J. Hunter Young

Differential Susceptibility to Hypertension Is Due to Selection during the Out-of-Africa Expansion

Hypertension is a leading cause of stroke, heart disease, and kidney failure. The genetic basis of blood pressure variation is largely unknown but is likely to involve genes that influence renal salt handling and arterial vessel tone. Here we argue that susceptibility to hypertension is ancestral and that differential susceptibility to hypertension is due to differential exposure to selection pressures during the out-of-Africa expansion. The most important selection pressure was climate, which produced a latitudinal cline in heat adaptation and, therefore, hypertension susceptibility. Consistent with this hypothesis, we show that ecological variables, such as latitude, temperature, and rainfall, explain worldwide variation in heat adaptation as defined by seven functional alleles in five genes involved in blood pressure regulation. The latitudinal cline in heat adaptation is consistent worldwide and is largely unmatched by latitudinal clines in short tandem repeat markers, control single nucleotide polymorphisms, or non-functional single nucleotide polymorphisms within the five genes. In addition, we show that latitude and one of these alleles, GNB3 (G protein β3 subunit) 825T, account for a major portion of worldwide variation in blood pressure. These results suggest that the current epidemic of hypertension is due to exposures of the modern period interacting with ancestral susceptibility. Modern populations differ in susceptibility to these new exposures, however, such that those from hot environments are more susceptible to hypertension than populations from cold environments. This differential susceptibility is likely due to our history of adaptation to climate.

Blood Pressure and Decline in Kidney Function: Findings from the Systolic Hypertension in the Elderly Program (SHEP)

The association between BP and decline in kidney function in older persons and the BP component most responsible for kidney disease are unknown. This study investigated the relationship between baseline BP and an incident decline in kidney function among 2181 men and women enrolled in the placebo arm of the Systolic Hypertension in the Elderly Program (SHEP). A decline in kidney function was defined as an increase in serum creatinine equal to or greater than 0.4 mg/dl over 5 yr of follow-up. The incidence and relative risk of a decline in kidney function increased at higher levels of BP for all BP components, independent of age, gender, ethnicity, smoking, diabetes, and history of cardiovascular disease. Systolic BP imparted the highest risk of decline in kidney function. The adjusted relative risk (95% confidence interval) associated with the highest compared with the lowest quartile of BP was 2.44 (1.67 to 3.56) for systolic; 1.29 (0.87 to 1.91) for diastolic; 1.80 (1.21 to 2.66) for pulse; and 2.03 (1.39 to 2.94) for mean arterial pressure. The risk associated with systolic BP remained strong in models containing other BP components, while diastolic, pulse, and mean arterial pressure had no significant association with a decline in kidney function in models containing systolic BP. Therefore, systolic BP is a strong, independent predictor of a decline in kidney function among older persons with isolated systolic hypertension.

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

Blood Viscosity and Hematocrit as Risk Factors for Type 2 Diabetes Mellitus The Atherosclerosis Risk in Communities (ARIC) Study

Several lines of evidence support the notion that elevated blood viscosity may predispose to insulin resistance and type 2 diabetes mellitus by limiting delivery of glucose, insulin, and oxygen to metabolically active tissues. To test this hypothesis, the authors analyzed longitudinal data on 12,881 initially nondiabetic adults, aged 45–64 years, who were participants in the Atherosclerosis Risk in Communities (ARIC) Study (1987–1998). Whole blood viscosity was estimated by using a validated formula based on hematocrit and total plasma proteins at baseline. At baseline, estimated blood viscosity was independently associated with several features of the metabolic syndrome. In models adjusted simultaneously for known predictors of diabetes, estimated whole blood viscosity and hematocrit predicted incident type 2 diabetes mellitus in a graded fashion (Ptrend (linear) < 0.001): Compared with their counterparts in the lowest quartiles, adults in the highest quartile of blood viscosity (hazard ratio = 1.68, 95% confidence interval: 1.53, 1.84) and hematocrit (hazard ratio = 1.63, 95% confidence interval: 1.49, 1.79) were over 60% more likely to develop diabetes. Therefore, elevated blood viscosity and hematocrit deserve attention as emerging risk factors for insulin resistance and type 2 diabetes mellitus.

