Obesity risk in young adults from the Jerusalem Perinatal Study (JPS): the contribution of polygenic risk and early life exposure.

BACKGROUND/OBJECTIVES: The effects of early life exposures on offspring life-course health are well established. This study assessed whether adding early socio-demographic and perinatal variables to a model based on polygenic risk score (PRS) improves prediction of obesity risk. METHODS: We used the Jerusalem Perinatal study (JPS) with data at birth and body mass index (BMI) and waist circumference (WC) measured at age 32. The PRS was constructed using over 2.1M common SNPs identified in genome-wide association study (GWAS) for BMI. Linear and logistic models were applied in a stepwise approach. We first examined the associations between genetic variables and obesity-related phenotypes (e.g., BMI and WC). Secondly, socio-demographic variables were added and finally perinatal exposures, such as maternal pre-pregnancy BMI (mppBMI) and gestational weight gain (GWG) were added to the model. Improvement in prediction of each step was assessed using measures of model discrimination (area under the curve, AUC), net reclassification improvement (NRI) and integrated discrimination improvement (IDI). RESULTS: One standard deviation (SD) change in PRS was associated with a significant increase in BMI (ß = 1.40) and WC (ß = 2.45). These associations were slightly attenuated (13.7-14.2%) with the addition of early life exposures to the model. Also, higher mppBMI was associated with increased offspring BMI (ß = 0.39) and WC (ß = 0.79) (p < 0.001). For obesity (BMI ≥ 30) prediction, the addition of early socio-demographic and perinatal exposures to the PRS model significantly increased AUC from 0.69 to 0.73. At an obesity risk threshold of 15%, the addition of early socio-demographic and perinatal exposures to the PRS model provided a significant improvement in reclassification of obesity (NRI, 0.147; 95% CI 0.068-0.225). CONCLUSIONS: Inclusion of early life exposures, such as mppBMI and maternal smoking, to a model based on PRS improves obesity risk prediction in an Israeli population-sample.

Women's attitudes towards disclosure of genetic information in pregnancy with varying levels of penetrance.

BACKGROUND: Chromosomal-microarray-analysis (CMA) may reveal susceptibility-loci (SL) of varied penetrance for autism-spectrum-disorder (ASD) and other neurodevelopmental conditions. Attitudes of women/parents to disclosure of SL during pregnancy are understudied. METHODS: A multiple-choice questionnaire was distributed to postpartum women. Data were collected on women's interest to receive prenatal genetic information with various levels of penetrance. RESULTS: Women's (n = 941) disclosure choices were dependent on the magnitude of risk: approximately 70% supported disclosure of either full or 40% penetrance, 53% supported disclosure at a 20% risk threshold, and 40% supported disclosure at 10% or less. Although most women supported, rejected or were indecisive about disclosure consistently across all risk levels, nearly one-quarter (24%) varied their responses based on penetrance, and this was associated with religiosity, education, parity and concern about fetal health (p-values <0.04). Among those who varied their choices, the risk threshold was lower among secular women (20%) than among ultraorthodox women (40%). In a multivariable analysis, ultraorthodox women were much less likely to vary their choices on ASD disclosure compared with secular women (aOR = 0.37, p < 0.001). CONCLUSION: Women's attitudes toward disclosure are influenced by the level of risk and their individual characteristics. We therefore encourage engaging women/couples in disclosure decisions regarding uncertain and probabilistic results from prenatal genomic tests.

Perinatal exposures and adolescence overweight: The role of shared maternal-offspring pathways.

BACKGROUND AND AIMS: Early life exposures affect offspring health across the life-course. We aimed to examine whether prevalent perinatal exposures and obstetric complications are independently associated with offspring overweight in adolescence. We then assessed whether shared maternal-offspring pathways drive the association of perinatal exposures with offspring overweight. METHODS: Using data from the Jerusalem Perinatal Study birth cohort, two perinatal scores were constructed: obstetric complications (OC) and prevalent perinatal exposures (PPE) scores. PPE score, generated by principal component analysis, included three primary components. Logistic regressions were used to assess associations of scores with offspring overweight, with and without adjustment for maternal life-course survival. RESULTS: OC and PPE scores were independently associated with offspring overweight (OROC = 1.15, 95%CI:1.07,1.25; ORPPE1- SEP and lifestyle = 0.85, 95%CI:0.79,0.91; ORPPE2- Maternal body size = 1.20, 95%CI: 1.13,1.28; ORPPE3-Fetal growth = 1.18, 95%CI:1.11,1.26). Maternal survival was associated with offspring overweight (OR = 1.38, 95%CI:1.08,1.76), yet introducing PPE score to the same model attenuated this association (OR = 1.16, 95%CI:0.90, 1.49). When OC score and maternal survival were included in the same model, their associations with offspring overweight remained unchanged. CONCLUSIONS: Mother-offspring shared factors, captured by maternal life-course survival, underlie the effect of prevalent perinatal exposures on offspring overweight. However, the effect of obstetric complications was independent, highlighting the contribution of additional pathways.

