Monique M. Hedderson, Ph.D. - US grants

DESCRIPTION (provided by applicant): Gestational diabetes mellitus (GDM) has short and long-term consequences for both the mother and her offspring. Women with GDM are more likely to deliver a large for gestational (LGA) infant and up to 50% of them will develop type 2 diabetes. However, up to half of women with GDM have no known risk factors, suggesting that other factors must be involved. Biomarkers associated with various metabolic pathways (insulin resistance, inflammation and oxidative stress) might be useful for identifying women at risk of GDM who could be targeted for prevention and may also further our understanding of the pathophysiology of GDM and its consequences. The metabolic and hormonal changes intrinsic to pregnancy make it important to assess these metabolic biomarkers before pregnancy to determine the temporal sequence of the associations. In three primary aims we propose to evaluate whether biomarkers of: 1) insulin resistance (adiponectin, HMW adiponectin, Fetuin-A and LDL-C particle size), 2) inflammation (CRP), and 3) oxidative stress (GGT) assessed before pregnancy, are associated with increased risk GDM. We will explore in the secondary aims whether: 4) pregravid levels of adiponectin and its isoforms are associated with the risk of having a LGA infant and whether this association is mediated by GDM;5) among the women with GDM, pre-gravid levels of biomarkers of insulin resistance, inflammation, and oxidative stress and their long-term changes are associated with T2DM and degree of insulin resistance. We propose a nested case-control study within a multi-ethnic cohort of 4,084 women who took part in the Kaiser Permanente Northern California (KPNC) multiphasic health checkup (MHC) exam between 1984-1996, had serum samples stored, and had a subsequent pregnancy. We will study 235 women with GDM and 470 normoglycemic control women matched on year of MHC exam, age at MHC exam and age at pregnancy. No studies to date have examined biomarkers of metabolic risk before pregnancy and risk of GDM. This study will fill a gap in scientific knowledge by determining if pregravid biomarkers, measured among healthy young women, are associated with the risk of GDM, a metabolic alteration occurring early in life. This research could have translational value in the prevention of GDM its progression to T2DM, and health sequelae in their offspring. PUBLIC HEALTH RELEVANCE: The incidence of GDM is increasing in the United States, however much remains unknown about its underlying cause. This study will determine for the first time if the proposed pregravid biomarkers measured among healthy young women are associated with the risk of GDM, excessive fetal growth (LGA) and progression to type 2 diabetes. Identification of pregravid metabolic biomarkers of GDM and its adverse health consequences may give insights to the underlying causes leading to the development of GDM and its consequences. This information can be used to inform strategies for GDM and diabetes prevention.

? DESCRIPTION (provided by applicant) Metformin, a biguanide, is used as first-line therapy to treat type 2 diabetes (T2D), yet over 35% of patients on metformin monotherapy fail to achieve acceptable glycemic control. In addition, studies indicate that there are profound inter-ethnic differences in the pharmacokinetics and pharmacodynamics of metformin, and that genetic factors contribute to metformin response. To date, there has been only a single published genomewide association study (GWAS) of metformin response in Europeans, and no GWAS in other ethnic The major goal of our study is to identify the genetic loci and pathways that confer nonresponse to metformin in a large multi-ethnic cohort of T2D patients on metformin. Our second goal is to identify rare causal variants that underlie variation in response to metformin through detailed cellular and clinical studies. To this end, we have assembled rich and diverse clinical cohorts including two groups. large multi-ethnic cohorts of patients with T2D on metformin who have provided DNA samples and clinical information (N = 15,000) made available largely through partnerships with the Kaiser Permanente Northern California (KPNC) Research Program on Genes, Environment and Health (RPGEH) and MetGen, an international consortium, which includes multiple cohorts from Europe and the U.S. of patients on metformin (N ~ 10,000). Our overall aims are to: Aim 1. Identify genetic variants that impact response to metformin in 28,000 participants from multiple ethnic groups in the U.S. and Europe; and Aim 2. Identify the causal variants of genes discovered in Aim 1, using a multi-tier approach. In particular, we will first use genomewide approaches with meta analyses to discover variants that underlie variation in response to metformin. Next targeted resequencing will be used to associate rare variants in genes that are identified in our GWAS with metformin response. Functional genomic studies in cells will be performed to identify functional variants, which will then be associated with metformin response in our clinical cohorts. Finally, in Aim 3, we will conduct endophenotypic clinical studies to determine clinical measurements of insulin sensitivity and glucose tolerance to understand the mechanisms through which the variants modulate metformin response. Collectively, this research proposal provides a robust multi-tier approach beginning with the largest cohort of patients with T2D on metformin to identify rare and common genetic variants that underlie variation in response to metformin and importantly, to understand their mechanisms. Data generated in this project will contribute enormously to predictive models that ultimately will be used for data-driven prescribing and precision medicine for anti- diabetic drug therapy.

