Modification by N-acetyltransferase 1 genotype on the association between dietary heterocyclic amines and colon cancer in a multiethnic study

OBJECTIVE: Colorectal cancer incidence is greater among African Americans, compared to whites in the U.S., and may be due in part to differences in diet, genetic variation at metabolic loci, and/or the joint effect of diet and genetic susceptibility. We examined whether our previously reported associations between meat-derived heterocyclic amine (HCA) intake and colon cancer were modified by N-acetyltransferase 1 (NAT1) or 2 (NAT2) genotypes and whether there were differences by race. METHODS: In a population-based, case-control study of colon cancer, exposure to HCAs was assessed using a food-frequency questionnaire with a meat-cooking and doneness module, among African Americans (217 cases and 315 controls) and whites (290 cases and 534 controls). RESULTS: There was no association with NAT1*10 versus NAT1-non*10 genotypes for colon cancer. Among whites, there was a positive association for NAT2-"rapid/intermediate" genotype [odds ratio (OR)=1.4; 95% confidence interval (CI)=1.0, 1.8], compared to the NAT2-"slow" that was not observed among African Americans. Colon cancer associations with HCA intake were modified by NAT1, but not NAT2, regardless of race. However, the "at-risk" NAT1 genotype differed by race. For example, among African Americans, the positive association with 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) was confined to those with NAT1*10 genotype (OR=1.8; 95% CI=1.0, 3.3; P for interaction=0.02, comparing highest to lowest intake), but among whites, an association with 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) was confined to those with NAT1-non*10 genotype (OR=1.9; 95% CI=1.1, 3.1; P for interaction=0.03). CONCLUSIONS: Our data indicate modification by NAT1 for HCA and colon cancer associations, regardless of race. Although the at-risk NAT1 genotype differs by race, the magnitude of the individual HCA-related associations in both race groups are similar. Therefore, our data do not support the hypothesis that NAT1 by HCA interactions contribute to differences in colorectal cancer incidence between African Americans and whites.     

Gene Polymorphisms of ADIPOQ +45T>G,UCP2 -866G>A,and FABP2 Ala54Thr on the Risk of Colorectal Cancer: A Matched Case-Control Study

As insulin resistance (IR) is an established risk factor for colorectal cancer (CRC), we explored the association between each of the IR-related gene polymorphisms of adiponectin (ADIPOQ) rs2241766, uncoupling protein 2 (UCP2) rs659366, and fatty acid-binding protein (FABP2) rs1799883 and CRC risk. Genotyping of blood samples and collection of lifestyle and dietary habits were performed for 400 case-control pairs. Unconditional logistic regression (ULR) was applied to assess the effects of the three single nucleotide polymorphisms (SNP), environmental factors. Both ULR and generalized multifactor dimensionality reduction (GMDR) were used to test the gene-gene and gene-environment interactions on CRC risk. Subjects carrying the ADIPOQ rs2241766 TG+GG genotype had a higher CRC risk than those carrying the TT genotype (OR = 1.429, 95% CI 1.069–1.909). The additive and multiplicative interactions between ADIPOQ rs2241766 and FABP2 rs1799883 on CRC were found by ULR (RERI = 0.764, 95%CI 0.218∼1.311, AP = 0.514, 95%CI 0.165∼0.864, S = −1.745, 95%CI is unachievable, and P_multi = 0.017, respectively). Furthermore, the high order gene-gene interaction of the three SNPs were found by GMDR (P = 0.0107). A significant dosage effect with an increasing number of risk genotypes was observed as the risk of CRC increased (P_trend = 0.037). In GMDR, the gene-environment interaction among the three SNPs and red meat consumption on CRC risk was significant (P = 0.0107). Compared with subjects with low red meat consumption and null risk genotypes, those with high-red meat consumption and three risk genotypes had 3.439-fold CRC risk (95% CI 1.410–8.385). In conclusion, the results showed that the ADIPOQ rs2241766 TG+GG genotype increased CRC risk. Given the complexity of the carcinogen for CRC, ADIPOQ rs2241766, UCP2 rs659366, FABP2 rs1799883 and red meat consumption potentially worked together in affecting CRC risk.     

