Michael J. Klag

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.

Choices for Healthy Outcomes In Caring for End Stage Renal Disease

In the CHOICE study, a multidisciplinary research team is conducting several complementary research projects designed to better understand how dialysis care practice influences health outcomes and costs. The study places a special emphasis on the perspective of the patient. The effort includes the development of patient‐centered instruments for assessment of health‐related quality of life, patient preferences and patient satisfaction. Our hope is to provide information and tools to guide physicians and providers in selecting optimal dialysis practices for their patients with ESRD.

Body Mass Index and Risk of Incident Hypertension over the Life Course: The Johns Hopkins Precursors Study

Background— The obesity-hypertension link over the life course has not been well characterized, although the prevalence of obesity and hypertension is increasing in the United States. Methods and Results— We studied the association of body mass index (BMI) in young adulthood, into middle age, and through late life with risk of developing hypertension in 1132 white men of The Johns Hopkins Precursors Study, a prospective cohort study. Over a median follow-up period of 46 years, 508 men developed hypertension. Obesity (BMI ≥30 kg/m2) in young adulthood was strongly associated with incident hypertension (hazard ratio, 4.17; 95% confidence interval, 2.34–7.42). Overweight (BMI 25 to <30 kg/m2) also signaled increased risk (hazard ratio, 1.58; 95% confidence interval, 1.28–1.96). Men of normal weight at age 25 years who became overweight or obese at age 45 years were at increased risk compared with men of normal weight at both times (hazard ratio, 1.57; 95% confidence interval, 1.20–2.07), but not men who were overweight or obese at age 25 years who returned to normal weight at age 45 years (hazard ratio, 0.91; 95% confidence interval, 0.43–1.92). After adjustment for time-dependent number of cigarettes smoked, cups of coffee taken, alcohol intake, physical activity, parental premature hypertension, and baseline BMI, the rate of change in BMI over the life course increased the risk of incident hypertension in a dose-response fashion, with the highest risk among men with the greatest increase in BMI (hazard ratio, 2.52; 95% confidence interval, 1.82–3.49). Conclusions— Our findings underscore the importance of higher weight and weight gain in increasing the risk of hypertension from young adulthood through middle age and into late life.

Small apolipoprotein(a) size predicts mortality in end-stage renal disease: The CHOICE study.

Background—The high mortality rate in end-stage renal disease has engendered interest in nontraditional atherosclerotic cardiovascular disease (ASCVD) risk factors that are more prevalent in end-stage renal disease, such as elevated lipoprotein(a) [Lp(a)] levels. Previous studies suggest that high Lp(a) levels and small apolipoprotein(a) [apo(a)] isoform size are associated with ASCVD, but none have investigated the relationship between Lp(a) level, apo(a) size, and mortality. Methods and Results—An inception cohort of 864 incident dialysis patients was followed prospectively. Lp(a) was measured by an apo(a) size-independent ELISA and apo(a) size by Western blot after SDS-agarose gel electrophoresis. Comorbid conditions were determined by medical record review. Time to death was ascertained through dialysis clinic and Health Care Financing Administration follow-up. Survival analyses were performed with adjustment for baseline demographic, comorbid conditions, albumin, and lipids. Median follow-up was 33.7 months, with 346 deaths, 162 transplantations, and 10 losses to follow-up during 1999 person-years of follow-up. Cox regression analysis showed no association between Lp(a) level and mortality. However, an association between small apo(a) isoform size and mortality was found (hazard ratio, 1.36;P =0.004) after adjusting for age, race, sex, comorbidity score, cause of renal disease, and congestive heart failure. The association was somewhat lower in white patients (hazard ratio 1.34;P =0.019) than in black patients (1.69;P =0.04). No interaction by age, race, sex, diabetes, ASCVD, or Lp(a) level was present. Conclusions—Small apo(a) size, but not Lp(a) level, independently predicts total mortality risk in dialysis patients.

