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Genetic factors underlying leukocyte telomere length (LTL) may provide insights into telomere homeostasis, with direct links to disease susceptibility. Genetic evaluation of 23,096 Singaporean Chinese samples identifies 10 genome-wide loci ( P  < 5 × 10 −8 ). Several of these contain candidate genes ( TINF2 , PARP1 , TERF1 , ATM and POT1 ) with potential roles in telomere biology and DNA repair mechanisms. Meta-analyses with additional 37,505 European individuals reveals six more genome-wide loci, including associations at MPHOSPH6 , NKX2-3 and TYMS . We demonstrate that longer LTL associates with protection against respiratory disease mortality [HR = 0.854(0.804–0.906), P  = 1.88 × 10 −7 ] in the Singaporean Chinese samples. We further show that the LTL reducing SNP rs7253490 associates with respiratory infections ( P  = 7.44 × 10 −4 ) although this effect may not be strongly mediated through LTL. Our data expands on the genetic basis of LTL and may indicate on a potential role of LTL in immune competence. Shortening of leukocyte telomere length (LTL) is associated with age and increased risk for various chronic diseases. Here, the authors report genome-wide association studies for LTL in Singaporean Chinese populations and find that longer LTL associates with less severe outcomes of respiratory disease phenotypes.

To study the association between mode of delivery and offspring BMI in late adolescence in a large cohort that predated the obesity epidemic, and assess the role of maternal pre-pregnancy BMI (ppBMI) in this association. We conducted a historical prospective study in the setting of the Jerusalem Perinatal Study (JPS), a population-based cohort that includes all 17,003 births to residents of West Jerusalem, between 1974 and 1976. Offspring's BMI at age 17 was obtained upon army recruitment and was available for 11,001 of cohort participants. The associations were examined using logistic regressions, adjusting for socio-demographic characteristics and for proxies for indication for C-Section birth. Analyses were then stratified by quartiles of ppBMI. C-Section was associated with offspring overweight/obesity, with adjusted OR of 1.44 (95%CI:1.14-1.82). Significant interaction of ppBMI with mode of delivery was observed, such that the associations of C-Section with overweight/obesity were limited to the upper quartile of ppBMI (adjusted OR = 1.70, 95%CI:1.18-2.43). Restricting the analyses to singleton first births and excluding pregnancies complicated with toxemia and gestational diabetes yielded similar findings. C-Section was positively associated with being overweight/obese at age 17. Importantly, ppBMI modified this association, with a significant association between C-Section and overweight/obesity evident only among offspring born to mothers in the highest ppBMI quartile. In light of the growing rates of obesity in women of reproductive age, these results should be considered in patient-doctor shared decisions related to selection of mode of delivery, in the absence of a clear medical indication.

Aims/hypothesisThere 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.MethodsWe 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).ResultsUsing 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/interpretationIn 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.

AimThis study aims to examine whether early-life factors are associated with adult ovarian reserve, measured by anti-Müllerian hormone (AMH) levels.MethodsThe 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.ResultsLow 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 (β = 0.180, p = 0.03).ConclusionsThis prospective study demonstrates the association of birth weight and adult ovarian reserve. Underlying mechanisms are yet to be fully understood.

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.

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: 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=-0.053, p=0.007) and CRP (-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. Conclusions: Our findings demonstrate that in a sample including also 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.

ObjectivesTo investigate the effect of birth weight (BW) and maternal pre-pregnancy BMI (mBMI) on blood pressure (BP) in adolescence.MethodsA 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.ResultsBW 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 PracticeOur 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.

