HDL Cholesterol and Risk of Type 2 Diabetes: A Mendelian Randomization Study

Abstract

Observationally, low levels of HDL cholesterol are consistently associated with increased risk of type 2 diabetes. Therefore, plasma HDL cholesterol increasing has been suggested as a novel therapeutic option to reduce the risk of type 2 diabetes. Whether levels of HDL cholesterol are causally associated with type 2 diabetes is unknown. In a prospective study of the general population (n = 47,627), we tested whether HDL cholesterol-related genetic variants were associated with low HDL cholesterol levels and, in turn, with an increased risk of type 2 diabetes. HDL cholesterol-decreasing gene scores and allele numbers associated with up to 213 and 220% reductions in HDL cholesterol levels. The corresponding theoretically predicted hazard ratios for type 2 diabetes were 1.44 (95% CI 1.38-1.52) and 1.77 (1.61-1.95), whereas the genetic estimates were nonsignificant. Genetic risk ratios for type 2 diabetes for a 0.2 mmol/L reduction in HDL cholesterol were 0.91 (0.75-1.09) and 0.93 (0.78-1.11) for HDL cholesterol-decreasing gene scores and allele numbers, respectively, compared with the corresponding observational hazard ratio of 1.37 (1.32-1.42). In conclusion, genetically reduced HDL cholesterol does not associate with increased risk of type 2 diabetes, suggesting that the corresponding observational association is due to confounding and/or reverse causation.

Risk factors for neuropathic pain in diabetes mellitus

“…The previous point can be further strengthened by running Mendelian randomization studies, something that has been used in DM. 16 Mendelian randomization studies establish causal relationship by comparing 2 groups of individuals with and without a genetic marker known to influence the variable being studied. As genotype assignment is random and not subject to confounding typically found in epidemiological studies, a higher prevalence of disease in the group with the marker implies causality.…”

Unexplained reciprocal regulation of diabetes and lipoproteins

“…Furthermore, genetically determined increases in cholesterol specifically on large and extra-large HDL particles is associated with lower fasting glucose [37]. In contrast, an independent study showed no effect of HDL-cholesterol on diabetes risk [38]. …”

Development of Type-2 Diabetes Mellitus is associated with Low Levels of ApoA1

“…The data presented in Table 3 and Figure 3B indicated that HDL-C should not be considered as a substitute for ApoA1 in risk prediction for new T2DM. In addition to a growing body of evidence suggesting that HDL-C concentration does not accurately reflect the heterogeneous HDL particles and the HDL's vascular protective function [34,35], a recently published Mendelian randomization study [18] showed that low levels of HDL-C due to genetic variation do not increase risk of T2DM in the general population, which suggesting that the previously observed association between low levels of HDL-C and development of T2DM may be due to reverse causation of a state of prediabetes [18]. Similarly, a Mendelian randomization study showed that raised triglyceride levels were not causally associated with the risk of T2DM [36].…”

“…Previous studies demonstrated that the most commonly identified risk factors for development of T2DM include older age [4], positive family history of diabetes [5], higher body mass index (BMI) [4], abdominal obesity [6], smoking [7], hypertension [8], higher fasting glucose level [9], physical inactivity [10] and metabolic syndrome [11]. There have been inconsistent reports on associations of ApoA1 and HDL-C with development of T2DM [12][13][14][15][16][17][18]. We examined the incidence of new T2DM over 4 years for association of clinical factors and lipids with development of T2DM among Chinese subjects who participated in a community-organized health checkout in both 2009 and 2013.…”