Chao Qiang Lai

Common Missense Variant in the Glucokinase Regulatory Protein Gene Is Associated With Increased Plasma Triglyceride and C-Reactive Protein but Lower Fasting Glucose Concentrations

OBJECTIVE—Using the genome-wide association approach, we recently identified the glucokinase regulatory protein gene (GCKR, rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes, including measures of glucose homeostasis, to evaluate the GCKR locus in samples of non-European ancestry and to fine- map across the associated genomic interval. RESEARCH DESIGN AND METHODS—We performed association studies in 12 independent cohorts comprising >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the U.S., African Americans from the U.S., Hispanics of Caribbean origin, and Chinese, Malays, and Asian Indians from Singapore). We conducted genetic fine-mapping across the ∼417-kb region of linkage disequilibrium spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap single nucleotide polymorphisms (SNPs) and genotyping 104 SNPs across the associated genomic interval. RESULTS—We provide comprehensive evidence that GCKR rs780094 is associated with opposite effects on fasting plasma triglyceride (Pmeta = 3 × 10−56) and glucose (Pmeta = 1 × 10−13) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reactive protein (CRP) level (P = 5 × 10−5). Both fine-mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r2 = 0.93 with rs780094) as the strongest association signal in the region. CONCLUSIONS—These findings point to a molecular mechanism in humans by which higher triglycerides and CRP can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism.

Fenofibrate Effect on Triglyceride and Postprandial Response of Apolipoprotein A5 Variants The GOLDN Study

Objective—Apolipoprotein A5 (APOA5) is a key determinant of plasma triglyceride (TG) concentrations. Genetic variation at the APOA5 locus could be responsible for some of the observed differences in response to fenofibrate therapy. Methods and Results—We examined the association between tag SNPs (−1131T>C and 56C>G) at APOA5 and TG and HDL-C response to fenofibrate and a postprandial lipid challenge in 791 men and women participating in the GOLDN study. After 3-week drug treatment, APOA5 56G carriers displayed significant decrease in TG (P=0.006), and increase in HDL-C (P=0.002) levels relative to their basal values in the fasting state when compared with noncarriers (a TG reduction of −35.8±2.8% versus −27.9±0.9% and a HDL-C increase of 11.8±1.3% versus 6.9±0.5%, respectively). In the postprandial lipemia after a fat load, the 56G carriers showed a significant decrease in the area under curve for TG and increase for HDL-C than the noncarriers. These diverse beneficial responses of 56G carriers to fenofibrate were further characterized by a higher increase in large LDL-C concentrations and LDL size. On the other hand, subjects with different APOA5-1131T>C genotypes showed no significant response to fenofibrate intervention. Conclusion—This study suggests that the APOA5 56G carriers benefited more from the fenofibrate treatment than noncarriers in lowering plasma TG and increasing HDL-C levels.

CLOCK genetic variation and metabolic syndrome risk: modulation by monounsaturated fatty acids

BACKGROUNDnDisruption of the circadian system may be causal for manifestations of the metabolic syndrome (MetS).nnnOBJECTIVEnThe objective was to study the associations of 5 CLOCK polymorphisms with MetS features by analyzing fatty acid (FA) composition from dietary and red blood cell (RBC) membrane sources.nnnDESIGNnParticipants (n = 1100) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study were included. Dietary intake was estimated with a validated questionnaire. Anthropometric and biochemical measurements and genotypes were determined. Postprandial lipids and the FA composition of RBC membranes were analyzed.nnnRESULTSnCLOCK single nucleotide polymorphisms were significantly associated with obesity and individual components of MetS. For single nucleotide polymorphism rs4580704, minor allele carriers had a 46% lower risk of hypertension than did noncarriers. The monounsaturated fatty acid (MUFA) content of RBC membranes, particularly oleic acid, changed according to CLOCK genetic variants (P < 0.05). We identified significant gene-diet interactions associated with MetS at the CLOCK locus. By dichotomizing MUFA intake, we found different effects across rs4580704 genotypes for glucose (P = 0.020) and insulin resistance (P = 0.026). The protective effect of the minor allele on insulin sensitivity was only present when MUFA intake was >13.2% of energy. We also found different effects across CLOCK 3111T-->C genotypes for saturated fatty acid intake (% of energy) (P = 0.017). The deleterious effect of gene variants on waist circumference was only found with high saturated fatty acid intakes (>11.8%).nnnCONCLUSIONSnCLOCK polymorphisms interact with FAs to modulate MetS traits. The dietary source and membrane content of MUFAs are implicated in the relations between alterations in the circadian system and MetS.