Socioeconomic position (SEP) has been associated with breast cancer incidence and survival. We examined the associations between two socioeconomic indicators and long-term breast cancer incidence and survival in a population-based cohort of parous women. Residents of Jerusalem who gave birth between 1964-1976 (n = 40,586) were linked to the Israel Cancer Registry and Israel Population Registry to determine breast cancer incidence and vital status through mid-2008. SEP was assessed by husband's occupation and the woman's education. We used log ranks tests to compare incidence and survival curves by SEP, and Cox proportional hazard models to adjust for demographic, reproductive and diagnostic factors and assess effect modification by ethnic origin. In multivariable models, women of high SEP had a greater risk of breast cancer compared to women of low SEP (Occupation: HR 1.18, 95 % CI 1.03-1.35; Education: HR 1.39, 95 % CI 1.21-1.60) and women of low SEP had a greater risk of mortality after a breast cancer diagnosis (Occupation: HR 1.33, 95 % CI 1.04-1.70; Education: HR 1.37, 95 % CI 1.06-1.76). The association between education and survival was modified by ethnic origin, with a gradient effect observed only among women of European origin. Women of Asian, North African and Israeli origin showed no such trend. SEP was associated with long-term breast cancer incidence and survival among Israeli Jews. Education had a stronger effect on breast cancer outcomes than occupation, suggesting that a behavioral mechanism may underlie disparities. More research is needed to explain the difference in the effect of education on survival among European women compared to women of other ethnicities.

Cardiometabolic traits pose a major global public health burden. Large-scale genome-wide association studies (GWAS) have identified multiple loci accounting for up to 30% of the genetic variance in complex traits such as cardiometabolic traits. However, the contribution of parent-of-origin effects (POEs) to complex traits has been largely ignored in GWAS. Family-based studies enable the assessment of POEs in genetic association analyses. We investigated POEs on a range of complex traits in 3 family-based studies. The discovery phase was carried out in large pedigrees from the Kibbutzim Family Study (n = 901 individuals) and in 872 parent–offspring trios from the Jerusalem Perinatal Study. Focusing on imprinted genomic regions, we examined parent-specific associations with 12 complex traits (i.e., body-size, blood pressure, lipids), mostly cardiometabolic risk traits. Forty five of the 11,967 SNPs initially found to have POE were evaluated for replication (p value < 1 × 10−4) in Framingham Heart Study families (max n = 8000 individuals). Three common variants yielded evidence of POE in the meta-analysis. Two variants, located on chr6 in the HLA region, showed a paternal effect on height (rs1042136: βpaternal = −0.023, p value = 1.5 × 10−8 and rs1431403: βpaternal = −0.011, p value = 5.4 × 10−6). The corresponding maternally-derived effects were statistically nonsignificant. The variant rs9332053, located on chr13 in RCBTB2 gene, demonstrated a maternal effect on hip circumference (βmaternal = −4.24, p value = 9.6 × 10−6; βpaternal = 1.29, p value = 0.23). These findings provide evidence for the utility of incorporating POEs into association studies of cardiometabolic traits, especially anthropometric traits. The study highlights the benefits of using family-based data for deciphering the genetic architecture of complex traits.

Recent genome-wide association studies (GWAS) have identified multiple loci associated with coronary artery disease (CAD) among predominantly Europeans. However, their relevance to multi-ethnic populations from Southeast Asia is largely unknown. We performed a meta-analysis of four GWAS comprising three Chinese studies and one Malay study (Total N = 2,169 CAD cases and 7,376 controls). Top hits ( P  < 5 × 10 −8 ) were further evaluated in 291 CAD cases and 1,848 controls of Asian Indians. Using all datasets, we validated recently identified loci associated with CAD. The involvement of known canonical pathways in CAD was tested by Ingenuity Pathway Analysis. We identified a missense SNP (rs2075291, G > T, G185C) in APOA5 for CAD that reached robust genome-wide significance ( Meta P  = 7.09 × 10 −10 , OR = 1.636). Conditional probability analysis indicated that the association at rs2075291 was independent of previously reported index SNP rs964184 in APOA5 . We further replicated 10 loci previously identified among predominantly Europeans ( P: 1.33 × 10 −7 –0.047). Seven pathways ( P : 1.10 × 10 −5 –0.019) were identified. We identified a missense SNP, rs2075291, in APOA5 associated with CAD at a genome-wide significance level and provided new insights into pathways contributing to the susceptibility to CAD in the multi-ethnic populations from Southeast Asia.