Different inverse association of large high-density lipoprotein subclasses with exacerbation of insulin resistance and incidence of type 2diabetes: the Nagahama study", Diabetes Res Clin Pract, 127, pp.123~131 (2017)
- Freathy RM, "Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI", Diabetes, 57, pp.1419~1426 (2008)
- Fall T, "Age- and sex-specific causal effects of adiposity on cardiovascular risk factors", Diabetes, 64, pp.1841~1852 (2015)
- Xu L, "The role of glycaemic and lipid risk factors in mediating the effect of BMI on coronary heart disease: a two-step, two-sample Mendelian randomisation study", Diabetologia, 60, pp.2210~2220 (2017)
- Yang J, "FTO genotype is associated with phenotypic variability of body mass index", Nature, 490, pp.267~272 (2012)
- Locke AE, "Genetic studies of body mass index yield new insights for obesity biology", Nature, 518, pp.197~206 (2015)
- Fall T, "The role of adiposity in cardiometabolic traits: a Mendelian randomization analysis", PLoS Med, 10, pp.e1001474~ (2013)
- Lim LS, "Relation of age-related cataract with obesity and obesity genes in an Asian population", Am J Epidemiol, 169, pp.1267~1274 (2009)
- Dongiovanni P, "Causal relationship of hepatic fat with liver damage and insulin resistance in nonalcoholic fatty liver", J Intern Med, 283, pp.356~370 (2018)
- Wang N, "Vitamin D and nonalcoholic fatty liver disease: bidirectional Mendelian randomization analysis", EBioMedicine, 28, pp.187~193 (2018)
- Tanaka T, "Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake", Am J Clin Nutr, 97, pp.1395~1402 (2013)
- Chu AY, "Novel locus including FGF21is associated with dietary macronutrient intake", Hum Mol Genet, 22, pp.1895~1902 (2013)
- Holmes MV, "Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data", BMJ, 349, pp.g4164~ (2014)
- Ding R, "Diet", lifestyle and risk of diabetes and glycemic traits: a Mendelian randomization study, 2018, pp.17, 18~
- Moen GH, "Are serum concentrations of vitamin B-12causally related to cardiometabolic risk factors and disease? A Mendelian randomization study", Am J Clin Nutr, 108, pp.398~404 (2018)