Population Admixture Associated With Disease Prevalence in the Boston Puerto Rican Health Study

Older Puerto Ricans living in the continental U.S. suffer from higher rates of diabetes, obesity, cardiovascular disease and depression compared to non-Hispanic White populations. Complex diseases, such as these, are likely due to multiple, potentially interacting, genetic, environmental and social risk factors. Presumably, many of these environmental and genetic risk factors are contextual. We reasoned that racial background may modify some of these risk factors and be associated with health disparities among Puerto Ricans. The contemporary Puerto Rican population is genetically heterogeneous and originated from three ancestral populations: European settlers, native Taíno Indians, and West Africans. This rich-mixed ancestry of Puerto Ricans provides the intrinsic variability needed to untangle complex gene–environment interactions in disease susceptibility and severity. Herein, we determined whether a specific ancestral background was associated with either of four major disease outcomes (diabetes, obesity, cardiovascular disease, and depression). We estimated the genetic ancestry of 1,129 subjects from the Boston Puerto Rican Health Study based on genotypes of 100 ancestry informative markers (AIMs). We examined the effects of ancestry on tests of association between single AIMs and disease traits. The ancestral composition of this population was 57.2% European, 27.4% African, and 15.4% Native American. African ancestry was negatively associated with type 2 diabetes and cardiovascular disease, and positively correlated with hypertension. It is likely that the high prevalence rate of diabetes in Africans, Hispanics, and Native Americans is not due to genetic variation alone, but to the combined effects of genetic variation interacting with environmental and social factors.

A High Intake of Saturated Fatty Acids Strengthens the Association between the Fat Mass and Obesity-Associated Gene and BMI

Evidence that physical activity (PA) modulates the association between the fat mass and obesity-associated gene (FTO) and BMI is emerging; however, information about dietary factors modulating this association is scarce. We investigated whether fat and carbohydrate intake modified the association of FTO gene variation with BMI in two populations, including participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (n = 1069) and in the Boston Puerto Rican Health (BPRHS) study (n = 1094). We assessed energy, nutrient intake, and PA using validated questionnaires. Genetic variability at the FTO locus was characterized by polymorphisms rs9939609 (in the GOLDN) and rs1121980 (in the GOLDN and BPRHS). We found significant interactions between PA and FTO on BMI in the GOLDN but not in the BPRHS. We found a significant interaction between SFA intake and FTO on BMI, which was stronger than that of total fat and was present in both populations (P-interaction = 0.007 in the GOLDN and P-interaction = 0.014 in BPRHS for categorical; and P-interaction = 0.028 in the GOLDN and P-interaction = 0.041 in BPRHS for continuous SFA). Thus, homozygous participants for the FTO-risk allele had a higher mean BMI than the other genotypes only when they had a high-SFA intake (above the population mean: 29.7 ± 0.7 vs. 28.1 ± 0.5 kg/m²; P = 0.037 in the GOLDN and 33.6. ± 0.8 vs. 31.2 ± 0.4 kg/m²; P = 0.006 in BPRHS). No associations with BMI were found at lower SFA intakes. We found no significant interactions with carbohydrate intake. In conclusion, SFA intake modulates the association between FTO and BMI in American populations.

ADIPOQ Polymorphisms, Monounsaturated Fatty Acids, and Obesity Risk : The GOLDN Study