Obesity Prediction in Young Adults from the Jerusalem Perinatal Study: Contribution of Polygenic Risk and Early Life Exposures.

We assessed whether adding early life exposures to a model based on polygenic risk score (PRS) improves prediction of obesity risk. We used a birth cohort with data at birth and BMI and waist circumference (WC) measured at age 32. The PRS was composed of SNPs identified in GWAS for BMI. Linear and logistic models were used to explore associations with obesity-related phenotypes. Improvement in prediction was assessed using measures of model discrimination (AUC), and net reclassification improvement (NRI). One SD change in PRS was associated with a significant increase in BMI and WC. These associations were slightly attenuated (13.7%-14.2%) with the addition of early life exposures to the model. Also, higher maternal pre-pregnancy BMI was associated with increase in offspring BMI and WC (p<0.001). For prediction obesity (BMI ≥ 30), the addition of early life exposures to the PRS model significantly increase the AUC from 0.69 to 0.73. At an obesity risk threshold of 15%, the addition of early life exposures to the PRS model provided a significant improvement in reclassification of obesity (NRI, 0.147; 95% CI 0.068-0.225). We conclude that inclusion of early life exposures to a model based on PRS improves obesity risk prediction in an Israeli population-sample.

A five-safes approach to a secure and scalable genomics data repository.

Genomic researchers increasingly utilize commercial cloud service providers (CSPs) to manage data and analytics needs. CSPs allow researchers to grow Information Technology (IT) infrastructure on demand to overcome bottlenecks when combining large datasets. However, without adequate security controls, the risk of unauthorized access may be higher for data stored on the cloud. Additionally, regulators are mandating data access patterns and specific security protocols for the storage and use of genomic data. While CSP provides tools for security and regulatory compliance, building the necessary controls required for cloud solutions is not trivial. Research Assets Provisioning and Tracking Online Repository (RAPTOR) by the Genome Institute of Singapore is a cloud-native genomics data repository and analytics platform that implements a "five-safes" framework to provide security and governance controls to data contributors and users, leveraging CSP for sharing and analysis of genomic datasets without the risk of security breaches or running afoul of regulations.

Receiving uncertain results from prenatal chromosomal microarray analysis: Women's decisions on continuation or termination of pregnancy.

BACKGROUND: Chromosomal microarray analysis (CMA) may detect variants of uncertain clinical significance (VUS) and susceptibility loci (SL) with incomplete penetrance for neurodevelopmental disorders. This qualitative study provides empirical data on women's experiences with receiving such findings in pregnancy and their decisions regarding continuation or termination of the pregnancy. METHODS: Semi-structured interviews were conducted with women who received a VUS and/or SL from prenatal CMA in the last 2-4 years and were analyzed using Grounded Theory. RESULTS: The vast majority of women recalled being stressed by the findings. All women sought further advice and information to be able to decide whether to continue or terminate their pregnancy. The three pregnancies that were terminated have in common a de novo SL with a 10%-20% penetrance. Similar reasoning (coping with uncertainty, the quest for a perfect child, and a chance for recurrence in future pregnancies) led different women to contradicting conclusions regarding their pregnancies. All women felt satisfied with their decisions. CONCLUSION: Although uncertain/probabilistic information commonly involves a psychological burden, it may also be perceived as valuable and actionable. Pre-test parental choice regarding the disclosure of such information could allow personalized utilization of advanced genomic tests in pregnancy.

Familial aggregation of the aging process: biological age measured in young adult offspring as a predictor of parental mortality.

