Resolving the fibrotic niche of human liver cirrhosis at single-cell level.

Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2+CD9+ subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1+ and PLVAP+ endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα+ collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.

Nutritional factors and non-Hodgkin lymphoma survival in an ethnically diverse population: the Multiethnic Cohort.

BACKGROUND/OBJECTIVES: To understand the possible effect of modifiable health behaviors on the prognosis of the increasing number of non-Hodgkin lymphoma (NHL) survivors, we examined the pre-diagnostic intake of major food groups with all-cause and NHL-specific survival in the Multiethnic Cohort (MEC). SUBJECTS/METHODS: This analysis included 2339 participants free of NHL at cohort entry and diagnosed with NHL as identified by cancer registries during follow-up. Deaths were ascertained through routine linkages to state and national death registries. Cox proportional hazards regression was applied to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and NHL-specific mortality according to pre-diagnostic intake of vegetables, fruits, red meat, processed meat, fish, legumes, dietary fiber, dairy products and soy foods assessed by food frequency questionnaire. RESULTS: The mean age at diagnosis was 71.8±8.5 years. During 4.5±4.1 years of follow-up, 1348 deaths, including 903 NHL-specific deaths, occurred. In multivariable models, dairy intake was associated with higher all-cause mortality (highest vs lowest tertile: HR=1.14, 95% CI 1.00-1.31, Ptrend=0.03) and NHL-specific (HR=1.16, 95% CI 0.98-1.37) mortality. Legume intake above the lowest tertile was related to significant 13-16% lower all-cause and NHL-specific mortality, whereas red meat and fish intake in the intermediate tertiles was associated with lower NHL-specific mortality. No association with survival was detected for the other food groups. CONCLUSIONS: These data suggest that pre-diagnostic dietary intake may not appreciably contribute to NHL survival, although the higher mortality for dairy products and the better prognosis associated with legumes agree with known biologic effects of these foods.

Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: Reanalysis of eighteen prospective studies.

Epidemiological studies have examined breast cancer risk in relation to sex hormone concentrations measured by different methods: "extraction" immunoassays (with prior purification by organic solvent extraction, with or without column chromatography), "direct" immunoassays (no prior extraction or column chromatography), and more recently with mass spectrometry-based assays. We describe the associations of estradiol, estrone and testosterone with both body mass index and breast cancer risk in postmenopausal women according to assay method, using data from a collaborative pooled analysis of 18 prospective studies. In general, hormone concentrations were highest in studies that used direct assays and lowest in studies that used mass spectrometry-based assays. Estradiol and estrone were strongly positively associated with body mass index, regardless of the assay method; testosterone was positively associated with body mass index for direct assays, but less clearly for extraction assays, and there were few data for mass spectrometry assays. The correlations of estradiol with body mass index, estrone and testosterone were lower for direct assays than for extraction and mass spectrometry assays, suggesting that the estimates from the direct assays were less precise. For breast cancer risk, all three hormones were strongly positively associated with risk regardless of assay method (except for testosterone by mass spectrometry where there were few data), with no statistically significant differences in the trends, but differences may emerge as new data accumulate. Future epidemiological and clinical research studies should continue to use the most accurate assays that are feasible within the design characteristics of each study.

Estimating risks for variants of unknown significance according to their predicted pathogenicity classes with application to BRCA1.

Sequence-based testing of disease-susceptibility genes has identified many variants of unknown significance (VUSs) whose pathogenicity is unknown at the time of their measurement. Female breast cancer cases aged 20-49 years at diagnosis and who have VUSs in BRCA1 and no mutations in BRCA2 have previously been identified through the population-based Los Angeles County Cancer Surveillance Program. These nominal BRCA1 VUSs have been classified as "low," "medium," and "high" risk by four classification methods: Align-GVGD, Polyphen, Grantham matrix scores, and sequence conservation in mammalian species. Average hazard ratios (HRs) for classes of variants, i.e., the age-specific incidences of cancer for carriers of such variants divided by the population incidences, were estimated from the cancer family histories of first- and second-degree relatives of the index cases using modified segregation analysis. The study sample comprised 270 index cases and 4,543 of their relatives. There was weak evidence that the risk of breast cancer increases with the degree of sequence conservation (P = 0.03) and that missense variants at highly conserved sites are associated with a 5.6-fold (95 % confidence interval 1.4-22.2; P = 0.05) increased incidence of breast cancer. An upper bound of 2.3 is given for the average breast cancer HRs corresponding to variants classified as "low risk" by any of the four VUS classification methods. In summary, we have given a method to estimate cancer risks for groups of VUSs by combining existing classification methods with traditional penetrance analyses. This analysis suggests that classification methods for BRCA1 variants based on sequence conservation might be useful in a clinical setting. We have shown in principle that our method can be used to classify VUSs into clinically useful risk categories, but our specific findings should not be put into clinical practice unless confirmed by larger studies.

