Hao Mei

Longitudinal Replication Studies of GWAS Risk SNPs Influencing Body Mass Index over the Course of Childhood and Adulthood

Genome-wide association studies (GWAS) have identified multiple common variants associated with body mass index (BMI). In this study, we tested 23 genotyped GWAS-significant SNPs (p-value<5*10-8) for longitudinal associations with BMI during childhood (3–17 years) and adulthood (18–45 years) for 658 subjects. We also proposed a heuristic forward search for the best joint effect model to explain the longitudinal BMI variation. After using false discovery rate (FDR) to adjust for multiple tests, childhood and adulthood BMI were found to be significantly associated with six SNPs each (q-value<0.05), with one SNP associated with both BMI measurements: KCTD15 rs29941 (q-value<7.6*10-4). These 12 SNPs are located at or near genes either expressed in the brain (BDNF, KCTD15, TMEM18, MTCH2, and FTO) or implicated in cell apoptosis and proliferation (FAIM2, MAP2K5, and TFAP2B). The longitudinal effects of FAIM2 rs7138803 on childhood BMI and MAP2K5 rs2241423 on adulthood BMI decreased as age increased (q-value<0.05). The FTO candidate SNPs, rs6499640 at the 5 ′-end and rs1121980 and rs8050136 downstream, were associated with childhood and adulthood BMI, respectively, and the risk effects of rs6499640 and rs1121980 increased as birth weight decreased. The best joint effect model for childhood and adulthood BMI contained 14 and 15 SNPs each, with 11 in common, and the percentage of explained variance increased from 0.17% and 9.0*10−6% to 2.22% and 2.71%, respectively. In summary, this study evidenced the presence of long-term major effects of genes on obesity development, implicated in pathways related to neural development and cell metabolism, and different sets of genes associated with childhood and adulthood BMI, respectively. The gene effects can vary with age and be modified by prenatal development. The best joint effect model indicated that multiple variants with effects that are weak or absent alone can nevertheless jointly exert a large longitudinal effect on BMI.

Common variants in epithelial sodium channel genes contribute to salt sensitivity of blood pressure: The GenSalt study.

Background— Rare mutations of the epithelial sodium channel (ENaC) lead to mendelian forms of salt-sensitive hypertension or salt-wasting hypotension. We aimed to examine the association between common variants in the ENaC genes and salt sensitivity of blood pressure (BP). Methods and Results— A total of 1906 Han Chinese participated in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study, which includes a 7-day low-sodium intake (51.3 mmol sodium/d) followed by a 7-day high-sodium intake (307.8 mmol sodium/d). Nine BP measurements were obtained at baseline and each intervention period using a random-zero sphygmomanometer. Single-nucleotide polymorphisms, both tagging and functional, from the 3 ENaC subunits, &agr;, &bgr;, and &ggr; (SCNN1A, SCNN1B, and SCNN1G), were genotyped. Multiple common single-nucleotide polymorphisms in SCNN1G were significantly associated with BP response to low-sodium intervention (rs4073930, P=1.7×10−5; rs4073291, P=1.1×10−5; rs7404408, P=1.9×10−5; rs5735, P=3.0×10−4; rs4299163, P=0.004; and rs4499238, P=0.002) even after correcting for multiple testing. For example, under an additive model, the minor allele G of SNP rs4073291 was associated with 1.33 mm Hg lower systolic BP reduction during low-sodium intervention. Conclusions— This large dietary sodium intervention study indicates that common variants of ENaC subunits may contribute to the variation of BP response to dietary sodium intake. Future studies are warranted to confirm these findings in an independent population and to identify functional variants for salt sensitivity. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00721721.

Effect of soybean protein on novel cardiovascular disease risk factors: a randomized controlled trial.