Measures of biological age (BA) integrate information across organ systems to quantify "biological aging," i.e., inter-individual differences in aging-related health decline. While longevity and lifespan aggregate in families, reflecting transmission of genes and environments across generations, little is known about intergenerational continuity of biological aging or the extent to which this continuity may be modified by environmental factors. Using data from the Jerusalem Perinatal Study (JPS), we tested if differences in offspring BA were related to mortality in their parents. We measured BA using biomarker data collected from 1473 offspring during clinical exams in 2007-2009, at age 32 ± 1.1. Parental mortality was obtained from population registry data for the years 2004-2016. We fitted parametric survival models to investigate the associations between offspring BA and parental all-cause and cause-specific mortality. We explored potential differences in these relationships by socioeconomic position (SEP) and offspring sex. Participants' BAs widely varied (SD = 6.95). Among those measured to be biologically older, parents had increased all-cause mortality (HR = 1.10, 95% CI: 1.08, 1.13), diabetes mortality (HR = 1.19, 95% CI: 1.08, 1.30), and cancer mortality (HR = 1.07, 95% CI: 1.02, 1.13). The association with all-cause mortality was stronger for families with low compared with high SEP (Pinteraction = 0.04) and for daughters as compared to sons (Pinteraction < 0.001). Using a clinical-biomarker-based BA estimate, observable by young adulthood prior to the onset of aging-related diseases, we demonstrate intergenerational continuity of the aging process. Furthermore, variation in this familial aggregation according to household socioeconomic position (SEP) at offspring birth and between families of sons and daughters proposes that the environment alters individuals' aging trajectory set by their parents.

The Relationships of Fibrinogen and C-Reactive Protein With Gait Performance: A 20-Year Longitudinal Study.

Background: Gait speed, a central marker of aging, has been linked to various health outcomes, such as cognitive and physical functions in middle-aged adults. Although long-term systemic low-grade inflammation is considered a mechanism underlying a variety of aging-related risk factors, the longitudinal associations between inflammation markers and gait speed are yet to be fully investigated. Objective: To explore the associations of CRP and fibrinogen levels, measured two decades ago, with gait speed among community dwelling adults, considering the contribution of cardio-metabolic factors and cognition. Methods: Study participants took part in two phases of the of the "Kibbutzim Family Study" (i.e., Phase II, 1999-2000 and Phase III, 2017-2019). Blood samples collected in Phase II (baseline) were used to determine level of inflammatory markers. Gait speed was assessed under single-task (ST) and dual-task (DT) conditions in Phase III. Demographic, anthropometric and clinical data were collected in both phases. Linear regression models were used to assess the adjusted associations of inflammation and gait speed. Results: A total of 373 individuals aged 34-99 (mean 64 ± 13 years) in Phase III were included in the study. Gait speed under ST was negatively associated with baseline levels of fibrinogen (b per standard deviation (SD) = -0.053, p = 0.0007) and CRP (b per SD = -0.043, p = 0.010), after adjusting for baseline and concurrent cardiometabolic risk factors. Accounting for executive functions, associations of fibrinogen with gait under ST were somewhat attenuated, yet associations remained statistically significant (p < 0.05). Associations with CRP were attenuated to the null. In contrast, there were no associations between inflammation markers and gait under DT. Conclusion: Our findings demonstrate that in a sample including younger to older adults, higher systemic inflammatory activity was linked with gait 20 years later, beyond age and cardiometabolic health, and to a certain extent, beyond executive functions. Thus, systemic inflammation may serve as an early marker to identify individuals at risk for gait decline.

Postpartum women's attitudes to disclosure of adult-onset conditions in pregnancy.

BACKGROUND: Advanced prenatal genomic technologies can identify risks for adult-onset (AO) conditions in the fetus, challenging the traditional purpose of prenatal testing. Professional guidelines commonly support disclosure of high-penetrance AO actionable conditions, yet attitudes of women/parents to these findings and factors affecting their attitudes are understudied. METHODS: We explored 941 (77% response rate) postpartum women's attitudes towards receiving prenatal genetic information, and associations of sociodemographic, medical and psychological characteristics with their choices, focusing on AO conditions. RESULTS: Women largely support the disclosure of actionable AO findings (58.4%), in line with professional guidelines. A third of the women also supported the disclosure of non-actionable AO conditions. Stronger religious observance (p < 0.001) and higher psychological distress (p = 0.024) were associated with decreased interest in receiving actionable AO conditions, whereas higher concern for fetal health yielded increased interest (p = 0.032). Attitudes towards disclosure were strongly associated with women's perceived benefit of such information for their own, partner's, and future child's health. Termination of pregnancy based on such information received very little support. CONCLUSION: In-light of the demonstrated understanding of nuanced genetic information and the observed diversity in attitudes, a culturally competent opt-in/out policy could be considered. If full-disclosure is practiced, support should be provided to those expressing higher levels of distress.