Processed and Unprocessed Red Meat and Risk of Colorectal Cancer: Analysis by Tumor Location and Modification by Time

Although the association between red meat consumption and colorectal cancer (CRC) is well established, the association across subsites of the colon and rectum remains uncertain, as does time of consumption in relation to cancer development. As these relationships are key for understanding the pathogenesis of CRC, they were examined in two large cohorts with repeated dietary measures over time, the Nurses’ Health Study (n = 87,108 women, 1980–2010) and Health Professionals Follow-up Study (n = 47,389 men, 1986–2010). Cox proportional hazards regression models generated hazard ratios (HRs) and 95% confidence intervals (CIs), which were pooled by random-effects meta-analysis. In combined cohorts, there were 2,731 CRC cases (1,151 proximal colon, 816 distal colon, and 589 rectum). In pooled analyses, processed red meat was positively associated with CRC risk (per 1 serving/day increase: HR = 1.15, 95% CI: 1.01–1.32; P for trend 0.03) and particularly with distal colon cancer (per 1 serving/day increase; HR = 1.36; 95% CI: 1.09–1.69; P for trend 0.006). Recent consumption of processed meat (within the past 4 years) was not associated with distal cancer. Unprocessed red meat was inversely associated with risk of distal colon cancer and a weak non-significant positive association between unprocessed red meat and proximal cancer was observed (per 1 serving/day increase: distal HR = 0.75; 95% CI: 0.68–0.82; P for trend <0.001; proximal HR = 1.14, 95% CI: 0.92–1.40; P for trend 0.22). Thus, in these two large cohorts of US health professionals, processed meat intake was positively associated with risk of CRC, particularly distal cancer, with little evidence that higher intake of unprocessed red meat substantially increased risk of CRC. Future studies, particularly those with sufficient sample size to assess associations by subsites across the colon are needed to confirm these findings and elucidate potentially distinct mechanisms underlying the relationship between processed meat and subtypes of unprocessed red meat with CRC.     

Perceived Stress and Coping Strategies in Relation to Body Mass Index: Cross-Sectional Study of 12,045 Japanese Men and Women

BackgroundAccumulated evidence suggests a weak positive relationship between psychosocial stress and body mass index (BMI), but little is known about stress coping strategies and BMI.ObjectiveWe aimed to examine if perceived stress and coping strategies are related to BMI, with any of their mutual interactions on BMI.MethodsThis cross-sectional study included 5,063 men and 6,982 women aged 40-69 years. A self-administered questionnaire ascertained perceived stress and 5 items of coping strategies (emotion expression, emotional support seeking, positive reappraisal, problem solving, and disengagement). Analyses were performed by gender with adjustment for age, socioeconomic status, and lifestyle factors.ResultsNo significant associations were detected between perceived stress and BMI in either men (P_trend = 0.09) or women (P_trend = 0.58). In men, however, ‘disengagement’ showed an inverse association with BMI (P_trend < 0.001), and ‘positive reappraisal’ and ‘problem solving’ revealed a positive association with BMI (P_trend = 0.04 and 0.007, respectively) even after controlling for perceived stress. A possible interaction between perceived stress and ‘disengagement’ on BMI was found in men (P_interaction = 0.027); the inverse association between ‘disengagement’ and BMI was more evident in higher levels of stress (β = −0.13, P_trend = 0.21 in low; β = −0.22, P_trend = 0.01 in medium; and β = −0.24, P_trend = 0.06 in high). In men, ‘disengagement’ was inversely associated with overweight/obesity (odds ratio 0.79, 95% confidential interval 0.67-0.95), and “positive reappraisal” was positively associated with it (1.25, 1.02-1.54).ConclusionsCoping strategies may have an important role in developing overweight/obesity, particularly in men.     

Race/Ethnicity-Specific Association of Vitamin D and Global DNA Methylation: Cross-Sectional and Interventional Findings