End-Stage Renal Disease in US Minority Groups

Medicares End-Stage Renal Disease (ESRD) Program makes renal replacement services accessible for the majority of Americans with renal failure. National data from Medicare demonstrate complex and variable patterns of use of renal replacement services among US racial and ethnic groups. The black population has consistently suffered from a greater than 3.5-fold higher rate of treated ESRD than has the white population. The rates of hypertensive, diabetic, and glomerulopathic ESRD are all substantially greater in blacks than in whites, and hypertension has accounted for a far greater proportion of ESRD in blacks than any other diagnosis. There is a paucity of national data on the occurrence of ESRD in Hispanic Americans. However, data from Texas strongly suggest that the incidence rate of treated ESRD is much higher in Mexican Americans than in non-Hispanic whites. Higher rates are apparent for each of the three most important causes of ESRD: hypertension, diabetes, and glomerulonephritis. Native Americans experience ESRD at a rate intermediate between those of whites and blacks, but their rate of diabetic ESRD is higher than in either blacks or whites. However, considerable diversity exists among Native American tribal groups. Significant barriers to the acquisition of preventive care have been identified, especially for blacks. While these barriers to preventive care are accompanied by a significantly impaired health status of the black American population, a specific causal relationship between impaired access to care for blacks and their predisposition to ESRD has not been established.

Coffee intake and coronary heart disease.

We examined the risk of coronary heart disease (CHD) associated with coffee intake in 1040 male medical students followed for 28 to 44 years. During the follow-up, CHD developed in 111 men. The relative risks (95% confidence interval) associated with drinking 5 cups of coffee/d were 2.94 (1.27, 6.81) for baseline, 5.52 (1.31, 23.18) for average, and 1.95 (0.86, 4.40) for most recent intake after adjustment for baseline age, serum cholesterol levels, calendar time, and the time-dependent covariates number of cigarettes, body mass index, and incident hypertension and diabetes. Risks were elevated in both smokers and nonsmokers and were stronger for myocardial infarction. Most of the excess risk was associated with coffee drinking prior to 1975. The diagnosis of hypertension was associated with a subsequent reduction in coffee intake. Negative results in some studies may be due to the assessment of coffee intake later in life or to differences in methods of coffee preparation between study populations or over calendar time.

Effect of age on the efficacy of blood pressure treatment strategies.

To study whether the proportion of excess cardiovascular events attributable to various levels of systolic blood pressure varies with age, we calculated the population-attributable risk of all-cause mortality, fatal and nonfatal cardiovascular events (stroke, coronary heart disease, angina, congestive heart failure, and peripheral vascular disease), and stroke incidence due to systolic blood pressure in men and women 45 years of age or older in the United States during 1980. Our estimates are based on US census counts, blood pressure prevalence distributions from the second National Health and Nutrition Examination Survey, and the annual risk of cardiovascular complications during 18 years of follow-up in the Framingham cohort We then determined the impact of age on the relative efficacy of mass treatment and case-finding strategies in preventing systolic blood pressure-related events. At 45–54 years of age, only 30–40% of systolic blood pressure-related excess events occur in hypertensive individuals (systolic blood pressure ≥160 mm Hg). With increasing age, however, the percentage of systolic blood pressure-related events that occur in hypertensive individuals rose substantially, in the oldest age group (≥75 years), 65–70% of fatal and nonfatal cardiovascular disease events occur in hypertensive persons. The pattern is similar for men and women. The potential impact of a mass treatment strategy designed to shift the distribution of blood pressure downward by a small amount is greater in younger than in older groups, whereas an opposite trend is seen for a high-risk, hypertensive case-finding and treatment approach. In every age, a combined mass and high-risk treatment strategy is superior to either strategy alone. Our analysis suggests that the age of the target population should be considered when designing interventions to prevent blood pressure-related cardiovascular disease

Alcohol consumption and blood pressure: a comparison of native Japanese to American men