Independent associations of inter-spousal gaps in age and education with long-term mortality and cancer survival: The Jerusalem Perinatal Study 1964-2016.

PURPOSE: To identify factors responsible for variation in health among married individuals, we investigated the independent associations of gaps in spousal age and education (or "heterogamy") with all-cause and cause-specific mortality as well as with survival of cancer patients. METHODS: Using over four decades of follow-up data on 36,717 couples from Jerusalem (1964-2016), we compared heterogamous with homogamous couples. RESULTS: Having a less educated spouse was associated with an increased risk for several outcomes in both genders, such as all-cause mortality in males (hazard ratio [HR] = 1.18, 95% confidence interval [CI]: 1.12, 1.25) and in females (HR = 1.11, CI: 1.01, 1.22). Having a more educated spouse was associated with decreased all-cause mortality in males (HR = 0.93, CI: 0.87, 0.99), but not in females. Having an older spouse was detrimental for health of both genders. For example, increased all-cause mortality was seen in men (HR = 1.22, CI: 1.10, 1.34) and in women (HR = 1.10, CI: 1.02, 1.19). A younger spouse was beneficial for some of the outcomes in males, such as decreased cancer-specific mortality (HR = 0.88, CI: 0.78, 0.99), but not in females. CONCLUSIONS: Spousal gaps in education and age may be independently associated with health outcomes. The observed relationships may be driven by combined amounts of marital strain as well as shared spousal resources (such as knowledge or income) depending on gender.

Pre- and Perinatal Factors Predicting Inflammatory Bowel Disease: A Population-Based Study with Fifty Years of Follow-Up.

BACKGROUND: Pre- and perinatal events may be associated with an increased risk of inflammatory bowel disease [IBD]. We aimed to investigate the role of pre- and perinatal factors as potential risk factors for the development of IBD in a population with a follow-up of 50 years. METHODS: We conducted a nested case-control study, reporting IBD incidence among individuals born in 1964-76, for whom pre- and perinatal exposures were reported as part of the Jerusalem Perinatal Study [JPS], by linking them to the database of the epidemiology group of the Israeli IBD Research Nucleus [epi-IIRN], including all IBD patients in Israel since 2005 and their matched controls. RESULTS: We identified 2789 individuals within the epi-IIRN cohort who were also included in the JPS cohort [n = 90 079]: 746 IBD patients (405 with Crohn's disease [CD] and 341 with ulcerative colitis [UC]) and 2043 non-IBD controls. Those with a 'Non-western' family origin had decreased odds of developing CD and UC. High socioeconomic status was associated with CD but not UC. Low birth weight [≤2500 g] occurred less frequently in IBD cases compared to controls, especially in UC patients, showing a protective effect. Being the first born was associated with CD, and having older siblings lowered the odds of developing CD, decreasing 7% with each additional sibling. Smoking and breastfeeding data were available for a subset of individuals, but neither was associated with IBD development. CONCLUSION: This population-based study identifies several pre- and perinatal variables as predictors of IBD development. This information may be helpful to facilitate implementation of early diagnosis interventions and family follow-up protocols.

Perinatal socio-behavioral and obstetric predictors of metabolically healthy and unhealthy obesity in adult offspring.