ObjectivesUnderstanding of the influence of vitamin D deficiency on epigenome will provide novel insights into the chronic disease risk. We tested our hypotheses that 1) vitamin D deficiency is associated with global hypomethylation and this association may be race/ethnicity dependent; and 2) vitamin D supplementation will increase global DNA methylation level.MethodsA two-stage design, cross-sectional observation followed by a 16 week randomized, double- blinded, placebo-controlled trial (RCT) of vitamin D3 supplementation, was undertaken. Global DNA methylation level (percentage of 5-methylcytosine, %5-mC) was quantified using leukocyte DNA with the MethylFlash^TM Methylated DNA Quantification kit (Epigentek). Global methylation data was obtained from 454 Caucasians and African Americans (42%) in the observation cohort and 58 African Americans with vitamin D deficiency in the dose responsive RCT.ResultsIn the cross-sectional study, African Americans had lower %5-mC than Caucasians (P = 0.04). A significant interaction was detected between plasma 25(OH)D and race on %5-mC (P = 0.05), as a positive association was observed between plasma 25(OH)D and %5-mC in African Americans (β = 0.20, p<0.01), but not in Caucasians (β = 0.03, p = 0.62). In the 16-week RCT, a dose-response benefit of vitamin D₃ supplementation was observed for %5-mC, as indicated by a significant linear upward trend (-0.01 ± 0.01%, placebo; 0.11 ± 0.01%, ~600 IU/day; 0.30 ± 0.01%, ~2,000 IU/day; and 0.65 ± 0.01%, ~4,000 IU/day group; P-trend = 0.04).ConclusionsVitamin D deficiency is associated with global hypomethylation in African Americans. Vitamin D3 supplementation increases global DNA methylation in a dose-response manner in African Americans with vitamin D deficiency.     

Atenolol Induced HDL-C Change in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) Study

We sought to identify novel pharmacogenomic markers for HDL-C response to atenolol in participants with mild to moderate hypertension. We genotyped 768 hypertensive participants from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study on the Illumina HumanCVD Beadchip. During PEAR, participants were randomized to receive atenolol or hydrochlorothiazide. Blood pressure and cholesterol levels were evaluated at baseline and after treatment. This study focused on participants treated with atenolol monotherapy. Association with atenolol induced HDL-C change was evaluated in 232 whites and 152 African Americans using linear regression. No SNPs achieved a Bonferroni corrected P-value. However, we identified 13 regions with consistent association across whites and African Americans. The most interesting of these regions were seven with prior associations with HDL-C, other metabolic traits, or functional implications in the lipid pathway: GALNT2, FTO, ABCB1, LRP5, STARD3NL, ESR1, and LIPC. Examples are rs2144300 in GALNT2 in whites (P=2.29x10^-4, β=-1.85 mg/dL) and rs12595985 in FTO in African Americans (P=2.90x10^-4, β=4.52 mg/dL), both with consistent regional association (P<0.05) in the other race group. Additionally, baseline GALNT2 expression differed by rs2144300 genotype in whites (P=0.0279). In conclusion, we identified multiple gene regions associated with atenolol induced HDL-C change that were consistent across race groups, several with functional implications or prior associations with HDL-C.     

Baseline Plasma Fatty Acids Profile and Incident Cardiovascular Events in the SU.FOL.OM3 Trial: The Evidence Revisited

Objective

We aimed to investigate the association between baseline plasma fatty acids profile and the risk of future major cardiovascular events in patients with a history of ischaemic heart disease or ischemic stroke.

Methods

Baseline plasma fatty acids as well as established cardiovascular risk factors were measured in 2,263 patients enrolled in the SUpplementation with FOLate, vitamins B-6 and B-12 and/or OMega-3 fatty acids randomized controlled trial. Incident major cardiovascular, cardiac and cerebrovascular events were ascertained during the 4.7 years of follow up. Hazard ratios were obtained from Cox proportional hazards models after adjustment for cardiovascular risk factors.

Results

During the follow-up, 154, 379 and 84 patients had major cardiovascular, cardiac and cerebrovascular events respectively. Upon adjustment for gender, initial event, baseline age and BMI, the risk of developing a major cardiovascular event decreased significantly in successive quartiles of arachidonic acid (P_trend<0.002), total omega 3 polyunsaturated fatty acids (P_trend<0.03), docosapentaenoic acid (P_trend<0.019), docosahexaenoic acid (P_trend<0.004), eicosapentaenoic acid + docosahexaenoic acid (P_trend<0.03) and eicosapentaenoic acid + docosapentaenoic acid + docosahexaenoic acid (P_trend<0.02). This inverse association was borderline significant with increased quartiles of stearidonic acid (P_trend<0.06). In the full model, only stearidonic acid remained inversely associated with the risk of developing a major cardiovascular event (P_trend<0.035), a cardiac event (P_trend<0.016) or a cerebrovascular event (P_trend<0.014), while arachidonic acid was inversely associated with the risk a cerebrovascular event (P_trend<0.033).

Conclusion

The inverse association of long chain omega 3 polyunsaturated fatty acids with recurrence of Cardiovascular diseases was mainly driven by well-known cardiovascular risk factors.