Background/objectives:Cardiovascular disease (CVD) is the leading cause of death in the United States and the world. Clinical trials have suggested that soybean protein lowers lipids and blood pressure. The effect of soybean protein on novel CVD risk factors has not been well studied. The objective of this study was to examine the effect of soybean protein on biomarkers of inflammation, endothelial dysfunction and adipocytokines.Subjects/methods:The effect of 8 weeks of 40 g of soybean protein supplement (89.3 mg isoflavones), 40 g of milk protein supplement and 40 g of complex carbohydrate placebo was examined in a randomized, placebo-controlled, double-blind, three-phase crossover trial among adults in New Orleans, Louisiana and Jackson, Mississippi. Plasma levels of inflammation biomarkers (C-reactive protein, interleukin-6, tumor necrosis factor-α), endothelial dysfunction biomarkers (E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, thrombomodulin) and adipocytokines (high-molecular weight adiponectin, leptin, resistin) were measured at baseline and at the end of each intervention using immunoturbidimetric and enzyme-linked immunosorbent assay techniques.Results:Soy protein supplementation resulted in a significant mean net change (95% confidence interval) in plasma E-selectin of −3.93 ng/ml (−7.05 to −0.81 ng/ml; P=0.014) compared with milk protein, and in plasma leptin of −2089.8 pg/ml (−3689.3 to −490.3 pg/ml; P=0.011) compared with carbohydrate. There were no significant changes in any other risk factors.Conclusions:Soy protein supplementation may reduce levels of E-selectin and leptin. Further research is warranted to investigate the mechanisms through which protein may confer protective effects on novel CVD risk factors.

Adult hypertension is associated with blood pressure variability in childhood in blacks and whites: the bogalusa heart study.

BACKGROUND Blood pressure (BP) is a variable physiological parameter in health and disease. Increased BP variability over time in adults is associated with severity of end-organ damage and a higher rate of cardiovascular events, even after adjusting for the mean levels. This study tested the hypothesis that childhood BP variability, besides the mean levels, is also predictive of adulthood hypertension. METHODS The study cohort consisted of 1,797 subjects (1,091 whites and 706 blacks; age = 21-48 years) enrolled in the Bogalusa Heart Study since childhood. BP variability was depicted as s.d. of 4-8 serial measurements in childhood. RESULTS Blacks showed significantly greater childhood systolic BP (SBP) variability than whites. In multivariable logistic regression analyses, adjusting for race, sex, mean childhood age, s.d. of childhood body mass index (BMI), mean childhood BP levels, adulthood age and BMI, adult hypertension was significantly associated with s.d. of childhood SBP (odds ratio (OR) (95% confidence intervals) = 1.28 (1.09, 1.51), P = 0.002) and s.d. of childhood diastolic BP (DBP; 1.36 (1.16, 1.58), P < 0.001). When using adulthood BP levels as continuous dependent variables in linear regression models, adjusting for the same covariates, adulthood SBP and DBP levels were significantly associated with s.d. of childhood SBP (standardized regression coefficient β = 0.086, P < 0.001) and s.d. of childhood DBP (β = 0.105, P < 0.001), respectively. CONCLUSIONS Increases in BP variations as well as levels in early life are predictive of adult hypertension, which underscore the childhood origin of the natural history of essential hypertension.

Heritability of blood pressure responses to cold pressor test in a Chinese population.

BACKGROUND Genetic determinants of blood pressure (BP) responses to the cold pressor test (CPT), a phenotype associated with risk of hypertension and cardiovascular disease has not been well studied. METHODS We examined the heritability of BP response to CPT in 1,994 subjects from 627 families in rural north China. BP was measured before and at 0, 1, 2, and 4 min after the participants immersed their hand in ice water for 1 min. Heritabilities of baseline BP and responses at 0 min, maximum response, and area-under-the-curve (AUC) during CPT were computed using a variance components method. Additionally, bivariate heritabilities were calculated to test the existence of shared genetic determinants between baseline BP and responses to CPT. RESULTS Heritabilities of baseline BP and responses to CPT were estimated from 14 to 35%, which all significantly differed from 0 (P < or = 0.002). Genetic correlations (s.e.) due to the same genes between baseline BP and responses to CPT ranged from -0.07 (0.14) to 0.21 (0.15), which were not significantly different from 0. Genetic correlations between reactivity and recovery were 0.67 (0.10) and 0.59 (0.10) for systolic (SBP) and diastolic BP (DBP), respectively, which were significantly different from 0. CONCLUSIONS We concluded that (i) baseline BP and BP responses to CPT had strong genetic determinants; (ii) baseline BP and BP response to CPT did not share the same genetic components; and (iii) BP reactivity and recovery shared the same genetic components. These findings may lead to a better understanding of the genetic mechanism of BP responses to CPT.