Serum adiponectin levels have been positively associated with insulin sensitivity and are decreased in type 2 diabetes (T2D) and obesity. Genetic and environmental factors influence serum adiponectin and may contribute to risk of metabolic syndrome and T2D. Therefore, we investigated the effect of ADIPOQ single‐nucleotide polymorphisms (SNPs), −11377C>G and −11391G>A, on metabolic‐related traits, and their modulation by dietary fat in white Americans. Data were collected from 1,083 subjects participating in the Genetics of Lipid Lowering Drugs and Diet Network study. Mean serum adiponectin concentration was higher for carriers of the −11391A allele (P = 0.001) but lower for the −11377G allele carriers (P = 0.017). Moreover, we found a significant association with obesity traits for the −11391G>A SNP. Carriers of the −11391A allele had significantly lower weight (P = 0.029), BMI (P = 0.019), waist (P = 0.003), and hip circumferences (P = 0.004) compared to noncarriers. Interestingly, the associations of the −11391G>A with BMI and obesity risk were modified by monounsaturated fatty acids (MUFAs) intake (P‐interaction = 0.021 and 0.034 for BMI and obesity risk, respectively). In subjects with MUFA intake above the median (≥13% of energy intake), −11391A carriers had lower BMI (27.1 kg/m2 for GA+AA vs. 29.1 kg/m2 for GG, P = 0.002) and decreased obesity risk (odds ratio for −11391A = 0.52, 95% confidence interval (CI); 0.28–0.96; P = 0.031). However, we did not detect genotype‐related differences for BMI or obesity in subjects with MUFA intake <13%. Our findings support a significant association between the −11391G>A SNPs and obesity‐related traits and the potential to moderate such effects using dietary modification.

Genetic variants in human CLOCK associate with total energy intake and cytokine sleep factors in overweight subjects (GOLDN population)

Despite the importance of total energy intake in circadian system regulation, no study has related human CLOCK gene polymorphisms and food-intake measures. The aim of this study was to analyze the associations of CLOCK single-nucleotide polymorphisms (SNPs) with food intake and to explore the specific role of the cytokine system. A total of 1100 individual participants in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study were included. Dietary intake was estimated with a validated questionnaire. Interleukin-6 (IL-6), monocyte chemotactic protein 1 (MCP1), tumor necrosis factor-α (TNF-α), IL-2 soluble receptor-α (IL-2sR-α) and adiponectin plasma concentrations were measured. Our results showed that four of five CLOCK SNPs selected were significantly associated with total energy intake (P<0.05). For SNP rs3749474, the energy intake and total fat, protein and carbohydrate intakes were significantly higher in minor allele carriers than in non-carriers. Frequency of the minor allele was greater in subjects with high energy intake than in those with low intake. Subjects with the minor allele were 1.33 times more likely to have high energy intake than non-carriers (95% CI 1.09–1.72, P=0.0350). All CLOCK SNPs were associated with plasma cytokine values, in particular with those that were highly correlated with energy intake: MCP1, IL-6 and adiponectin. Interestingly, minor allele carriers with high energy intake showed decreased cytokine values, which could be related with a lower anorectic effect and decreased sleep in these subjects. In conclusion, we show a novel association of genetic variation at CLOCK with total energy intake, which was particularly relevant for SNP rs3749474. Associations could be mediated through the alteration of cytokine levels that may influence energy intake and sleep pattern.

ADIPOQ polymorphisms, monounsaturated fatty acids, and obesity risk

Serum adiponectin levels have been positively associated with insulin sensitivity and are decreased in type 2 diabetes (T2D) and obesity. Genetic and environmental factors influence serum adiponectin and may contribute to risk of metabolic syndrome and T2D. Therefore, we investigated the effect of ADIPOQ single‐nucleotide polymorphisms (SNPs), −11377C>G and −11391G>A, on metabolic‐related traits, and their modulation by dietary fat in white Americans. Data were collected from 1,083 subjects participating in the Genetics of Lipid Lowering Drugs and Diet Network study. Mean serum adiponectin concentration was higher for carriers of the −11391A allele (P = 0.001) but lower for the −11377G allele carriers (P = 0.017). Moreover, we found a significant association with obesity traits for the −11391G>A SNP. Carriers of the −11391A allele had significantly lower weight (P = 0.029), BMI (P = 0.019), waist (P = 0.003), and hip circumferences (P = 0.004) compared to noncarriers. Interestingly, the associations of the −11391G>A with BMI and obesity risk were modified by monounsaturated fatty acids (MUFAs) intake (P‐interaction = 0.021 and 0.034 for BMI and obesity risk, respectively). In subjects with MUFA intake above the median (≥13% of energy intake), −11391A carriers had lower BMI (27.1 kg/m2 for GA+AA vs. 29.1 kg/m2 for GG, P = 0.002) and decreased obesity risk (odds ratio for −11391A = 0.52, 95% confidence interval (CI); 0.28–0.96; P = 0.031). However, we did not detect genotype‐related differences for BMI or obesity in subjects with MUFA intake <13%. Our findings support a significant association between the −11391G>A SNPs and obesity‐related traits and the potential to moderate such effects using dietary modification.

