ABSTRACT
Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.
Subject(s)
Exercise , Genetic Loci/genetics , Lipids/blood , Lipids/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Asian People/genetics , Black People/genetics , Brazil , Calcium-Binding Proteins/genetics , Cholesterol/blood , Cholesterol, HDL/blood , Cholesterol, HDL/genetics , Cholesterol, LDL/blood , Cholesterol, LDL/genetics , Female , Genome-Wide Association Study , Genotype , Hispanic or Latino/genetics , Humans , LIM-Homeodomain Proteins/genetics , Lipid Metabolism/genetics , Male , Membrane Proteins/genetics , Microtubule-Associated Proteins/genetics , Middle Aged , Muscle Proteins/genetics , Nerve Tissue Proteins/genetics , Transcription Factors/genetics , Triglycerides/blood , Triglycerides/genetics , White People/genetics , Young AdultABSTRACT
Populations of African descent are at the forefront of the worldwide epidemic of type 2 diabetes mellitus (T2DM). The burden of T2DM is amplified by diagnosis after preventable complications of the disease have occurred. Earlier detection would result in a reduction in undiagnosed T2DM, more accurate statistics, more informed resource allocation and better health. An underappreciated factor contributing to undiagnosed T2DM in populations of African descent is that screening tests for hyperglycaemia, specifically, fasting plasma glucose and HbA1c, perform sub-optimally in these populations. To offset this problem, combining tests or adding glycated albumin (a nonfasting marker of glycaemia), might be the way forward. However, differences in diet, exercise, BMI, environment, gene-environment interactions and the prevalence of sickle cell trait mean that neither diagnostic tests nor interventions will be uniformly effective in individuals of African, Caribbean or African-American descent. Among these three populations of African descent, intensive lifestyle interventions have been reported in only the African-American population, in which they have been found to provide effective primary prevention of T2DM but not secondary prevention. Owing to a lack of health literacy and poor glycaemic control in Africa and the Caribbean, customized lifestyle interventions might achieve both secondary and primary prevention. Overall, diagnosis and prevention of T2DM requires innovative strategies that are sensitive to the diversity that exists within populations of African descent.