Genome-Wide Linkage and Positional Candidate Gene Study of Blood Pressure Response to Dietary Potassium Intervention The Genetic Epidemiology Network of Salt Sensitivity Study

Background—Genetic determinants of blood pressure (BP) response to potassium, or potassium sensitivity, are largely unknown. We conducted a genome-wide linkage scan and positional candidate gene analysis to identify genetic determinants of potassium sensitivity. Methods and Results—A total of 1906 Han Chinese participants took part in a 7-day high-sodium diet followed by a 7-day high-sodium plus potassium dietary intervention. BP measurements were obtained at baseline and after each intervention using a random-zero sphygmomanometer. Significant linkage signals (logarithm of odds [LOD] score, >3) for BP responses to potassium were detected at chromosomal regions 3q24-q26.1, 3q28, and 11q22.3-q24.3. Maximum multipoint LOD scores of 3.09 at 3q25.2 and 3.41 at 11q23.3 were observed for absolute diastolic BP (DBP) and mean arterial pressure (MAP) responses, respectively. Linkage peaks of 3.56 at 3q25.1 and 3.01 at 11q23.3 for percent DBP response and 3.22 at 3q25.2, 3.01 at 3q28, and 4.48 at 11q23.3 for percent MAP response also were identified. Angiotensin II receptor, type 1 (AGTR1), single-nucleotide polymorphism rs16860760 in the 3q24-q26.1 region was significantly associated with absolute and percent systolic BP responses to potassium (P=0.0008 and P=0.0006, respectively). Absolute (95% CI) systolic BP responses for genotypes C/C, C/T, and T/T were −3.71 (−4.02 to −3.40), −2.62 (−3.38 to −1.85), and 1.03 (−3.73 to 5.79) mm Hg, respectively, and percent responses (95% CI) were −3.07 (−3.33 to −2.80), −2.07 (−2.74 to −1.41), and 0.90 (−3.20 to 4.99), respectively. Similar trends were observed for DBP and MAP responses. Conclusions—Genetic regions on chromosomes 3 and 11 may harbor important susceptibility loci for potassium sensitivity. Furthermore, the AGTR1 gene was a significant predictor of BP responses to potassium intake. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00721721.

Principal-component-based multivariate regression for genetic association studies of metabolic syndrome components.

BackgroundQuantitative traits often underlie risk for complex diseases. For example, weight and body mass index (BMI) underlie the human abdominal obesity-metabolic syndrome. Many attempts have been made to identify quantitative trait loci (QTL) over the past decade, including association studies. However, a single QTL is often capable of affecting multiple traits, a quality known as gene pleiotropy. Gene pleiotropy may therefore cause a loss of power in association studies focused only on a single trait, whether based on single or multiple markers.ResultsWe propose using principal-component-based multivariate regression (PCBMR) to test for gene pleiotropy with comprehensive evaluation. This method generates one or more independent canonical variables based on the principal components of original traits and conducts a multivariate regression to test for association with these new variables. Systematic simulation studies have shown that PCBMR has great power. PCBMR-based pleiotropic association studies of abdominal obesity-metabolic syndrome and its possible linkage to chromosomal band 3q27 identified 11 susceptibility genes with significant associations. Whereas some of these genes had been previously reported to be associated with metabolic traits, others had never been identified as metabolism-associated genes.ConclusionsPCBMR is a computationally efficient and powerful test for gene pleiotropy. Application of PCBMR to abdominal obesity-metabolic syndrome indicated the existence of gene pleiotropy affecting this syndrome.

Genome-wide Linkage and Positional Association Study of Blood Pressure Response to Dietary Sodium Intervention The GenSalt Study