OBJECTIVE: The purpose of this study was to investigate whether obstetric and perinatal socio-behavioral characteristics at the time of pregnancy predict obesity phenotypes of adult offspring. METHODS: The Jerusalem Perinatal Study was conducted among 17,003 deliveries during 1974 to 1976. Follow-up studies were conducted during 2007 to 2009 and 2017 to 2019 among 1,440 offspring undergoing examinations. Offspring were classified into four phenotypes according to obesity and metabolic status: metabolically healthy normal weight (MHNW, reference group), unhealthy normal weight, healthy obesity (MHO), and unhealthy obesity (MUO). Regression models were carried out to identify perinatal predictors for risk phenotypes at age 30 to 35 years, emphasizing the differentiation between socio-behavioral and obstetric features. RESULTS: A total of 15.7% of participants were classified as MUO, and 5.4% were classified as MHO. Low socioeconomic status was associated with both obesity phenotypes (e.g., odds ratio [OR]MHO/MHNW = 2.98, p < 0.001). High socioeconomic status was associated with MUO (ORMUO/MHNW = 1.93, p = 0.002). Maternal low education was also associated with both obesity phenotypes (ORMUO/MHNW = 2.46, p < 0.001, ORMHO/MHNW = 2.45, p = 0.005). Participants with MUO were more likely to have a smoking father (ORMUO/MHNW = 1.48, p = 0.021). CONCLUSIONS: Perinatal socio-behavioral characteristics are associated with adult obesity phenotypes. The findings point to possible mechanisms underlying the development of obesity in young adults and, thus, contribute toward identifying high-risk groups that would mostly benefit from obesity risk-reduction interventions.

Early-life factors and adult anti-Müllerian hormone levels.

AIM: This study aims to examine whether early-life factors are associated with adult ovarian reserve, measured by anti-Müllerian hormone (AMH) levels. METHODS: The work is based on the Jerusalem Perinatal Study (JPS), an extensive birth cohort with detailed information on all pregnancies and deliveries in Jerusalem between 1974 and 1976. A subset of individuals participated in a follow-up study that took place between 2007 and 2009 in which they completed questionnaires and were physically examined at mean age of 32. A blood sample was additionally drawn from each participant, and AMH was measured in a sample of 239 women. The associations between each early-life factors, including birth weight, maternal pre-pregnancy weight, gestational weight gain (GWG), socioeconomic position at birth, and parental smoking during pregnancy, were assessed with AMH levels at the age of 32.Multivariable regression models were used to examine the associations with AMH, adjusting for potential confounders at birth and at the age of 32. RESULTS: Low birth weight was significantly associated with lower ovarian reserve reflected by lower levels of AMH at age 32 (range 30-36), independent of other early-life factors and after adjusting for confounders (ß = 0.180, p = 0.03). CONCLUSIONS: This prospective study demonstrates the association of birth weight and adult ovarian reserve. Underlying mechanisms are yet to be fully understood.

Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population.

The role of low frequency variants associated with telomere length homeostasis in chronic diseases and mortalities is relatively understudied in the East-Asian population. Here we evaluated low frequency variants, including 1,915,154 Asian specific variants, for leukocyte telomere length (LTL) associations among 25,533 Singapore Chinese samples. Three East Asian specific variants in/near POT1, TERF1 and STN1 genes are associated with LTL (Meta-analysis P 2.49×10-14-6.94×10-10). Rs79314063, a missense variant (p.Asp410His) at POT1, shows effect 5.3 fold higher and independent of a previous common index SNP. TERF1 (rs79617270) and STN1 (rs139620151) are linked to LTL-associated common index SNPs at these loci. Rs79617270 is associated with cancer mortality [HR95%CI = 1.544 (1.173, 2.032), PAdj = 0.018] and 4.76% of the association between the rs79617270 and colon cancer is mediated through LTL. Overall, genetically determined LTL is particularly associated with lung adenocarcinoma [HR95%CI = 1.123 (1.051, 1.201), Padj = 0.007]. Ethnicity-specific low frequency variants may affect LTL homeostasis and associate with certain cancers.

The association of genetically determined serum glycine with cardiovascular risk in East Asians.

BACKGROUND AND AIMS: Glycine is involved in a wide range of metabolic pathways and increased circulating glycine is associated with reduced risk of cardio-metabolic diseases in Europeans but the genetic association between circulating glycine and cardiovascular risk is largely unknown in East Asians. METHODS AND RESULTS: We conducted a genome-wide association study (GWAS) in Singaporean Chinese participants and investigated if genetically determined serum glycine were associated with incident coronary artery disease (CAD) (711 cases and 1,246 controls), cardiovascular death (1,886 cases and 21,707 controls) and angiographic CAD severity (as determined by the Modified Gensini score, N = 1,138). CONCLUSION: Our study, a first in East Asians, suggest a protective role of glycine against CAD.