Trial Registration

Controlled-Trials.com ISRCTN41926726     

Interactions between Diet,Lifestyle and IL10, IL1B,and PTGS2/COX-2 Gene Polymorphisms in Relation to Risk of Colorectal Cancer in a Prospective Danish Case-Cohort Study

Background & Aims

Diet contributes to colorectal cancer development and may be potentially modified. We wanted to identify the biological mechanisms underlying colorectal carcinogenesis by assessment of diet-gene interactions.

Methods

The polymorphisms IL10 C-592A (rs1800872), C-rs3024505-T, IL1b C-3737T (rs4848306), G-1464C (rs1143623), T-31C (rs1143627) and PTGS2 (encoding COX-2) A-1195G (rs689466), G-765C (rs20417), and T8473C (rs5275) were assessed in relation to risk of colorectal cancer (CRC) and interaction with diet (red meat, fish, fibre, cereals, fruit and vegetables) and lifestyle (non-steroid-anti-inflammatory drug use and smoking status) was assessed in a nested case-cohort study of nine hundred and seventy CRC cases and 1789 randomly selected participants from a prospective study of 57,053 persons.

Results

IL1b C-3737T, G-1464C and PTGS2 T8473C variant genotypes were associated with risk of CRC compared to the homozygous wildtype genotype (IRR=0.81, 95%CI: 0.68-0.97, p=0.02, and IRR=1.22, 95%CI: 1.04-1.44, p=0.02, IRR=0.75, 95%CI: 0.57-0.99, p=0.04, respectively). Interactions were found between diet and IL10 rs3024505 (P-value for interaction (P_int); meat=0.04, fish=0.007, fibre=0.0008, vegetables=0.0005), C-592A (P_int; fibre=0.025), IL1b C-3737T (P_int; vegetables=0.030, NSAID use=0.040) and PTGS2 genotypes G-765C (P_int; meat=0.006, fibre=0.0003, fruit 0.004), and T8473C (P_int; meat 0.049, fruit=0.03) and A-1195G (P_int; meat 0.038, fibre 0.040, fruit=0.059, vegetables=0.025, and current smoking=0.046).

Conclusions

Genetically determined low COX-2 and high IL-1β activity were associated with increased risk of CRC in this northern Caucasian cohort. Furthermore, interactions were found between IL10, IL1b, and PTGS2 and diet and lifestyle factors in relation to CRC. The present study demonstrates that gene-environment interactions may identify genes and environmental factors involved in colorectal carcinogenesis.     

Association between toenail zinc concentrations and incidence of asthma among American young adults: The CARDIA study

BackgroundAs an essential micronutrient, zinc plays an important role in modulating the immune system. However, data on the association between zinc concentrations and asthma incidence are sparse, especially in adults.MethodsWe prospectively followed up 3682 individuals aged 20–32 years without history of asthma or current asthma at baseline from 1987–1988 to 2015–2016. Zinc concentrations were measured in toenail clippings collected at Exam Year 2 using inductively-coupled-plasma mass spectroscopy. Asthma was diagnosed by a physician and/or reported medication use for asthma control with verification. Cox regression was used to model the association between toenail zinc concentrations and asthma incidence.ResultsOver an average of 22.5 years of follow-up, 508 incident cases of asthma were identified. After adjustment for potential confounders, no statistically significant association was found between zinc concentration and asthma incidence (HR = 0.81; 95% CI: 0.62, 1.07; P_{linear trend} = 0.26). The observed association was not materially modified by sex, body mass index, smoking or atopic status. When stratifying data by race, a significant inverse linear association was found among African Americans (per 1 standard deviation increment in toenail zinc concentrations: HR = 0.86; 95% CI: 0.75, 0.99; P_{linear trend} = 0.03), but not in Caucasians (HR = 1.07; 95% CI: 0.91, 1.25; P_{linear trend} = 0.42), though the test for interaction was not statistically significant (P_interaction = 0.099).ConclusionsFindings from this prospective cohort study do not support a significant longitudinal association between toenail zinc concentrations and incidence of asthma among American young adults. Future studies are needed to confirm our findings.     

