Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD

“I haven't even taken them to the doctors, because I have that fear of what to expect”: a qualitative description study exploring perceptions and experiences of early childhood healthcare among ethnically diverse caregivers in Aotearoa New ZealandResearch in context

Summary: Background: Equity underpins Aotearoa New Zealand's publicly funded healthcare system; however, ethnic inequality persists. This qualitative study explored the perceptions and experiences of ethnically diverse parents accessing health services for their children. Methods: A qualitative description methodology informed interviews and focus groups that were conducted with caregivers of preschool aged children who identified as being of Māori, Pacific, Asian and/or European ethnicity (n = 145). Data were analysed following a reflexive thematic analytic approach. Findings: Five themes were constructed. Hierarchies of knowledge and trust Caregivers relied on multiple sources of health information and particularly trusted providers or other caregivers who had children. Relational versus transactional health encounters Caregivers were often disappointed that health providers did not build trusting relationships to support positive experiences. Bad mother vibe Mothers often felt judged by providers when accessing care and felt pressure to conform. The ‘slow burn’ of waiting Caregivers were often frustrated by how slow and fragmented the health system was, which was particularly distressing if their child was unwell or required referral. Navigating complexity Caregivers had to be proactive and assertive to ensure their child received care amidst the numerous barriers they faced, including discrimination and bias. While many commonalities were shared by ethnicity, unique to Indigenous Māori caregivers were the ongoing colonial traumas that impacted their ability to trust the healthcare system. Interpretation: A non-judgemental, competent, and culturally sensitive approach by healthcare professionals and services may help foster trusting relationships and positive health encounters. Strategies to improve trust, ease of access and navigation are needed to mitigate existing complexity, fragmentation, and counter-intuitive nature of the NZ healthcare system. Caregivers require more autonomy over decisions about their child's care and availability of services that reflect their cultural values. Policies are required to alleviate the indirect costs of accessing healthcare, prioritising of whānau/family-centred care, and addressing pervasive racism and bias within the system. Funding: Health Research Council of New Zealand (19/263)

Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD. Copyright © 2022 The Authors, some rights reserved

The impact of global and local Polynesian genetic ancestry on complex traits in Native Hawaiians.

Epidemiological studies of obesity, Type-2 diabetes (T2D), cardiovascular diseases and several common cancers have revealed an increased risk in Native Hawaiians compared to European- or Asian-Americans living in the Hawaiian islands. However, there remains a gap in our understanding of the genetic factors that affect the health of Native Hawaiians. To fill this gap, we studied the genetic risk factors at both the chromosomal and sub-chromosomal scales using genome-wide SNP array data on ~4,000 Native Hawaiians from the Multiethnic Cohort. We estimated the genomic proportion of Native Hawaiian ancestry ("global ancestry," which we presumed to be Polynesian in origin), as well as this ancestral component along each chromosome ("local ancestry") and tested their respective association with binary and quantitative cardiometabolic traits. After attempting to adjust for non-genetic covariates evaluated through questionnaires, we found that per 10% increase in global Polynesian genetic ancestry, there is a respective 8.6%, and 11.0% increase in the odds of being diabetic (P = 1.65×10-4) and having heart failure (P = 2.18×10-4), as well as a 0.059 s.d. increase in BMI (P = 1.04×10-10). When testing the association of local Polynesian ancestry with risk of disease or biomarkers, we identified a chr6 region associated with T2D. This association was driven by an uniquely prevalent variant in Polynesian ancestry individuals. However, we could not replicate this finding in an independent Polynesian cohort from Samoa due to the small sample size of the replication cohort. In conclusion, we showed that Polynesian ancestry, which likely capture both genetic and lifestyle risk factors, is associated with an increased risk of obesity, Type-2 diabetes, and heart failure, and that larger cohorts of Polynesian ancestry individuals will be needed to replicate the putative association on chr6 with T2D