Holocaust Experience and Mortality Patterns: 4-Decade Follow-up in a Population-Based Cohort.

Research on mortality associated with exposure to the Holocaust is relevant for a better understanding of the effects of genocides on survivors. To our knowledge, previous studies have not investigated the long-term cause-specific mortality of Holocaust survivors. We compared mortality rates among Israelis born in European countries controlled by the Nazis during World War II with those among Israelis of European descent who did not have this exposure. Records of 22,671 people (45% women; 5,042 survivors) from the population-based Jerusalem Perinatal Study (1964-1976) were linked to the Israeli Population Registry, which was updated through 2016. Cox models were used for analysis, with 2-sided tests of statistical significance. Risk of all-cause mortality was higher among exposed women (hazard ratio (HR) = 1.15, 95% confidence interval (CI): 1.05, 1.27) than in unexposed women. No association was found between Holocaust exposure and male all-cause mortality. In both sexes, survivors had higher cancer-specific mortality (HR = 1.17 (95% CI: 1.01, 1.35) in women and HR = 1.14 (95% CI: 1.01, 1.28) in men). Exposed men also had excess mortality due to coronary heart disease (HR = 1.39, 95% CI: 1.09, 1.77) and lower mortality from other known causes combined (HR = 0.86, 95% CI: 0.75, 0.99). In summary, experiencing the Holocaust was associated with excess all-cause and cancer-specific mortality in women and cancer- and coronary heart disease-specific mortality in men.

Birth Weight and Maternal Body Size as Determinants of Blood Pressure at Age 17: Results from the Jerusalem Perinatal Study Cohort.

OBJECTIVES: To investigate the effect of birth weight (BW) and maternal pre-pregnancy BMI (mBMI) on blood pressure (BP) in adolescence. METHODS: A Population-based cohort of 11,729 births in Jerusalem during 1974-1976, with archival data on maternal and birth characteristics was performed. Measurements at age 17 were assessed and linear regression models were used to evaluate the associations of birth characteristics with BP outcomes. RESULTS: BW was inversely associated with both systolic (SBP) and diastolic (DBP) BP at age 17 (SBP: B = - 0.829, p = 0.002; DBP: B = - 0.397, p = 0.033). The interaction term between BW and weight at age 17 was significant for DBP (p = 0.017) and pulse pressure (p = 0.005). mBMI yielded significant positive associations with BP, independent of BW. CONCLUSIONS FOR PRACTICE: Our findings indicate that there are at least two distinct pathways linking early life characteristics with subsequent BP: Intrauterine growth, as reflected by BW and other genetic or environmental factors, reflected by mBMI and maternal education, contribute to offspring adolescent BP. These results warrant replication in other birth cohorts and underline the need to explore specific mechanisms that account for these associations.

Effect of plasma polyunsaturated fatty acid levels on leukocyte telomere lengths in the Singaporean Chinese population.

BACKGROUND: Shorter telomere length (TL) has been associated with poor health behaviors, increased risks of chronic diseases and early mortality. Excessive shortening of telomere is a marker of accelerated aging and can be influenced by oxidative stress and nutritional deficiency. Plasma n6:n3 polyunsaturated fatty acid (PUFA) ratio may impact cell aging. Increased dietary intake of marine n-3 PUFA is associated with reduced telomere attrition. However, the effect of plasma PUFA on leukocyte telomere length (LTL) and its interaction with genetic variants are not well established. METHODS: A nested coronary artery disease (CAD) case-control study comprising 711 cases and 638 controls was conducted within the Singapore Chinese Health Study (SCHS). Samples genotyped with the Illumina ZhongHua-8 array. Plasma n-3 and n-6 PUFA were quantified using mass spectrometry (MS). LTL was measured with quantitative PCR method. Linear regression was used to test the association between PUFA and LTL. The interaction between plasma PUFAs and genetic variants was assessed by introducing an additional term (PUFA×genetic variant) in the regression model. Analysis was carried out in cases and controls separately and subsequently meta-analyzed using the inverse-variance weighted method. We further assessed the association of PUFA and LTL with CAD risk by Cox Proportional-Hazards model and whether the effect of PUFA on CAD was mediated through LTL by using structural equation modeling. RESULTS: Higher n6:n3 ratio was significantly associated with shorter LTL (p = 0.018) and increased CAD risk (p = 0.005). These associations were mainly driven by elevated plasma total n-3 PUFAs, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (p < 0.05). There was a statistically significant interaction for an intergenic single nucleotide polymorphism (SNP) rs529143 with plasma total n-3 PUFA and DHA on LTL beyond the genome-wide threshold (p < 5 ×  10- 8). Mediation analysis showed that PUFA and LTL affected CAD risk independently. CONCLUSIONS: Higher plasma n6:n3 PUFA ratio, and lower EPA and DHA n-3 PUFAs were associated with shorter LTL and increased CAD risk in this Chinese population. Furthermore, genetic variants may modify the effect of PUFAs on LTL. PUFA and LTL had independent effect on CAD risk in our study population.

