It has been recently hypothesized that many of the signals detected in genome-wide association studies (GWAS) to T2D and other diseases, despite being observed to common variants, might in fact ...result from causal mutations that are rare. One prediction of this hypothesis is that the allelic associations should be population-specific, as the causal mutations arose after the migrations that established different populations around the world. We selected 19 common variants found to be reproducibly associated to T2D risk in European populations and studied them in a large multiethnic case-control study (6,142 cases and 7,403 controls) among men and women from 5 racial/ethnic groups (European Americans, African Americans, Latinos, Japanese Americans, and Native Hawaiians). In analysis pooled across ethnic groups, the allelic associations were in the same direction as the original report for all 19 variants, and 14 of the 19 were significantly associated with risk. In summing the number of risk alleles for each individual, the per-allele associations were highly statistically significant (P<10(-4)) and similar in all populations (odds ratios 1.09-1.12) except in Japanese Americans the estimated effect per allele was larger than in the other populations (1.20; P(het) = 3.8×10(-4)). We did not observe ethnic differences in the distribution of risk that would explain the increased prevalence of type 2 diabetes in these groups as compared to European Americans. The consistency of allelic associations in diverse racial/ethnic groups is not predicted under the hypothesis of Goldstein regarding "synthetic associations" of rare mutations in T2D.
To assess whether plasma neurofilament light chain (NfL) levels are elevated before amyotrophic lateral sclerosis (ALS) diagnosis and to evaluate whether prediagnostic NfL levels are associated with ...metabolic alterations.
We conducted a matched case-control study nested in 3 large prospective US cohorts (the Nurses' Health Study, the Health Professionals Follow-up Study, and the Multiethnic Cohort Study) and identified 84 individuals who developed ALS during follow-up and had available plasma samples prior to disease diagnosis. For each ALS case, we randomly selected controls from those who were alive at the time of the case diagnosis and matched on birth year, sex, race/ethnicity, fasting status, cohort, and time of blood draw. We measured NfL in the plasma samples and used conditional logistic regression to estimate rate ratios (RRs) and 95% confidence intervals (CIs) for ALS, adjusting for body mass index, smoking, physical activity, and urate levels.
Higher NfL levels were associated with a higher ALS risk in plasma samples collected within 5 years of the ALS diagnosis (RR per 1 SD increase 2.68, 95% CI 1.18-6.08), but not in samples collected further away from the diagnosis (RR per 1 SD increase 1.16, 95% CI 0.78-1.73). A total of 21 metabolites were correlated with prediagnostic NfL levels in ALS cases (
< 0.05), but none of these remained significant after multiple comparison adjustments.
Plasma NfL levels were elevated in prediagnostic ALS cases, indicating that NfL may be a useful biomarker already in the earliest stages of the disease.
This study provides Class II evidence that plasma NfL levels are elevated in prediagnostic ALS.
Better information on lung cancer occurrence in lifelong nonsmokers is needed to understand gender and racial disparities and to examine how factors other than active smoking influence risk in ...different time periods and geographic regions.
We pooled information on lung cancer incidence and/or death rates among self-reported never-smokers from 13 large cohort studies, representing over 630,000 and 1.8 million persons for incidence and mortality, respectively. We also abstracted population-based data for women from 22 cancer registries and ten countries in time periods and geographic regions where few women smoked. Our main findings were: (1) Men had higher death rates from lung cancer than women in all age and racial groups studied; (2) male and female incidence rates were similar when standardized across all ages 40+ y, albeit with some variation by age; (3) African Americans and Asians living in Korea and Japan (but not in the US) had higher death rates from lung cancer than individuals of European descent; (4) no temporal trends were seen when comparing incidence and death rates among US women age 40-69 y during the 1930s to contemporary populations where few women smoke, or in temporal comparisons of never-smokers in two large American Cancer Society cohorts from 1959 to 2004; and (5) lung cancer incidence rates were higher and more variable among women in East Asia than in other geographic areas with low female smoking.
These comprehensive analyses support claims that the death rate from lung cancer among never-smokers is higher in men than in women, and in African Americans and Asians residing in Asia than in individuals of European descent, but contradict assertions that risk is increasing or that women have a higher incidence rate than men. Further research is needed on the high and variable lung cancer rates among women in Pacific Rim countries.
