HDL levels modulate the impact of type 2 diabetes susceptibility alleles in older adults

Abstract

Background: Type 2 Diabetes (T2D) is influenced by genetic, environmental, and ageing factors. Ageing pathways exacerbate metabolic diseases. This study aimed to examine both clinical and genetic factors of T2D in older adults.

Methods: A total of 2,909 genotyped patients were enrolled in this study. Genome Wide Association Study was conducted, comparing T2D patients to non-diabetic older adults aged ≥ 60, ≥ 65, or ≥ 70 years, respectively. Binomial logistic regressions were applied to examine the association between T2D and various risk factors. Stepwise logistic regression was conducted to explore the impact of low HDL (HDL < 40 mg/dl) on the relationship between the genetic variants and T2D. A further validation step using data from the UK Biobank with 53,779 subjects was performed.

Results: The association of T2D with both low HDL and family history of T2D increased with the age of control groups. T2D susceptibility variants (rs7756992, rs4712523 and rs10946403) were associated with T2D, more significantly with increased age of the control group. These variants had stronger effects on T2D risk when combined with low HDL cholesterol levels, especially in older control groups.

Conclusions: The findings highlight a critical role of age, genetic predisposition, and HDL levels in T2D risk. The findings suggest that individuals over 70 years who have high HDL levels without the T2D susceptibility alleles may be at the lowest risk of developing T2D. These insights can inform tailored preventive strategies for older adults, enhancing personalized T2D risk assessments and interventions.

Keywords: Diabetes risk; Genetic variants; HDL; Older age groups.

Fig. 1

Forest plot of the binomial logistic regression showing evidence of association between T2D and different risk factors stratified by gender, taking (a) noT2D ≥ 60 years, (b) noT2D ≥ 65 years and (c) noT2D ≥ 70 years as control groups. CI: Confidence Interval. T2D: Type 2 Diabetes. Fx: Family history. BMI: Body Mass Index. CVD: Cardiovascular disease

Fig. 2

a Manhattan plot for the genome-wide association analysis with T2D using individuals aged ≥ 70 years without diabetes as controls. b Quantile–Quantile (Q-Q) plot of the GWAS results showing the distribution of p-values, plotted against the expected distribution. c Regional association plots for the loci associated with T2D among the older adults in the Lebanese population. GWAS: genome-wide association study. T2D: Type 2 Diabetes. a X-axis shows chromosomal positions. Y axis represents the − log₁₀(P-value obtained) by logistic regression analysis (additive model). The horizontal solid blue line indicates the suggestive genome-wide threshold of P = 1 × 10^–5. Each point denotes a Single nucleotide polymorphism (SNP), SNPs with significance P < 1 × 10^–8 are shown above the genome-wide significance in red. b This plot shows the association between each tested SNP and the observed -log10 p values, plotted on the vertical axis, compared to the expected –log10 p values under the null hypothesis. Each dot on the plot represents a SNP. The genomic control ratio (l) was 1.1238, which indicates that there is no strong effect of systematic error, such as population stratification. c Correlations between the SNPs with the lowest P value from GWAS (depicted in purple) and nearby SNPs within a 400 kb region. The r² values of the Linkage Disequilibrium (LD) heat map is based on the hg19/1000 genomes Nov 2014 EUR reference set