Insulin Sensitivity in African‐American and White Women: Association With Inflammation

Whether the contribution of inflammation to risk for chronic metabolic disease differs with ethnicity is not known. The objective of this study was to determine: (i) whether ethnic differences exist in markers of inflammation and (ii) whether lower insulin sensitivity among African Americans vs. whites is due to greater inflammatory status. Subjects were African‐American (n = 108) and white (n = 105) women, BMI 27–30 kg/m². Insulin sensitivity was assessed with intravenous glucose tolerance test and minimal modeling; fat distribution with computed tomography; body composition with dual‐energy X‐ray absorptiometry; markers of inflammation (tumor necrosis factor (TNF)‐α, soluble tumor necrosis factor receptor (sTNFR)‐1, sTNFR‐2, C‐reactive protein (CRP), and interleukin (IL)‐6) with enzyme‐linked immunosorbent assay (ELISA). Whites had greater intra‐abdominal adipose tissue (IAAT), insulin sensitivity, and concentrations of TNF‐α, sTNFR‐1, and sTNFR‐2 than African Americans. Greater TNF‐α in whites vs. African Americans was attributed to greater IAAT in whites. Among whites, but not African Americans, CRP was independently and inversely associated with insulin sensitivity, after adjusting for IAAT (r = ?0.29 P < 0.05, and r = ?0.13 P = 0.53, respectively). Insulin sensitivity remained lower in African Americans after adjusting for CRP (P < 0.001). In conclusion, greater IAAT among whites may be associated with greater inflammation. Insulin sensitivity was lower among African Americans, independent of obesity, fat distribution, and inflammation.     

Obesity,End‐stage Renal Disease,and Survival in an Elderly Cohort With Cardiovascular Disease

Obesity is highly prevalent in African Americans and is associated with increased risk of End‐Stage Renal Disease (ESRD) and death. It is not known if the effect of obesity is similar among blacks and whites. The aim of this study is to examine racial differences in the association of obesity with ESRD and survival in elderly patients (age >65). Data were obtained for 74,167 Medicare patients with acute myocardial infarction (AMI) between February 1994 and July 1995. BMI was calculated as weight (kg) divided by height (m²). We evaluated the association of BMI class with ESRD incidence and death using multivariable Cox proportional hazards models, testing for race‐BMI interactions. Compared to whites, African Americans had higher BMI (26.9 vs. 26.0, P < 0.0001) and estimated glomerular filtration rate (72.4 ml/min/1.73 m² vs. 66.6 ml/min/1.73 m², P < 0.0001). Crude ESRD rates increased with increasing obesity among whites but not among blacks. However, after adjusting for age, sex, and other comorbidities, obesity was not associated with increased ESRD rate among blacks or whites and the interaction between race and BMI was not significant. Furthermore, for both races, patients classified as overweight, class 1 obese, or class 2 obese had similar, significantly better survival abilities compared to normal weight patients and the race BMI interaction was not significant. In conclusion, obesity does not increase risk of ESRD among black or white elderly subjects with cardiovascular disease (CVD). However, both obese blacks and whites, in this population, experience a survival benefit. Further studies need to explore this obesity paradox.     

Genetic variation in the HSD17B1 gene and risk of prostate cancer

Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17β-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Δ5-androsterone-3β,17β-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G) or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002) inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes these subgroup analyses less reliable. These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites.     

Genetic architecture of lipid traits changes over time and differs by race: Princeton Lipid Follow-up Study

Dyslipidemia is a major risk factor for CVD. Previous studies on lipid heritability have largely focused on white populations assessed after the obesity epidemic. Given secular trends and racial differences in lipid levels, this study explored whether lipid heritability is consistent across time and between races. African American and white nuclear families had fasting lipids measured in the 1970s and 22–30 years later. Heritability was estimated, and bivariate analyses between visits were conducted by race using variance components analysis. A total of 1,454 individuals (age 14.1/40.6 for offspring/parents at baseline; 39.6/66.5 at follow-up) in 373 families (286 white, 87 African American) were included. Lipid trait heritabilities were typically stronger during the 1970s than the 2000s. At baseline, additive genetic variation for LDL was significantly lower in African Americans than whites (P = 0.015). Shared genetic contribution to lipid variability over time was significant in both whites (all P < 0.0001) and African Americans (P ≤ 0.05 for total, LDL, and HDL cholesterol). African American families demonstrated shared environmental contributions to lipid variation over time (all P ≤ 0.05). Lower heritability, lower LDL genetic variance, and durable environmental effects across the obesity epidemic in African American families suggest race-specific approaches are needed to clarify the genetic etiology of lipids.     

