OBJECTIVE Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters labeled: β-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed. RESEARCH DESIGN AND METHODS Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) and tested for cross-sectional association with T2D-related outcomes, including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD). RESULTS Despite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. Increased obesity and lipodystrophy cluster pPS, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The lipodystrophy and liver/lipid cluster pPS were each associated with CAD, with increasing and decreasing effects, respectively. An increased liver/lipid cluster pPS was also significantly associated with reduced renal function. The liver/lipid cluster includes known loci linked to liver lipid metabolism (e.g., GCKR, PNPLA3, and TM6SF2), and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway. CONCLUSIONS Our findings support that genetically driven pathways leading to T2D also predispose differentially to clinical outcomes.

Genome-wide scans have shown that common risk alleles for orofacial clefts (OFC) tend to be located in noncoding regulatory elements and cumulatively explain only part of the heritability of OFCs. Low-frequency variants may account for some of the "missing" heritability. Therefore, we scanned low-frequency variants located within putative craniofacial enhancers to identify novel OFC risk variants and implicate new regulatory elements in OFC pathogenesis. Analyses were performed in a multiethnic sample of 1,995 cases of cleft lip with or without cleft palate (CL/P), 221 cases with cleft palate (CP) only, and 1,576 unaffected controls. One hundred and nineteen putative craniofacial enhancers identified from ChIP-Seq studies in craniofacial tissues or cell lines contained multiple low-frequency (0.01-1%) variants, which we genotyped in participants using a custom Illumina panel. Two complementary statistical approaches, sequence kernel association test and combined multivariate and collapsing, were used to test association of the aggregated low-frequency variants across each enhancer region with CL/P and CP. We

For the past 30 years, there has been a lack of objective tools for diagnosing Gulf War Illness (GWI), which is largely characterized by central nervous system (CNS) symptoms emerging from 1991 Gulf War (GW) veterans. In a recent preliminary study, we reported the presence of autoantibodies against CNS proteins in the blood of veterans with GWI, suggesting a potential objective biomarker for the disorder. Now, we report the results of a larger, confirmatory study of these objective biomarkers in 171 veterans with GWI compared to 60 healthy GW veteran controls and 85 symptomatic civilian controls (n = 50 myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and n = 35 irritable bowel syndrome (IBS)). Specifically, we compared plasma markers of CNS autoantibodies for diagnostic characteristics of the four groups (GWI, GW controls, ME/CFS, IBS). For veterans with GWI, the results showed statistically increased levels of nine of the ten autoantibodies against neuronal “tubulin, neurofilament protein (NFP), Microtubule Associated Protein-2 (MAP-2), Microtubule Associated Protein-Tau (Tau), alpha synuclein (α-syn), calcium calmodulin kinase II (CaMKII)” and glial proteins “Glial Fibrillary Acidic Protein (GFAP), Myelin Associated Glycoprotein (MAG), Myelin Basic Protein (MBP), S100B” compared to healthy GW controls as well as civilians with ME/CFS and IBS. Next, we summed all of the means of the CNS autoantibodies for each group into a new index score called the Neurodegeneration Index (NDI). The NDI was calculated for each tested group and showed veterans with GWI had statistically significantly higher NDI values than all three control groups. The present study confirmed the utility of the use of plasma autoantibodies for CNS proteins to distinguish among veterans with GWI and other healthy and symptomatic control groups.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI) such as those from American football. Our understanding of this association is based on research in autopsied brains since CTE can only be diagnosed postmortem. Such studies are susceptible to selection bias, which needs to be accounted for to ensure a generalizable estimate of the association between RHI and CTE. We evaluated the relationship between level of American football play and CTE diagnosis after adjusting for selection bias. The sample included 290 deceased male former American football players who donated their brain to the Veterans Affairs-Boston University-Concussion Legacy Foundation Brain Bank (VA-BU-CLF) between 2008 and 2019. After adjusting for selection bias, college and professional football players have 2.38 (95% simulation interval (SI): 1.16,5.94) and 2.47 (95% SI: 1.46,4.79) times the risk of being diagnosed with CTE relative to high school players, respectively, which are larger than estimates with no selection bias adjustment. Since CTE is currently diagnosed only post-mortem, we additionally provide plausible scenarios for the risk ratios of these populations where we consider the outcome affecting former players during their lifetime. In conclusion, this study provides further evidence to support a dose-response relationship between football play and CTE.