Background: Healthy dietary patterns have been linked positively with health and longevity. However, prospective studies in diverse populations in the United States addressing dietary patterns and ...mortality are limited. Objective: We assessed the ability of the following 4 diet-quality indexes the Healthy Eating Index-2010 (HEI-2010), the Alternative HEI-2010 (AHEI-2010), the alternate Mediterranean diet score (aMED), and the Dietary Approaches to Stop Hypertension (DASH) to predict the reduction in risk of mortality from all causes, cardiovascular disease (CVD), and cancer. Design: White, African American, Native Hawaiian, Japanese American, and Latino adults (n = 215,782) from the Multiethnic Cohort completed a quantitative food-frequency questionnaire. Scores for each dietary index were computed and divided into quintiles for men and women. Mortality was documented over 13–18 y of follow-up. HRs and 95% CIs were computed by using adjusted Cox models. Results: High HEI-2010, AHEI-2010, aMED, and DASH scores were all inversely associated with risk of mortality from all causes, CVD, and cancer in both men and women (P -trend < 0.0001 for all models). For men, the HEI-2010 was consistently associated with a reduction in risk of mortality for all causes (HR: 0.75; 95% CI: 0.71, 0.79), CVD (HR: 0.74; 95% CI: 0.69, 0.81), and cancer (HR: 0.76; 95% CI: 0.70, 0.83) when lowest and highest quintiles were compared. In women, the AHEI and aMED showed large reductions for all-cause mortality (HR: 0.78; 95% CI: 0.74, 0.82), the AHEI showed large reductions for CVD (HR: 0.76; 95% CI: 0.69, 0.83), and the aMED showed large reductions for cancer (HR: 0.84; 95% CI: 0.76, 0. 92). Conclusion: These results, in a US multiethnic population, suggest that consuming a dietary pattern that achieves a high diet-quality index score is associated with lower risk of mortality from all causes, CVD, and cancer in adult men and women.
In a population of almost 184,000 prospectively studied participants, the risk of lung cancer was ascertained according to the level of cigarette smoking and ethnic or racial background. Among those ...who smoked no more than 30 cigarettes per day, the relative risk of lung cancer was highest among African Americans and native Hawaiians, as compared with whites, Hispanics, and Japanese Americans.
Among those who smoked no more than 30 cigarettes per day, the relative risk of lung cancer was highest among African Americans and native Hawaiians, as compared with whites, Hispanics, and Japanese Americans.
The incidence of lung cancer is substantially higher among blacks, Native Hawaiians, and other Polynesians and lower among Japanese Americans and Hispanics than among whites in the United States.
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The vast majority (80 to 90 percent) of these cases are attributable to cigarette smoking. Smoking behavior also varies widely among these ethnic and racial groups. In aggregated population surveys conducted in the United States, the age-adjusted prevalence of cigarette smoking was 30.1 percent among black adults and 27.3 percent among white adults.
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Only 8.0 percent of black smokers, however, were reported to be heavy smokers (smoking at least 25 cigarettes . . .
Variants on chromosome 8q24 contribute risk for prostate cancer; here, we tested whether they also modulate risk for colorectal cancer. We studied 1,807 affected individuals and 5,511 controls and ...found that one variant, rs6983267, is also significantly associated with colorectal cancer (odds ratio = 1.22; P = 4.4 × 10−6) and that the apportionment of risk among the variants differs significantly between the two cancers. Comprehensive testing in the region uncovered variants capturing significant additional risk. Our results show that variants at 8q24 have different effects on cancer development that depend on the tissue type.
The influence of dietary fiber, magnesium (Mg), and glycemic load (GL) on diabetes was examined in the Hawaii component of the Multiethnic Cohort. The 75,512 Caucasian, Japanese American, and Native ...Hawaiian participants aged 45-75 y at baseline completed a FFQ. After 14 y of follow-up, 8587 incident diabetes cases were identified through self-reports and health plans. We applied Cox regression stratified for age at cohort entry and adjusted for ethnicity, BMI, physical activity, education, and total energy with further stratifications by sex and ethnicity. When comparing extreme quintiles, total fiber intake was associated with reduced diabetes risk among all men hazard ratio (HR): 0.75; 95% CI: 0.67, 0.84; P-trend < 0.001) and women (HR: 0.95; 95% CI: 0.85, 1.06; P-trend = 0.05). High intake of grain fiber reduced diabetes risk significantly by 10% in men and women. High vegetable fiber intake lowered risk by 22% in all men but not women. Mg intake reduced risk (HR = 0.77 and 0.84 for men and women, respectively) and, due to its strong correlation with fiber (r = 0.83; P < 0.001), may explain the protective effect of fiber. The top GL quintile was associated with a significantly elevated diabetes incidence in Caucasian men and in all women except Japanese Americans. Overall, several associations were more pronounced in Caucasians than in the other groups. These findings suggest that protection against diabetes can be achieved through food choices after taking into account body weight, but, due to differences in commonly consumed foods, risk estimates may differ by ethnic group.