Higher Gravidity and Parity Are Associated with Increased Prevalence of Metabolic Syndrome among Rural Bangladeshi Women

Background

Parity increases the risk for coronary heart disease; however, its association with metabolic syndrome among women in low-income countries is still unknown.

Objective

This study investigates the association between parity or gravidity and metabolic syndrome in rural Bangladeshi women.

Methods

A cross-sectional study was conducted in 1,219 women aged 15–75 years from rural Bangladesh. Metabolic syndrome was defined according to the standard NCEP-ATP III criteria. Logistic regression was used to estimate the association between parity and gravidity and metabolic syndrome, with adjustment of potential confounding variables.

Results

Subjects with the highest gravidity (> = 4) had 1.66 times higher odds of having metabolic syndrome compared to those in the lowest gravidity (0-1) (P _trend = 0.02). A similar association was found between parity and metabolic syndrome (P _trend = 0.04), i.e., subjects in the highest parity (> = 4) had 1.65 times higher odds of having metabolic syndrome compared to those in the lowest parity (0-1). This positive association of parity and gravidity with metabolic syndrome was confined to pre-menopausal women (P _trend <0.01). Among the components of metabolic syndrome only high blood pressure showed positive association with parity and gravidity (P _trend = 0.01 and <0.001). Neither Parity nor gravidity was appreciably associated with other components of metabolic syndrome.

Conclusions

Multi parity or gravidity may be a risk factor for metabolic syndrome.     

Consistent Association of Type 2 Diabetes Risk Variants Found in Europeans in Diverse Racial and Ethnic Groups

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.     

Racial Differences in Urinary F2‐Isoprostane Levels and the Cross‐Sectional Association With bmi

Levels of four urinary F₂‐isoprostanes (F₂‐IsoPs) were examined in a large sample of the Insulin Resistance Atherosclerosis Study (IRAS) multiethnic cohort: 237 African Americans (AAs), 342 non‐Hispanic whites (NHWs), and 275 Hispanic whites (HWs). F₂‐IsoP isomers — iPF2a‐III, 2,3‐dinor‐iPF2a‐III, iPF2a‐VI, and 8,12‐iso‐iPF2a‐VI — were measured in 854 urine samples using liquid chromatography with tandem mass spectrometry detection. In AAs, levels of all four F₂‐IsoPs were lower compared with NHWs and HWs (P values <0.05). When stratified by BMI, this gap was not observed among participants with normal BMI but appeared among overweight participants and increased among obese participants. Examining the slopes of the associations between BMI and F₂‐IsoPs showed no association between these variables among AAs (P values >0.2), and positive associations among whites (P values <0.05). Taking into account that positive cross‐sectional associations between systemic F₂‐IsoP levels and BMI have been consistently demonstrated in many study populations, the lack of such an association among AAs reveals a new facet of racial/ethnic differences in obesity‐related risk profiles.     

Association analysis of miRNA-related genetic polymorphisms in miR-143/145 and KRAS with colorectal cancer susceptibility and survival

Background: There is accumulating evidence of aberrant expression of miR-143 and miR-145 and their target gene KRAS in colorectal cancer (CRC). We hypothesize that single nucleotide polymorphisms (SNPs) within or near mRNA–microRNA (miRNA) binding sites may affect miRNA/target gene interaction, resulting in differential mRNA/protein expression and promoting the development and progression of CRC. Methods: We conducted a case–control study of 507 patients with CRC recruited from a tertiary hospital and 497 population-based controls to assess the association of genetic polymorphisms in miR-143/145 and the KRAS 3′ untranslated region (3′UTR) with susceptibility to CRC and patients’ survival. In addition, genetic variations of genomic regions located from 500 bp upstream to 500 bp downstream of the miR-143/miR-145 gene and the 3′UTR of KRAS were selected for analysis using the Haploview and HaploReg software. Results: Using publicly available expression profiling data, we found that miR-143/145 and KRAS expression were all reduced in rectal cancer tissue compared with adjacent non-neoplastic large intestinal mucosa. The rs74693964 C/T variant located 65 bp downstream of miR-145 genomic regions was observed to be associated with susceptibility to CRC (adjusted odds ratio (OR): 2.414, 95% CI: 1.385–4.206). Cumulative effects of miR-143 and miR-145 on CRC risk were observed (P_trend=0.03). Patients having CRC carrying variant genotype TT of KRAS rs712 had poorer survival (log-rank P=0.044, adjusted hazard ratio (HR): 4.328, 95% CI: 1.236–15.147). Conclusions: Our results indicate that miRNA-related polymorphisms in miR-143/145 and KRAS are likely to be deleterious and represent potential biomarkers for susceptibility to CRC and patients’ survival.     

Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15×10⁻⁹⁴<P<5×10⁻⁸, odds ratio (OR) = 1.09 to 1.36). Fine-mapping revealed that 88 of 158 previously identified T2D or glucose homeostasis loci demonstrated nominal to highly significant association (2.2×10⁻²³ < locus-wide P<0.05). These novel and previously identified loci yielded a sibling relative risk of 1.19, explaining 17.5% of the phenotypic variance of T2D on the liability scale in African Americans. Overall, this study identified two novel susceptibility loci for T2D in African Americans. A substantial number of previously reported loci are transferable to African Americans after accounting for linkage disequilibrium, enabling fine mapping of causal variants in trans-ethnic meta-analysis studies.     

Role of an intronic polymorphism in the <Emphasis Type="Italic">PDCD1</Emphasis> gene with the risk of sporadic systemic lupus erythematosus and the occurrence of antiphospholipid antibodies

Recently, a polymorphism in intron 4 (G/A) of the programmed cell death 1 (PDCD1) gene was shown to be associated with systemic lupus erythematosus (SLE) risk in familial and sporadic patients of European, European American, and Mexican origin. In this investigation, we examined the role of this polymorphism in 311 SLE patients (276 European Americans and 35 African Americans) and 390 age-matched healthy controls (359 European Americans and 31 African Americans). The frequency of the A allele was significantly higher in European American controls than in African American controls (0.107 vs. 0.048; P=0.046). There was no significant difference in the frequency of the A allele between SLE cases and controls in either the European American (0.107 vs. 0.129; P=0.84) or African American (0.048 vs. 0.100; P=0.25) cohort. However, after adjustment for the status of the antiphospholipid antibodies (APA) in the logistic regression analysis, the risk for SLE associated with the PDCD1 polymorphism was statistically significant. The APA-adjusted odds ratio (OR) between A allele carriers (AA + AG genotypes) versus the GG genotype showed a modest association with SLE risk in European Americans (OR=1.52, 95% CI: 1.02–2.27; P=0.039), African Americans (OR=2.89, 95% CI: 0.61–13.76; P=0.183), and the ethnicity-combined sample (OR=1.59, 95% CI: 1.08–2.34; P=0.019). Furthermore, we observed that the A allele carriers were protected against the occurrence of APA in both controls (OR=0.399, 95% CI: 0.19–0.82; P=0.0098) and SLE cases (OR=0.566, 95% CI: 0.32–1.01; P=0.054). Our data indicate polymorphism in intron 4 of the PDCD1 gene affects the occurrence of APA and may slightly modify the risk of sporadic SLE.     

Interactions between meat intake and genetic variation in relation to colorectal cancer

Meat intake is associated with the risk of colorectal cancer. The objective of this systematic review was to evaluate interactions between meat intake and genetic variation in order to identify biological pathways involved in meat carcinogenesis. We performed a literature search of PubMed and Embase using “interaction”, “meat”, “polymorphisms”, and “colorectal cancer”, and data on meat–gene interactions were extracted. The studies were divided according to whether information on meat intake was collected prospectively or retrospectively. In prospective studies, interactions between meat intake and polymorphisms in PTGS2 (encoding COX-2), ABCB1, IL10, NFKB1, MSH3, XPC (P_int = 0.006, 0.01, 0.04, 0.03, 0.002, 0.01, respectively), but not IL1B, HMOX1, ABCC2, ABCG2, NR1I2 (encoding PXR), NR1H2 (encoding LXR), NAT1, NAT2, MSH6, or MLH1 in relation to CRC were found. Interaction between a polymorphism in XPC and meat was found in one prospective and one case–control study; however, the directions of the risk estimates were opposite. Thus, none of the findings were replicated. The results from this systematic review suggest that genetic variation in the inflammatory response and DNA repair pathway is involved in meat-related colorectal carcinogenesis, whereas no support for the involvement of heme and iron from meat or cooking mutagens was found. Further studies assessing interactions between meat intake and genetic variation in relation to CRC in large well-characterised prospective cohorts with relevant meat exposure are warranted.

Electronic supplementary material

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