Gain-of-Function Lipoprotein Lipase Variant rs13702 Modulates Lipid Traits through Disruption of a MicroRNA-410 Seed Site

Genome-wide association studies (GWAS) have identified hundreds of genetic variants that are associated with lipid phenotypes. However, data supporting a functional role for these variants in the context of lipid metabolism are scarce. We investigated the association of the lipoprotein lipase (LPL) variant rs13702 with plasma lipids and explored its potential for functionality. The rs13702 minor allele had been predicted to disrupt a microRNA (miR) recognition element (MRE) seed site (MRESS) for the human microRNA-410 (miR-410). Furthermore, rs13702 is in linkage disequilibrium (LD) with several SNPs identified by GWAS. We performed a meta-analysis across ten cohorts of participants that showed a statistically significant association of rs13702 with triacylglycerols (TAG) (p = 3.18 × 10(-42)) and high-density lipoprotein cholesterol (HDL-C) (p = 1.35 × 10(-32)) with each copy of the minor allele associated with 0.060 mmol/l lower TAG and 0.041 mmol/l higher HDL-C. Our data showed that an LPL 3 UTR luciferase reporter carrying the rs13702 major T allele was reduced by 40% in response to a miR-410 mimic. We also evaluated the interaction between intake of dietary fatty acids and rs13702. Meta-analysis demonstrated a significant interaction between rs13702 and dietary polyunsaturated fatty acid (PUFA) with respect to TAG concentrations (p = 0.00153), with the magnitude of the inverse association between dietary PUFA intake and TAG concentration showing -0.007 mmol/l greater reduction. Our results suggest that rs13702 induces the allele-specific regulation of LPL by miR-410 in humans. This work provides biological and potential clinical relevance for previously reported GWAS variants associated with plasma lipid phenotypes.

A genome-wide association study of inflammatory biomarker changes in response to fenofibrate treatment in the Genetics of Lipid Lowering Drug and Diet Network.

Objective Despite the evidence in support of the anti-inflammatory and triglyceride-lowering effects of fenofibrate, little is known about genetic determinants of the observed heterogeneity in treatment response. This study provides the first genome-wide examination of fenofibrate effects on systemic inflammation. Methods Biomarkers of inflammation were measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n=1092) before and after a 3-week daily treatment with 160 mg of fenofibrate. Two inflammatory patterns [high-sensitivity C-reactive protein-interleukin-6 and monocyte chemoattractant protein-1-tumor necrosis factor (MCP1-TNF-&agr;)] were derived using principal component analysis. Associations between single nucleotide polymorphisms on the Affymetrix 6.0 chip and phenotypes were assessed using mixed linear models, adjusted for age, sex, study center, and ancestry as fixed effects and pedigree as a random effect. Results Before fenofibrate treatment, the strongest evidence for association was observed for polymorphisms near or within the IL2RA gene with the high-sensitivity C-reactive protein-interleukin-6 (IL6) pattern (rs7911500, P=5×10−9 and rs12722605, P=5×10−8). Associations of the MCP1-TNF-&agr; pattern with loci in several biologically plausible genes [CYP4F8 (rs3764563), APBB1IP (rs1775246), COL13A1 (rs2683572), and COMMD10 (rs1396485)] approached genome-wide significance (P=3×10−7, 5×10−7, 6×10−7, and 7×10−7, respectively) before fenofibrate treatment. After fenofibrate treatment, the rs12722605 locus in IL2RA was also associated with the MCP1-TNF-&agr; pattern (P=3×10−7). The analyses of individual biomarker response to fenofibrate did not yield genome-wide significant results, but the rs6517147 locus near the immunologically relevant IFNAR2 gene was suggestively associated with IL6 (P=7×10−7). Conclusion We have identified several novel biologically relevant loci associated with systemic inflammation before and after fenofibrate treatment.