The authors conducted a genome-wide linkage scan and positional association analysis to identify the genetic determinants of salt sensitivity of blood pressure (BP) in a large family-based, dietary-feeding study. The dietary intervention was conducted among 1,906 participants in rural China (2003-2005). A 7-day low-sodium intervention was followed by a 7-day high-sodium intervention. Salt sensitivity was defined as BP responses to low- and high-sodium interventions. Signals of the logarithm of the odds to the base 10 (LOD ≥ 3) were detected at 33-42 centimorgans of chromosome 2 (2p24.3-2p24.1), with a maximum LOD score of 3.33 for diastolic blood pressure responses to high-sodium intervention. LOD scores were 2.35-2.91 for mean arterial pressure (MAP) and 0.80-1.49 for systolic blood pressure responses in this region, respectively. Correcting for multiple tests, single nucleotide polymorphism (SNP) rs11674786 (2.7 kilobases upstream of the family with sequence similarity 84, member A, gene (FAM84A)) in the linkage region was significantly associated with diastolic blood pressure (P = 0.0007) and MAP responses (P = 0.0007), and SNP rs16983422 (2.8 kilobases upstream of the visinin-like 1 gene (VSNL1)) was marginally associated with diastolic blood pressure (P = 0.005) and MAP responses (P = 0.005). An additive interaction between SNPs rs11674786 and rs16983422 was observed, with P = 7.00 × 10(-5) and P = 7.23 × 10(-5) for diastolic blood pressure and MAP responses, respectively. The authors concluded that genetic region 2p24.3-2p24.1 might harbor functional variants for the salt sensitivity of BP.

Common Variants in Epithelial Sodium Channel Genes Contribute to Salt Sensitivity of Blood PressureClinical Perspective

Background— Rare mutations of the epithelial sodium channel (ENaC) lead to mendelian forms of salt-sensitive hypertension or salt-wasting hypotension. We aimed to examine the association between common variants in the ENaC genes and salt sensitivity of blood pressure (BP). Methods and Results— A total of 1906 Han Chinese participated in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study, which includes a 7-day low-sodium intake (51.3 mmol sodium/d) followed by a 7-day high-sodium intake (307.8 mmol sodium/d). Nine BP measurements were obtained at baseline and each intervention period using a random-zero sphygmomanometer. Single-nucleotide polymorphisms, both tagging and functional, from the 3 ENaC subunits, &agr;, &bgr;, and &ggr; (SCNN1A, SCNN1B, and SCNN1G), were genotyped. Multiple common single-nucleotide polymorphisms in SCNN1G were significantly associated with BP response to low-sodium intervention (rs4073930, P=1.7×10−5; rs4073291, P=1.1×10−5; rs7404408, P=1.9×10−5; rs5735, P=3.0×10−4; rs4299163, P=0.004; and rs4499238, P=0.002) even after correcting for multiple testing. For example, under an additive model, the minor allele G of SNP rs4073291 was associated with 1.33 mm Hg lower systolic BP reduction during low-sodium intervention. Conclusions— This large dietary sodium intervention study indicates that common variants of ENaC subunits may contribute to the variation of BP response to dietary sodium intake. Future studies are warranted to confirm these findings in an independent population and to identify functional variants for salt sensitivity. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00721721.

Common Variants in Epithelial Sodium Channel Genes Contribute to Salt Sensitivity of Blood PressureClinical Perspective: The GenSalt Study

Background— Rare mutations of the epithelial sodium channel (ENaC) lead to mendelian forms of salt-sensitive hypertension or salt-wasting hypotension. We aimed to examine the association between common variants in the ENaC genes and salt sensitivity of blood pressure (BP). Methods and Results— A total of 1906 Han Chinese participated in the Genetic Epidemiology Network of Salt Sensitivity (GenSalt) study, which includes a 7-day low-sodium intake (51.3 mmol sodium/d) followed by a 7-day high-sodium intake (307.8 mmol sodium/d). Nine BP measurements were obtained at baseline and each intervention period using a random-zero sphygmomanometer. Single-nucleotide polymorphisms, both tagging and functional, from the 3 ENaC subunits, &agr;, &bgr;, and &ggr; (SCNN1A, SCNN1B, and SCNN1G), were genotyped. Multiple common single-nucleotide polymorphisms in SCNN1G were significantly associated with BP response to low-sodium intervention (rs4073930, P=1.7×10−5; rs4073291, P=1.1×10−5; rs7404408, P=1.9×10−5; rs5735, P=3.0×10−4; rs4299163, P=0.004; and rs4499238, P=0.002) even after correcting for multiple testing. For example, under an additive model, the minor allele G of SNP rs4073291 was associated with 1.33 mm Hg lower systolic BP reduction during low-sodium intervention. Conclusions— This large dietary sodium intervention study indicates that common variants of ENaC subunits may contribute to the variation of BP response to dietary sodium intake. Future studies are warranted to confirm these findings in an independent population and to identify functional variants for salt sensitivity. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00721721.