Interaction between a haptoglobin genetic variant and coronary artery disease (CAD) risk factors on CAD severity in Singaporean Chinese population.

BACKGROUND: Haptoglobin (Hp) is a plasma protein with strong anti-inflammation and antioxidant activities. Its plasma level is known to be inversely associated with many inflammatory diseases, including cardiovascular diseases. However, the association of HP genetic variants with coronary artery disease (CAD) severity/mortality, and how they interact with common CAD risk factors are largely unknown. METHODS: We conducted the analysis in a Singaporean Chinese CAD population with Gensini severity scores (N = 582) and subsequently evaluated the significant findings in an independent cohort with cardiovascular mortality (excluding stroke) as outcome (917 cases and 19,093 controls). CAD risk factors were ascertained from questionnaires, and stenosis information from medical records. Mortality was identified through linkage with the nationwide registry of births and deaths in Singapore. Linear regression analysis between HP genetic variant (rs217181) and disease outcome were performed. Interaction analyses were performed by introducing an interaction term in the same regression models. RESULTS: Although rs217181 was not significantly associated with CAD severity and cardiovascular mortality (excluding stroke) in all subjects, when stratified by hypertension status, hypertensive individuals with the minor T allele have more severe CAD (ß = 0.073, SE = 0.030, p = 0.015) and non-hypertensive individuals with the T allele have lower risk for mortality (odds ratio = 0.771 (0.607-0.980), p = 0.033). CONCLUSION: HP genetic variant is not associated with CAD severity and mortality in the general population. However, hypertensive individuals with the rs217181 T allele associated with higher Hp levels had more severe CAD while non-hypertensive individuals with the same allele had lower risk for mortality in the Chinese population.

Higher BMI is associated with smaller regional brain volume in older adults with type 2 diabetes.

AIMS/HYPOTHESIS: There are established relationships between adiposity (obesity) and higher dementia risk, faster cognitive decline and associated neural injury. Type 2 diabetes is strongly linked to greater adiposity and has been consistently associated with neural injury and poor cognitive outcomes. However, although obesity is a major cause of type 2 diabetes, there is limited evidence on the association of adiposity with brain atrophy among individuals with type 2 diabetes. METHODS: We examined the association of BMI (a measure of adiposity), and of long-term trajectories of BMI (three empirically identified groups of trajectories-'normal', 'overweight' and 'obese'-using SAS macro PROC TRAJ), with regional brain volume, in a sample of older individuals (aged 64-84) with type 2 diabetes participating in the Israel Diabetes and Cognitive Decline Study (n = 198). RESULTS: Using linear regression, we found that greater BMI was associated with smaller volumes of the inferior frontal gyrus (IFG) (r = -0.25, p = 0.001) and the middle temporal gyrus (r = -0.19; p = 0.010) after adjusting for sociodemographic covariates and total intracranial volume. In addition, there were significant differences between BMI trajectory groups in IFG volume (F = 4.34, p = 0.014), such that a long-term trajectory of obesity was associated with a smaller volume. Additional adjustment for cardiovascular and diabetes-related potential confounders did not substantively alter the results. There were no associations of adiposity with superior frontal gyrus, middle frontal gyrus or total grey matter volumes. CONCLUSIONS/INTERPRETATION: In older adults with type 2 diabetes, long-term adiposity may have a detrimental impact on volume of brain regions relevant to cognitive functioning. Further studies to identify the underlying mechanisms are warranted. Graphical abstract.