Blood Pressure Change and Risk of Hypertension Associated With Parental Hypertension: The Johns Hopkins Precursors Study

BACKGROUND Parental hypertension is used to classify hypertension risk in young adults, but the long-term association of parental hypertension with blood pressure (BP) change and risk of hypertension over the adult life span has not been well studied. METHODS We examined the association of parental hypertension with BP change and hypertension risk from young adulthood through the ninth decade of life in a longitudinal cohort of 1160 male former medical students with 54 years of follow-up. RESULTS In mixed-effects models using 29 867 BP measurements, mean systolic and diastolic BP readings were significantly higher at baseline among participants with parental hypertension. The rate of annual increase was slightly higher for systolic (0.03 mm Hg, P= .04), but not diastolic, BP in those with parental hypertension. After adjustment for baseline systolic and diastolic BP and time-dependent covariates--body mass index, alcohol consumption, coffee drinking, physical activity, and cigarette smoking--the hazard ratio (95% confidence interval [CI]) of hypertension development was 1.5 (1.2-2.0) for men with maternal hypertension only, 1.8 (1.4-2.4) for men with paternal hypertension only, and 2.4 (1.8-3.2) for men with hypertension in both parents compared with men whose parents never developed hypertension. Early-onset (at age <or=55 years) hypertension in both parents imparted a 6.2-fold higher adjusted risk (95% CI, 3.6-10.7) for the development of hypertension throughout adult life and a 20.0-fold higher adjusted risk (95% CI, 8.4-47.9) at the age of 35 years. CONCLUSION Hypertension in both mothers and fathers has a strong independent association with elevated BP levels and incident hypertension over the course of adult life.

NH2-Terminal Pro–Brain Natriuretic Peptide and Risk of Diabetes

Brain natriuretic peptide (BNP) has an established role in cardiovascular disease (CVD). However, recent animal studies suggest direct metabolic effects of BNP. To determine the association of BNP with the risk of diabetes, we conducted a prospective analysis of participants from the Atherosclerosis Risk in Communities (ARIC) study. We included 7,822 men and women without history of diabetes, CVD, or reduced kidney function at baseline. At baseline, NH2-terminal (NT)-proBNP, a cleavage product of BNP, was inversely associated with adiposity, fasting glucose, insulin, and cholesterol but positively associated with blood pressure and C-reactive protein levels. During a median follow-up of 12 years, 1,740 participants reported a new diagnosis of diabetes or medication use for diabetes. Baseline quartiles of NT-proBNP were inversely associated with diabetes risk, even after multivariable adjustment including fasting glucose. The adjusted HRs for diabetes were 1.0 (reference), 0.84 (95% CI 0.74–0.96), 0.79 (95% CI 0.68–0.90), and 0.75 (95% CI 0.64–0.87) for the 1st, 2nd, 3rd, and 4th quartiles of baseline NT-proBNP, respectively (P for trend <0.001). This inverse association was robust across sex, race, and obesity subgroups. Our results extend animal studies and support a direct and important metabolic role of BNP in humans.

Chronic inflammation role in the obesity-diabetes association: a case-cohort study