Ethnic differences in serum adipokine and C-reactive protein levels: the multiethnic cohort.

BACKGROUND: Ethnic disparities in metabolic disease risk may be the result of differences in circulating adipokines and inflammatory markers related to ethnic variations in obesity and body fat distribution. SUBJECTS/METHODS: In a cross-sectional design, we compared serum levels of leptin, adiponectin, C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in control subjects (321 men and 930 women) from two nested case-control studies conducted within the Multiethnic Cohort Study consisting of whites, Japanese Americans (JA), Latinos, African Americans (AA) and Native Hawaiians (NH). General linear models were applied to evaluate ethnic differences in log-transformed serum biomarker levels before and after adjusting for body mass index (BMI) at cohort entry. RESULTS: In comparison to whites, significant ethnic differences were observed for all biomarkers except TNF-α. JA men and women had significantly lower leptin and CRP levels than whites, and JA women also had lower adiponectin levels. Leptin was significantly higher in AA women (P < 0.01), adiponectin was significantly lower in AA men and women (P = 0.02 and P < 0.001), and CRP and IL-6 were significantly higher in AA men and women. Lower adiponectin (P < 0.0001) and CRP (P = 0.03) levels were the only biomarkers in NH women that differed from whites; no statistically significant differences were seen for NH men and for Latino men and women. When adjusted for BMI at cohort entry, the differences between the lowest and the highest values across ethnic groups decreased for all biomarkers except adiponectin in men indicating that ethnic differences were partially due to weight status. CONCLUSIONS: These findings demonstrate the ethnic variations in circulating adipokine and CRP levels before and after adjustment for BMI. Given the limitation of BMI as a general measure of obesity, further investigation with visceral and subcutaneous adiposity measures are warranted to elucidate ethnicity-related differences in adiposity in relation to disparities in obesity-related disease risk.

Genome-wide meta-analyses of smoking behaviors in African Americans.

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (ß = 0.040, s.e. = 0.007, P = 1.84 × 10(-8)). This variant is present in the 5'-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

Comprehensive analysis of hormone and genetic variation in 36 genes related to steroid hormone metabolism in pre- and postmenopausal women from the breast and prostate cancer cohort consortium (BPC3).

CONTEXT: Sex steroids play a central role in breast cancer development. OBJECTIVE: This study aimed to relate polymorphic variants in 36 candidate genes in the sex steroid pathway to serum concentrations of sex steroid hormones and SHBG. DESIGN: Data on 700 genetic polymorphisms were combined with existing hormone assays and data on breast cancer incidence, within the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Nurses' Health Study (NHS) cohorts; significant findings were reanalyzed in the Multiethnic Cohort (MEC). SETTING AND PARTICIPANTS: We analyzed data from a pooled sample of 3852 pre- and postmenopausal Caucasian women from EPIC and NHS and 454 postmenopausal women from MEC. MAIN OUTCOME MEASURES: Outcome measures were SHBG, testosterone, dehydroepiandrosterone (DHEAS), androstenedione, estrone (E1), and estradiol (E2) as well as breast cancer risk. RESULTS: Globally significant associations were found among pre- and postmenopausal women combined between levels of SHBG and the SHBG gene and between DHEAS and the FSHR and AKR1C3 genes. Among postmenopausal women, serum E1 and E2 were significantly associated with the genes CYP19 and FSHR, and E1 was associated with ESR1. None of the variants related to serum hormone levels showed any significant association with breast cancer risk. CONCLUSIONS: We confirmed associations between serum levels of SHBG and the SHBG gene and of E1 and E2 and the CYP19 and ESR1 genes. Novel associations were observed between FSHR and DHEAS, E1, and E2 and between AKR1C3 and DHEAS.