We compared the cross-sectional association of alcohol consumption with blood pressure in 810 Japanese men (JM) living in Tokyo and 946 white men (WM) living in New York. Mean systolic (JM and WM, p less than 0.001) and diastolic blood pressure (JM, p less than 0.002; WM, p less than 0.001) were associated with alcohol consumption in both groups. Compared to abstainers, the heaviest drinkers had the highest systolic (JM, p = 0.001; WM, p less than 0.01) and diastolic (JM, p less than 0.002; WM, p less than 0.05) blood pressures. The relation of blood pressure to alcohol intake was J-shaped in the Americans, but linear in the Japanese. Exploratory analyses revealed that the J-shape may have been due to under-reporting of heavy alcohol ingestion by American abstainers. When abstainers were excluded, the relationships were similar in both the American and Japanese. The positive association between blood pressure and alcohol consumption persisted after adjustment for age, cigarette smoking, use of antihypertensive medications, body mass index, heart rate, abdominal skinfold thickness, hematocrit, fasting blood glucose, serum uric acid levels and urinary sodium/potassium ratio. Alcohol use was also related to prevalence of hypertension. These findings confirm the presence of an independent association between alcohol intake and blood pressure in both JM and WM and suggest that, despite differences in the metabolism of alcohol, the relation of alcohol consumption to blood pressure is similar in both nationalities.

Alcohol Consumption and Domain-Specific Cognitive Function in Older Adults: Longitudinal Data From the Johns Hopkins Precursors Study

OBJECTIVES The association of alcohol consumption with performance in different cognitive domains has not been well studied. METHODS The Johns Hopkins Precursors Study was used to examine associations between prospectively collected information about alcohol consumption ascertained on multiple occasions starting at age 55 years on average with domain-specific cognition at age 72 years. Cognitive variables measured phonemic and semantic fluency, attention, verbal memory, and global cognition. RESULTS Controlling for age, hypertension, smoking status, sex, and other cognitive variables, higher average weekly quantity and frequency of alcohol consumed in midlife were associated with lower phonemic fluency. There were no associations with four other measures of cognitive function. With respect to frequency of alcohol intake, phonemic fluency was significantly better among those who drank three to four alcoholic beverages per week as compared with daily or almost daily drinkers. A measure of global cognition was not associated with alcohol intake at any point over the follow-up. DISCUSSION Results suggest that higher alcohol consumption in midlife may impair some components of executive function in late life.

Alcohol use and blood pressure in an unacculturated society.

Alcohol intake has been associated with higher blood pressure in acculturated populations but not in unacculturated societies. We performed a cross-sectional survey of a random community sample of 5023 male Yi rural farmers and 1656 Yi and 2173 Han men living in an urban setting. Average alcohol intake among drinkers was 36.4 g/d in Yi farmers, 56.5 g/d in Yi migrants, and 38.7 g/d in Han men. Age-adjusted mean diastolic blood pressure was 66.9, 70.5, and 71.7 mm Hg, respectively. Diastolic blood pressure was higher at higher alcohol intakes in all three groups (all P < .001). After adjustment for age, body mass index, heart rate, smoking, and physical activity, the change (95% confidence interval) in diastolic blood pressure for each standard drink was 0.50 (0.38-0.62), 0.31 (0.18-0.43), and 0.24 (0.07-0.40) mm Hg for Yi farmers, Yi migrants, and Han men, respectively. The percentage of variance in diastolic blood pressure explained by alcohol intake was 5% for Yi farmers, 4% for Yi migrants, and 2% for Han men. In a random sample of 831 men, these associations were independent of urinary sodium, potassium, calcium, and magnesium and sodium-potassium ratio. In the Yi farmers, associations were less strong for systolic blood pressure and no longer significant after adjustment. Approximately 33% of hypertension could be attributed to daily alcohol use in the Yi groups compared with 9.5% in the Han people.(ABSTRACT TRUNCATED AT 250 WORDS)