BackgroundChronic inflammation is related to both obesity and diabetes. Our aim was to investigate to what extent this inflammation contributes to the association between obesity and diabetes.MethodsUsing a case-cohort design, we followed 567 middle-aged individuals who developed diabetes and 554 who did not over 9 years within the ARIC Study. Weighted Cox proportional hazards analyses permitted statistical inference to the entire cohort.ResultsObese individuals (BMI≥30 kg/m2), compared to those with BMI<25 kg/m2, presented a large increased risk of developing diabetes (HR[obesity]=6.4, 95%CI 4.5–9.2), as did those in the highest (compared to the lowest) quartile of waist circumference (HR[waist]=8.3, 95%CI 5.6–12.3), in analyses adjusted for age, gender, ethnicity, study center, and parental history of diabetes. Notably, further adjustment for adiponectin and inflammation markers halved the magnitude of these associations (HR[obesity]=3.2, 95%CI 2.1–4.7; and HR[waist]=4.2, 95%CI 2.8–6.5). In similar modeling, attenuation obtained by adding fasting insulin, instead of these markers, was only slightly more pronounced HR[obesity]=2.7, 95%CI 1.7–4.1; and HR[waist]=3.6, 95%CI 2.3–5.8).ConclusionsThe marked decrease in the obesity-diabetes association after taking into account inflammation markers and adipokines indicates their major role in the pathways leading to adult onset of diabetes in obese individuals.

Single-Trait and Multi-Trait Genome-Wide Association Analyses Identify Novel Loci for Blood Pressure in African-Ancestry Populations

Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10−8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

Novel Risk Factors and the Prediction of Type 2 Diabetes in the Atherosclerosis Risk in Communities (ARIC) Study

OBJECTIVE The objective of this study was to determine potential added value of novel risk factors in predicting the development of type 2 diabetes beyond that provided by standard clinical risk factors. RESEARCH DESIGN AND METHODS The Atherosclerosis Risk in Communities (ARIC) Study is a population-based prospective cohort study in four U.S. communities. Novel risk factors were either measured in the full cohort or in a case-control sample nested within the cohort. We started with a basic prediction model, previously validated in ARIC, and evaluated 35 novel risk factors by adding them independently to the basic model. The area under the curve (AUC), net reclassification index (NRI), and integrated discrimination index (IDI) were calculated to determine if each of the novel risk factors improved risk prediction. RESULTS There were 1,457 incident cases of diabetes with a mean of >7.6 years of follow-up among 12,277 participants at risk. None of the novel risk factors significantly improved the AUC. Forced expiratory volume in 1 s was the only novel risk factor that resulted in a significant NRI (0.54%; 95% CI: 0.33–0.86%). Adiponectin, leptin, γ-glutamyl transferase, ferritin, intercellular adhesion molecule 1, complement C3, white blood cell count, albumin, activated partial thromboplastin time, factor VIII, magnesium, hip circumference, heart rate, and a genetic risk score each significantly improved the IDI, but net changes were small. CONCLUSIONS Evaluation of a large panel of novel risk factors for type 2 diabetes indicated only small improvements in risk prediction, which are unlikely to meaningfully alter clinical risk reclassification or discrimination strategies.

Lactate and risk of incident diabetes in a case-cohort of the atherosclerosis risk in communities (ARIC) study

Background Oxidative capacity is decreased in type 2 diabetes. Whether decreased oxidative capacity is a cause or consequence of diabetes is unknown. Our purpose is to evaluate whether lactate, a marker of oxidative capacity, is associated with incident diabetes. Methods and Findings We conducted a case-cohort study in the Atherosclerosis Risk in Communities (ARIC) study at year 9 of follow-up. We evaluated lactate’s association with diabetes risk factors at baseline and estimated the hazard ratio for incident diabetes by quartiles of plasma lactate in 544 incident diabetic cases and 533 non-cases. Plasma lactate showed a graded positive relationship with fasting glucose and insulin (P<0.001). The relative hazard for incident diabetes increased across lactate quartiles (P-trend ≤0.001). Following adjustment for demographic factors, medical history, physical activity, adiposity, and serum lipids, the hazard ratio in the highest quartile was 2.05 times the hazard in the lowest quartile (95% CI: 1.28, 3.28). After including fasting glucose and insulin the association became non-significant. Conclusions Lactate, an indicator of oxidative capacity, predicts incident diabetes independent of many other risk factors and is strongly related to markers of insulin resistance. Future studies should evaluate the temporal relationship between elevated lactate and impaired fasting glucose and insulin resistance.