The association of diabetes with colorectal cancer risk: the Multiethnic Cohort.

BACKGROUND: Diabetics have been found to have a greater risk of colorectal cancer than non-diabetics. METHODS: We examined whether this relationship differed by ethnic group, cancer site or tumour stage in a population-based prospective cohort, including 3549 incident colorectal cancer cases identified over a 13-year period (1993-2006) among 199 143 European American, African American, Native Hawaiian, Japanese American and Latino men and women in the Multiethnic Cohort. RESULTS: Diabetics overall had a significantly greater risk of colorectal cancer than did non-diabetics (relative risk (RR)=1.19, 95% confidence interval (CI)=1.09-1.29, P-value (P)<0.001). Positive associations were observed for colon cancer, cancers of both the right and left colon, and cancers diagnosed at a localised and regional/distant stage. The association with colorectal cancer risk was significantly modified by smoking status (P(Interaction)=0.0044), with the RR being higher in never smokers (RR=1.32, 95% CI=1.15-1.53, P<0.001) than past (RR=1.19, 95% CI=1.05-1.34, P=0.007) and current smokers (RR=0.90, 95% CI=0.70-1.15, P=0.40). CONCLUSION: These findings provide strong support for the hypothesis that diabetes is a risk factor for colorectal cancer.

Urinary phytoestrogen excretion and prostate cancer risk: a nested case-control study in the Multiethnic Cohort.

BACKGROUND: Phytoestrogens are of special interest in prostate cancer research because populations in Asia with a high consumption of phytoestrogens have a lower incidence of the disease than comparable populations in Western countries. METHODS: This case-control study is nested within a large multiethnic cohort in Hawaii and California. Urine samples were analysed for daidzein, genistein, equol, and enterolactone among 249 incident prostate cancer cases and 404 controls matched on age, race/ethnicity, date/time of specimen collection, and fasting status. RESULTS: The median excretion of daidzein was 0.173 nmol mg(-1) creatinine in cases and 0.291 in controls (P=0.01), and the median excretion of genistein was 0.048 in cases and 0.078 in controls (P=0.05). An inverse association was seen for daidzein overall (odds ratio for the highest vs lowest quintile=0.55, 95% confidence interval=0.31-0.98, P(trend)=0.03) and seemed to apply to localized (P(trend)=0.08) as well as advanced or high-grade cancer (P(trend)=0.09). This association was consistent across the four ethnic groups examined. Although the relationship was weaker for genistein, the odds ratios and trends were similarly inverse. Urinary excretion of equol and enterolactone was not significantly related to prostate cancer risk. CONCLUSION: Our findings suggest that high intake of isoflavones, as reflected by urinary excretion of daidzein and genistein, may be protective against prostate cancer.

A candidate gene approach to searching for low-penetrance breast and prostate cancer genes.

Most cases of breast and prostate cancer are not associated with mutations in known high-penetrance genes, indicating the involvement of multiple low-penetrance risk alleles. Studies that have attempted to identify these genes have met with limited success. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium--a pooled analysis of multiple large cohort studies with a total of more than 5,000 cases of breast cancer and 8,000 cases of prostate cancer--was therefore initiated. The goal of this consortium is to characterize variations in approximately 50 genes that mediate two pathways that are associated with these cancers--the steroid-hormone metabolism pathway and the insulin-like growth factor signalling pathway--and to associate these variations with cancer risk.

A Y chromosomal influence on prostate cancer risk: the multi-ethnic cohort study.