<a><i>Objective</i>: Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters: Beta cell, Proinsulin, Obesity, Lipodystrophy, and Liver/Lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed. </a> <p><i>Research Design and Methods</i>: Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in twelve studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n=454,193) and tested for cross-sectional association with T2D-related outcomes including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD). </p> <p><i>Results</i>: Despite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. <a>Increased Obesity and Lipodystrophy cluster pPS’s, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The Lipodystrophy and Liver/Lipid cluster pPS’s were each associated with CAD, with increasing and decreasing effects respectively. An increased Liver/Lipid cluster pPS was also significantly associated with reduced renal function. </a>The Liver/Lipid cluster includes known loci linked to liver lipid metabolism (e.g. <i>GCKR</i>, <i>PNPLA3,</i> and <i>TM6SF2)</i>, and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway. </p> <p><i>Conclusion</i>: Our findings support that genetically-driven pathways leading to T2D also predispose differentially to clinical outcomes. </p> <b><br> </b> <p><b> </b></p>

BACKGROUND: Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare, fatal, premature aging disease caused by a toxic protein called progerin. Circulating progerin has not been previously detected, precluding research using readily available biological samples. This study aimed to develop a plasma progerin assay to evaluate progerin’s quantity, response to progerin-targeted therapy, and relationship to patient survival. METHODS: Biological samples were collected by The Progeria Research Foundation Cell and Tissue Bank from a non-HGPS cohort cross-sectionally and a HGPS cohort longitudinally. HGPS donations occurred at baseline and intermittently while treated with farnesylation inhibitors lonafarnib±pravastatin and zoledronate, within 3 sequential open-label clinical trials at Boston Children’s Hospital totaling >10 years of treatment. An ultrasensitive single-molecule counting progerin immunoassay was developed with prespecified performance parameters. Intra- and interpatient group statistics were descriptive. The relationship between progerin and survival was assessed by using joint modeling with time-dependent slopes parameterization. RESULTS: The assay’s dynamic detection range was 59 to 30 000 pg/mL ( R 2 =0.9987). There was no lamin A cross-reactivity. Mean plasma progerin in non-HGPS participants (n=69; 39 male, 30 female; age, 0.2–71.3 years) was 351±251 pg/mL, and in drug-naive participants with HGPS (n=74; 37 female, 37 male; age, 2.1–17.5 years) was 33 261±12 346 pg/mL, reflecting a 95-fold increase in affected children ( P <0.0001). Progerin levels did not differ by sex ( P =0.99). Lonafarnib treatment resulted in an average per-visit progerin decrease from baseline of between 35% to 62% (all P <0.005); effects were not augmented by adding pravastatin and zoledronate. Progerin levels fell within 4 months of therapy and remained lower for up to 10 years. The magnitude of progerin decrease positively associated with patient survival ( P <0.0001; ie, 15 000 pg/mL decrease yields a 63.9% decreased risk of death). For any given decrease in progerin, life expectancy incrementally increased with longer treatment duration. CONCLUSIONS: A sensitive, quantitative immunoassay for progerin was developed and used to demonstrate high progerin levels in HGPS plasma that decreased with lonafarnib therapy. The extent of improved survival was associated with both the magnitude of progerin decrease and duration at lower levels. Thus, plasma progerin is a biomarker for HGPS whose reduction enables short- and long-term assessment of progerin-targeted treatment efficacy. REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT00879034 and NCT00916747

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Based on the framework of gene–environment interactions (G  E), the gene–culture interaction framework demonstrates that a more complete understanding of thoughts and behaviors relevant to health may come from incorporating both genetic and cultural factors. Genes may interact with culture such that genetic predispositions lead to different outcomes depending on culture, and cultural differences on a given outcome may vary depending on genetic predispositions. We provide an overview of G  E research and some of the underlying biological mechanisms of these interactions. We explain the gene–culture interaction framework and discuss how culture is an important form of environment to consider that makes theoretical contributions unique from other forms of environment typically studied in G  E research. We discuss theoretical questions raised by gene–culture interaction research and specify how the gene–culture interaction framework can be applied to certain health issues.