Abstract P215: Common Beta-cell-associated Genetic Variants and Hypertension or Anti-hypertensive Drugs do not Interact in Their Positive Associations With Risk for Rising Fasting Glucose or Incident Type 2 Diabetes in Framingham

Background: Hypertension (HTN) and some anti-HTN drugs raise fasting glucose (FG) levels and type 2 diabetes (T2D) risk. We hypothesized that common single nucleotide polymorphisms (SNPs) associated with FG or T2D that influence beta-cell function will interact with hypertension (HTN) or anti-HTN drugs in their positive associations with change over time in FG (ΔFG) or incident T2D. Methods: We studied 3,471 Framingham Offspring Study participants comprising 18,786 person-exams (mean age 49 yr; 54% women), in pooled (7 ∼4-yr periods) age-, sex-adjusted logistic regression models predicting T2D incidence, or age-, sex-, baseline FG-adjusted mixed linear models testing ΔFG (FG end minus beginning of period). T2D cases were excluded at baseline of each period, and people who started T2D treatment within a given period were removed for ΔFG analyses. We defined three HTN exposures: 1) HTN (SBP≥140/DBP≥90 mmHg) vs. no-HTN; 2) treated vs. untreated HTN; 3) five mutually-exclusive anti-HTN drug categories (beta-blockers, thiazides, renin-angiotensin system agents, combination, other) vs. untreated HTN, and two genetic exposures reflecting total beta-cell genetic risk burden: 16 FG-SNP and 33 T2D-SNP (only 8 overlap) additive genetic risk scores. We tested ∼4-year mean ΔFG and odds of T2D by HTN category and per-risk allele change in SNP scores, seeking first-order HTNxSNP significant interaction (P<0.05). Results: Versus no HTN, HTN (n=5,372 p-e) was associated with higher ∼4-year ΔFG (0.14 vs. 0.03 mmol/l; P<0.0001) and ∼3-fold increased odds of T2D (OR 3.3; P<0.0001). Versus untreated HTN, treated HTN (n=2,832 p-e) conferred higher ΔFG (0.18 vs. 0.12 mmol/l; P<0.0001) and 1.5-fold increased odds of T2D (P=0.0006). Versus untreated HTN, beta-blockers (n=676 p-e; OR=1.58), combined (n=499 p-e; OR=1.57) and other (n=569 p-e; OR=1.94) were associated with increased odds of T2D (all P<0.03). Per-SNP score risk allele, ΔFG increased by 0.03 mmol/l (P=2.2x10 −16 ) and odds of T2D increased 17% (P=3.1x10 −08 ). In joint models with interaction terms, all HTN-treatment category-by-SNP score interaction terms were non-significant. In joint models without interaction, HTN (P<0.0001) and HTN treatment (P<0.02), but no specific drugs (all but one P>0.02), and per FG-SNP or T2D-SNP risk allele (highest P value=0.0005), all independently predicted ΔFG or incident T2D. Conclusion: HTN, HTN treatment and common FG- and T2D-SNP genetic scores were independently associated with ΔFG and T2D incidence, but did not modify each other's association with ΔFG or T2D risk. Next, larger samples and individual SNP-by-specific drug category interaction tests might disclose some biological basis for T2D risk associated with anti-HTN therapy.