BACKGROUND: A Y chromosomal role in prostate cancer has previously been suggested by both cytogenetic findings and patterns of Y chromosomal gene expression. We took advantage of the well established and stable phylogeny of the non-recombining segment of the Y chromosome to investigate the association between Y chromosomal DNA variation and prostate cancer risk. METHODS: We examined the distribution of 116 Y lineages in 930 prostate cancer cases and 1208 controls from four ethnic groups from a cohort study in Hawaii and California. RESULTS: One lineage, found only among the Japanese group in our study, was associated with a statistically significant predisposition to prostate cancer (odds ratio (OR) = 1.63; 95% confidence interval (CI) 1.07 to 2.47), and, in particular, to high severity disease in younger individuals (OR = 3.89; 95% CI 1.34 to 11.31). CONCLUSIONS: This finding suggests that a Y chromosomal factor contributes significantly to the development of prostate cancer in Japanese men.

Risk factors for cardiovascular and cerebrovascular death among African Americans and Hispanics in Los Angeles, California.

OBJECTIVE: To describe the risk factors associated with cardiovascular mortality in the African American (AA) and Hispanic populations in Los Angeles County in an effort to define causes for the excess mortality seen in AAs. METHODS: This was a longitudinal analysis of all-cause, cardiovascular, and cerebrovascular mortality in a large, prospective multiethnic cohort of individuals aged 45-74 years. Death rates between AA and Hispanic men and women during the six-year period from 1993 to 1998 due to hypertension, cardiomyopathy, acute myocardial infarction (AMI), ischemic heart disease, and stroke were compared. RESULTS: There were 1,157 deaths due to cardiovascular disease (CVD) or cerebrovascular disease among the 71,798 eligible members of the cohort included in these analyses. Age-adjusted mortality rates were two to five times higher in AAs as compared with Hispanics (e.g., 373.15 in AAs for hypertensive disease vs 50.37 in Hispanics). A history of hypertension was the most common significant risk factor for CVD; other risk factors significantly associated with CVD mortality included cigarette smoking and a past history of diabetes and stroke. Adjusting for these factors did not remove the significance of AA ethnicity as a risk factor for CVD mortality in either subjects reporting or subjects not reporting hypertension at baseline. CONCLUSIONS: The evidence for both higher relative severity and higher incidence of hypertensive disease among AAs, and the consistency of the effect across gender, suggests that a major determinant of risk may be a gene environment interaction.

Germ-line HER-2 variant and breast cancer risk by stage of disease.

HER-2 gene amplification and protein overexpression has been associated with increased risk of advanced-stage breast cancer and poor prognosis. Recently, a single missense point mutation (Ile(655)Val) in the transmembrane domain of the HER-2 gene was associated with a 40% increase in breast cancer risk among women 45 years of age and younger. In this analysis, we measured the association between the Ile(655)Val variant and postmenopausal breast cancer among women participating in the Hawaii and Los Angeles Multiethnic Cohort. Risk of localized breast cancer was significantly elevated among women with the HER-2 variant, but not among women with regional or metastatic disease. Women with at least one copy of the Valine variant were approximately one-half as likely to have high-stage as low-stage breast cancer (P =.02), and this effect was present across racial/ethnic groups.

Cancer mortality in relation to environmental chromium exposure.

From the 1950s to the 1980s, hexavalent chromium compounds were used as additives at certain water-cooling towers at three southern California gas compressor facilities. Claims of potential residential chromium exposure prompted the examination of age-adjusted mortality rates during 1989 to 1998 for lung cancer, all cancer, and all deaths for neighborhoods near versus distant from the plants. Differences in the rates between areas tended to be small and not statistically significant. The only significant difference was a lower, rather than higher, rate of total cancer among women in the potentially exposed areas. Study limitations preclude a definitive assessment of risk, but similar to previous investigations of cancer in relation to environmental chromium exposure in other locations, this study found no evidence of a cancer hazard among residents living near these California gas compressor facilities.

Genetic determinants of serum prostate-specific antigen levels in healthy men from a multiethnic cohort.

