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Objective: We aimed to identify hemoglobin A 1c (HbA 1c )-associated genetic variants and examine their implications for glycemic status evaluated by HbA 1c in U.S. Hispanics/Latinos with diverse genetic ancestries., Research Design and Methods: We conducted a genome-wide association study (GWAS) of HbA 1c in 9,636 U.S. Hispanics/Latinos without diabetes from the Hispanic Community Health Study/Study of Latinos, followed by a replication among 4,729 U.S. Hispanics/Latinos from three independent studies., Results: Our GWAS and replication analyses showed 10 previously known and novel loci associated with HbA 1c at genome-wide significance levels ( P < 5.0 × 10 -8 ). In particular, two African ancestry-specific variants, HBB- rs334 and G6PD -rs1050828, which are causal mutations for sickle cell disease and G6PD deficiency, respectively, had ∼10 times larger effect sizes on HbA 1c levels (β = -0.31% [-3.4 mmol/mol]) and -0.35% [-3.8 mmol/mol] per minor allele, respectively) compared with other HbA 1c -associated variants (0.03-0.04% [0.3-0.4 mmol/mol] per allele). A novel Amerindian ancestry-specific variant, HBM -rs145546625, was associated with HbA 1c and hematologic traits but not with fasting glucose. The prevalence of hyperglycemia (prediabetes and diabetes) defined using fasting glucose or oral glucose tolerance test 2-h glucose was similar between carriers of HBB- rs334 or G6PD -rs1050828 HbA 1c -lowering alleles and noncarriers, whereas the prevalence of hyperglycemia defined using HbA 1c was significantly lower in carriers than in noncarriers (12.2% vs. 28.4%, P < 0.001). After recalibration of the HbA 1c level taking HBB -rs334 and G6PD -rs1050828 into account, the prevalence of hyperglycemia in carriers was similar to noncarriers (31.3% vs. 28.4%, P = 0.28)., Conclusions: This study in U.S. Hispanics/Latinos found several ancestry-specific alleles associated with HbA 1c through erythrocyte-related rather than glycemic-related pathways. The potential influences of these nonglycemic-related variants need to be considered when the HbA 1c test is performed., (© 2019 by the American Diabetes Association.)

Objective: Insulin receptor substrate 1 (IRS1) is central to insulin signaling pathways. This study aimed to examine the association of IRS1 variants with insulin resistance (IR) and related phenotypes, as well as potential modification by diet., Research Design and Methods: Two IRS1 variants (rs7578326 and rs2943641) identified by genome-wide association studies as related to type 2 diabetes were tested for their associations with IR and related traits and interaction with diet in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 820) and the Boston Puerto Rican Health Study (BPRHS) (n = 844)., Results: Meta-analysis indicated that rs7578326 G-allele carriers and rs2943641 T-allele carriers had a lower risk of IR, type 2 diabetes, and metabolic syndrome (MetS). Significant interactions on IR and MetS were found for these two variants and their haplotypes with diet. In GOLDN, rs7578326 G-allele carriers and rs2943641 T-allele carriers and their haplotype G-T carriers had a significantly lower risk of IR and MetS than noncarriers only when the dietary saturated fatty acid-to-carbohydrate ratio was low (≤ 0.24). In both GOLDN (P = 0.0008) and BPRHS (P = 0.011), rs7578326 G-allele carriers had a lower risk of MetS than noncarriers only when dietary monounsaturated fatty acids were lower than the median intake of each population., Conclusions: IRS1 variants are associated with IR and related traits and are modulated by diet in two populations of different ancestries. These findings suggest that IRS1 variants have important functions in various metabolic disorders and that dietary factors could modify these associations.

Objective: C-reactive protein (CRP) is an inflammatory marker that contributes to the prediction of cardiovascular disease. We investigated the influences of CRP polymorphisms on baseline CRP levels and fenofibrate-induced CRP changes in subjects with the metabolic syndrome., Research Design and Methods: We examined the association of CRP single nucleotide polymorphisms (SNPs) (m772A>G, m301G>A >T, i178T>A, 3u1273C>T, and 3u2131C>T) with baseline plasma CRP levels among 1,123 white U.S. participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study and the modulating effect of these SNPs on CRP response to a 3-week fenofibrate treatment among 290 participants with the metabolic syndrome., Results: There were strong associations of m301G>A>T (rs3091244; P = 0.003), i178T>A (rs1417938; P = 0.001), 3u1273C>T (rs1130864; P = 0.001), and 3u2131C>T (rs1205; P < 0.001) with baseline CRP levels. Moreover, among subjects with the metabolic syndrome, fenofibrate induced the greatest reduction in CRP levels for TT subjects of the i178T>A compared with TA and AA subjects (-30 for TT, -19 for TA, and -11% for AA; P = 0.004). Similarly, for the m301G>A>T, major allele carriers displayed maximal reduction of CRP over noncarriers (-20 for GG, -15 for GA and GT, and -0.3% for TA and AA; P = 0.020)., Conclusions: Our results demonstrate that common genetic variants within the CRP gene affect baseline CRP levels and further modulate CRP response in subjects with the metabolic syndrome treated with fenofibrate. This knowledge could contribute to a better prediction of therapeutic success.