African American (AA) women have a disproportionately high incidence of estrogen receptor-negative (ER-) breast cancer, a subtype with a largely unexplained etiology. Because childbearing patterns ...also differ by race/ethnicity, with higher parity and a lower prevalence of lactation in AA women, we investigated the relation of parity and lactation to risk of specific breast cancer subtypes.
Questionnaire data from two cohort and two case-control studies of breast cancer in AA women were combined and harmonized. Case patients were classified as ER+ (n = 2446), ER- (n = 1252), or triple negative (ER-, PR-, HER2-; n = 567) based on pathology data; there were 14180 control patients. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated in polytomous logistic regression analysis with adjustment for study, age, reproductive and other risk factors.
ORs for parity relative to nulliparity was 0.92 (95% CI = 0.81 to 1.03) for ER+, 1.33 (95% CI = 1.11 to 1.59) for ER-, and 1.37 (95% CI = 1.06 to 1.70) for triple-negative breast cancer. Lactation was associated with a reduced risk of ER- (OR = 0.81, 95% CI = 0.69 to 0.95) but not ER+ cancer. ER- cancer risk increased with each additional birth in women who had not breastfed, with an OR of 1.68 (95% CI = 1.15 to 2.44) for 4 or more births relative to one birth with lactation.
The findings suggest that parous women who have not breastfed are at increased risk of ER- and triple-negative breast cancer. Promotion of lactation may be an effective tool for reducing occurrence of the subtypes that contribute disproportionately to breast cancer mortality.
Abstract Objective To explore an independent association between self-reported sleep duration and cause-specific mortality. Methods Data were obtained from the Multiethnic Cohort Study conducted in ...Los Angeles and Hawaii. Results Among 61,936 men and 73,749 women with no history of cancer, heart attack or stroke, 19,335 deaths occurred during an average 12.9 year follow-up. Shorter (≤ 5 h/day) and longer (≥ 9 h/day) sleepers of both sexes (vs. 7 h/day) had an increased risk of all-cause and cardiovascular disease (CVD) mortality, but not of cancer mortality. Multivariable hazard ratios for CVD mortality were 1.13 (95% CI 1.00–1.28) for ≤ 5 h/day and 1.22 (95% CI 1.09–1.35) for ≥ 9 h/day among men; and 1.20 (95% CI 1.05–1.36) for ≤ 5 h/day and 1.29 (95% CI 1.13–1.47) for ≥ 9 h/day among women. This risk pattern was not heterogeneous across specific causes of CVD death among men (Phetero 0.53) or among women (Phetero 0.72). The U-shape association for all-cause and CVD mortality was observed in all five ethnic groups included in the study and by subgroups of age, smoking status, and body mass index. Conclusion Insufficient or excessive amounts of sleep were associated with increased risk of mortality from CVD and other diseases in a multiethnic population.
A sizable fraction of colorectal cancer (CRC) is expected to be explained by heritable factors, with heritability estimates ranging from 12 to 35% twin and family studies. Genome-wide association ...studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) associated with CRC risk. Although it has been shown that these CRC susceptibility SNPs only explain a small proportion of the genetic risk, it is not clear how much of the heritability these SNPs explain and how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we estimated the heritability of CRC under different scenarios using Genome-Wide Complex Trait Analysis in the Genetics and Epidemiology of Colorectal Cancer Consortium including 8025 cases and 10 814 controls. We estimated that the heritability explained by known common CRC SNPs identified in GWAS was 0.65% (95% CI:0.3-1%; P = 1.11 × 10-16), whereas the heritability explained by all common SNPs was at least 7.42% (95% CI: 4.71-10.12%; P = 8.13 × 10(-8)), suggesting that many common variants associated with CRC risk remain to be detected. Comparing the heritability explained by the common variants with that from twin and family studies, a fraction of the heritability may be explained by other genetic variants, such as rare variants. In addition, our analysis showed that the gene × smoking interaction explained a significant proportion of the CRC variance (P = 1.26 × 10(-2)). In summary, our results suggest that known CRC SNPs only explain a small proportion of the heritability and more common SNPs have yet to be identified.
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