We recently reported an association between prostate cancer risk and polymorphisms in the prostate-specific antigen (PSA) and androgen receptor (AR) genes. The purpose of this study is to test whether these two polymorphisms, AR CAG and PSA ARE1, influence serum PSA levels in healthy men. Serum PSA and the two genotypes were assayed for 420 healthy men from a multiethnic cohort, and regression models were fit to estimate the effects of AR CAG genotype and PSA ARE1 genotype on serum PSA levels. Predicted serum PSA decreased 3.5% with each additional AR CAG repeat decile (P = 0.01). Serum PSA was also associated with PSA ARE1 genotype, with PSA levels higher among men with the PSA AA genotype compared with men with the AG or GG genotypes (P = 0.02). The relationship between serum PSA level and AR CAG length differed according to PSA genotype (P = 0.049): for genotype GG, the slope was not significantly different from zero (P = 0.74); for genotype AG, serum PSA increased 4.5% with each decrease of one CAG repeat decile (P = 0.03); for genotype AA, serum PSA increased 7% with each decrease of one CAG repeat decile (P = 0.02). These results indicate that in healthy men, genetic variants in the PSA and AR genes contribute to variation in serum PSA levels. Men with the PSA AA genotype and short AR CAG alleles have, on average, higher serum PSA levels.

Do urinary estrogen metabolites reflect the differences in breast cancer risk between Singapore Chinese and United States African-American and white women?

Breast cancer risk is substantially lower in Singapore than in women from the United STATES: Part of the risk discrepancy is probably explained by differences in the production of endogenous estrogens, but differences in the pathway by which estrogen is metabolized may also play a role. We undertook a study to determine whether the ratio of urinary 2-hydroxyestrone (2OHE(1)):16alpha-hydroxyestrone (16alpha-OHE(1)) was higher in Singapore Chinese than in a group of United States (predominantly African-American) women living in Los ANGELES: We also wanted to determine whether any difference in estrogen metabolite ratio between these two groups of women was greater than that in estrone (E(1)), estradiol (E(2)) and estriol (E(3)). The participants in this study were randomly selected healthy, non-estrogen using women participating in the Singapore Chinese Health Study (n = 67) or the Hawaii/Los Angeles Multiethnic Cohort Study (n = 58). After adjusting for age and age at menopause, mean urinary 2-OHE(1) was only 23% (P = 0.03) higher in Singapore Chinese than in United States women, and there were no statistically significant differences in 16alpha-OHE(1) levels or in the ratio of 2-OHE(1):16alpha-OHE(1) between the two groups. The adjusted mean 2-OHE(1):16alpha-OHE(1) ratio was 1.63 in Singapore Chinese and 1.48 in United States women (P = 0.41). In contrast, the adjusted mean values of E1, E2, and E3 were 162% (P < 0.0001), 152% (P < 0.0001), and 92% (P = 0.0009) higher, respectively, in United States women than in Singapore Chinese women. Our study suggests that urinary E1, E2, and E3 reflect the differences in breast cancer risk between Singapore Chinese and United States women to a stronger degree than the estrogen metabolites 2OHE(1) and 16alpha-OHE(1) or the ratio of 2OHE(1):16alpha-OHE(1.)

Building a multigenic model of breast cancer susceptibility: CYP17 and HSD17B1 are two important candidates.

We conducted a nested case-control study to evaluate whether polymorphisms in two genes involved in estrogen metabolism, CYP17 and HSD17B1, were useful in developing a breast cancer risk model that could help discriminate women who are at higher risk of breast cancer. If polymorphisms in these genes affect the level of circulating estrogens, they may directly influence breast cancer risk. The base population for this study is a multiethnic cohort study that includes African-American, Non-Latina White, Japanese, Latina, and Native Hawaiian women. For this analysis, 1508 randomly selected controls and 850 incident breast cancer cases of the first four ethnic groups who agreed to provide a blood specimen were included (76 and 80% response rates, respectively). The CYP17 A2 allele and the HSD17B1 A allele were considered "high-risk" alleles. Subjects were then classified according to number of high-risk alleles. After adjusting for age, weight, and ethnicity, we found that carrying one or more high-risk alleles increases the risk of advanced breast cancer in a dose-response fashion. The risk among women carrying four high-risk alleles was 2.21 [95% confidence interval (CI), 0.98-5.00; P for trend = 0.03] compared with those who carried none. This risk was largely limited to women who were not taking hormone replacement therapy (relative risk, 2.60; 95% CI, 0.95-7.14) and was most pronounced among those weighing 170 pounds or less (RR, 3.05; 95% CI, 1.29-7.25). These findings suggest that breast cancer risk has a strong genetic component and supports the theory that the underlying mechanism of "complex traits" can be understood using a multigenic model of candidate genes.

Risk of endometrial cancer and estrogen replacement therapy history by CYP17 genotype.

Common variants among genes coding for enzymes in sex steroid biosynthetic pathways may influence the risk of endometrial cancer. We examined the association between endometrial cancer risk and estrogen replacement therapy (ERT) by CYP17 genotype using 51 incident cases and 391 randomly selected controls from a multiethnic cohort in Hawaii and Los Angeles, California. The relative risk of endometrial cancer was calculated for ever use versus never use of ERT by CYP17 genotype (TT, TC, and CC). We found that women who reported ever taking ERT were more than twice as likely to develop endometrial cancer as women who never took ERT [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.19-4.23]. Among these women, the risk of endometrial cancer was higher for women homozygous for the CYP17 T allele (OR, 4.10; 95% CI, 1.64-10.3), but not for women with the C allele (OR, 1.31; 95% CI, 0.53-3.21). These preliminary findings suggest that CYP17 or other variants in estrogen biosynthesis or metabolism pathways may be potential markers of endometrial cancer susceptibility due to ERT.

Elevated mortality rates from circulatory disease in African American men and women of Los Angeles County, California--a possible genetic susceptibility?

OBJECTIVE: Reports of higher mortality in African Americans have often focused on socioeconomic differences. Such differences do not explain the excess mortality in African Americans compared with Hispanics in Los Angeles County. We suggest the existence of genetic factors to explain at least some of the differences in mortality risk. METHODS: We compared the mortality rates from circulatory diseases in African American and Hispanic adults of Los Angeles County for 1988 to 1992 with the frequency of the angiotensin-converting enzyme (ACE) genotype. RESULTS: African American adults 45 to 74 years old had a 2-fold higher overall mortality rate than Hispanics. The largest differences were seen for hypertensive disease and cardiomyopathy in men; the most striking differences were seen in the youngest age group. Rates were lower in women than in men, but African American women also showed substantial excess compared with Hispanics. ACE genotype also showed a significant difference between the Hispanic and African American population; the latter had a significantly higher prevalence of the DD genotype, which is associated with a higher level of circulating enzyme, and lower prevalence of the II genotype, which is associated with a lower enzyme level. CONCLUSION: African American adults aged 45 to 74 years in Los Angeles County have a substantial excess mortality from hypertensive diseases compared with a similar Hispanic population. The frequency of the ACE DD genotype was higher in African Americans than in Hispanics. These studies may indirectly support the possibility of a genetic contribution to the excess hypertensive disease mortality in African Americans.

Declining cancer rates in the 1990s.

PURPOSE: To provide evidence of a substantial decline in cancer rates for the period 1991 through 1995 and characterize major risk factors that seem to be driving secular trends in cancer mortality and incidence. DESIGN: Incidence and mortality rates were calculated using national surveillance data collected through the Surveillance, Epidemiology, and End Results (SEER) program and the National Center for Health Statistics. RESULTS: All-sites cancer incidence and mortality fell in the period 1991 through 1995; this decline is largely attributable to decreases in the smoking-related cancers, especially lung cancer. Of the 20 leading incident cancers today, both incidence and mortality are decreasing among 11 sites for men and 12 for women. In men, the decline in mortality has been notable and is especially apparent for the smoking-related cancers, including those of the lung, oral cavity and pharynx, larynx, and, to a lesser extent, bladder. In women, all-sites mortality decreased only approximately 0.4% from 1991 through 1995. Three cancers continued to show substantial increases in mortality through 1995 for both men and women (liver, multiple myeloma, and non-Hodgkin's lymphoma), while incidence rates continued to climb for liver cancer, non-Hodgkin's lymphoma, and melanoma. CONCLUSION: Data from the SEER program on recent trends in cancer incidence and mortality show that cancer rates are generally on the decline, largely because of reductions in smoking-related cancers. A consistent increase in mortality rates due to liver cancer poses a new health care challenge, one that will require the development of an effective treatment for individuals currently infected with hepatitis C or B to prevent mortality rates from continuing to increase.