? DESCRIPTION (provided by applicant) Metformin, a biguanide, is used as first-line therapy to treat type 2 diabetes (T2D), yet over 35% of patients on metformin monotherapy fail to achieve acceptable glycemic control. In addition, studies indicate that there are profound inter-ethnic differences in the pharmacokinetics and pharmacodynamics of metformin, and that genetic factors contribute to metformin response. To date, there has been only a single published genomewide association study (GWAS) of metformin response in Europeans, and no GWAS in other ethnic The major goal of our study is to identify the genetic loci and pathways that confer nonresponse to metformin in a large multi-ethnic cohort of T2D patients on metformin. Our second goal is to identify rare causal variants that underlie variation in response to metformin through detailed cellular and clinical studies. To this end, we have assembled rich and diverse clinical cohorts including two groups. large multi-ethnic cohorts of patients with T2D on metformin who have provided DNA samples and clinical information (N = 15,000) made available largely through partnerships with the Kaiser Permanente Northern California (KPNC) Research Program on Genes, Environment and Health (RPGEH) and MetGen, an international consortium, which includes multiple cohorts from Europe and the U.S. of patients on metformin (N ~ 10,000). Our overall aims are to: Aim 1. Identify genetic variants that impact response to metformin in 28,000 participants from multiple ethnic groups in the U.S. and Europe; and Aim 2. Identify the causal variants of genes discovered in Aim 1, using a multi-tier approach. In particular, we will first use genomewide approaches with meta analyses to discover variants that underlie variation in response to metformin. Next targeted resequencing will be used to associate rare variants in genes that are identified in our GWAS with metformin response. Functional genomic studies in cells will be performed to identify functional variants, which will then be associated with metformin response in our clinical cohorts. Finally, in Aim 3, we will conduct endophenotypic clinical studies to determine clinical measurements of insulin sensitivity and glucose tolerance to understand the mechanisms through which the variants modulate metformin response. Collectively, this research proposal provides a robust multi-tier approach beginning with the largest cohort of patients with T2D on metformin to identify rare and common genetic variants that underlie variation in response to metformin and importantly, to understand their mechanisms. Data generated in this project will contribute enormously to predictive models that ultimately will be used for data-driven prescribing and precision medicine for anti- diabetic drug therapy.

Excessive gestational weight gain (GWG), defined as GWG above the current Institute of Medicine (IOM) GWG guidelines is associated with adverse short and long-term health complications for women and their infants. Overweight and obese women are at already at high risk of complications due to their elevated weight, and excessive GWG further exacerbates their high risk of complications. Thus, there is an urgent need to help reduce excessive GWG in this high-risk population. Traditional high-intensity interventions to improve GWG among overweight and obese women have achieved success but are too time intensive for some women. In addition, studies show women consider behavior change advice to be more persuasive if it comes from their clinician, but clinicians have insufficient training on weight counseling. Thus, interventions aimed at reducing excess GWG among overweight and obese women that are practical for both women and clinicians are needed. Emerging evidence and our pilot work suggest that mobile health (mHealth) interventions for weight management can be effective in pregnancy, but a large-scale randomized trial in the real-world clinical setting is needed. We will conduct a cluster randomized controlled trial of 56 clinicians (caring for 2040 pregnant overweight/obese women) randomized to usual care or usual care plus an mHealth intervention. We propose an adaptive intervention that increases in intensity according to patients? GWG in relation to the IOM guidelines. Technology-based tools?including a mobile app, wireless ?smart? scale, wearable activity tracker, and diet tracking app?will enable convenient self-monitoring, feedback, and goal setting. These tools will provide largely automated, real-time feedback to patients via text messaging and will transmit real-time GWG, physical activity and diet data to a lifestyle coach and obstetric clinician. All patients of clinicians in the intervention, receive the technology-based tools, automated text messages and weekly e-mails of core lifestyle intervention sessions (Step 1). Step 2 is the addition of personalized text messages; and Step 3 is the addition of personalized 1:1 telephone coaching sessions, with these latter 2 Steps reserved for patients who need them. Clinicians in the intervention also receive training and tools embedded in the EHR to facilitate discussing GWG with their patients. Our primary aim is to evaluate whether an adaptive mHealth intervention designed to help overweight/obese women and their clinicians manage GWG will improve GWG in comparison to usual care. Our secondary aim will evaluate whether an mHealth intervention improves postpartum weight retention at 6 weeks, the proportion of infants with appropriate birthweight (<10th and >90th percentile) and infant growth trajectory from birth to 12 months. We will evaluate the cost-effectiveness of the mHealth intervention and possible adoption using a RE-AIM framework. If this mHealth intervention is proven effective, it could become a complementary part of clinical care, leading to better outcomes for mothers and their infants.

Discovery of Pharmacogenomic Biomarkers for OATP1B1 and OATP1B3 In marked contrast to the plethora of genome-wide association studies (GWAS) focused on human disease, there has been a dearth of GWAS focused on pharmacogenomic traits such as variation in drug response and toxicity. Further, many of the pharmacogenomic GWAS have been underpowered and therefore few genetic variants at genomewide levels of significance have been discovered. Among the world's most widely prescribed drugs, sulfonylureas are associated with great inter-individual variation in response, with ~35% of patients with type 2 diabetes failing therapy after 5 years and frequently needing insulin therapy to achieve acceptable glycemic control. In exciting preliminary GWAS focused on response to sulfonylureas, we discovered a strong association between change in glycated hemoglobin levels (HbA1c) on sulfonylureas and a SNP in the SLCO1B1/1B3 locus encoding the transporters OATP1B1 and OATP1B3 at genome-wide levels of significance (p=4.8×10-8, N = 5,479). The major goals of this competing renewal application are to determine the pharmacologic mechanisms by which OATP1B1 and OATP1B3 associate with response to sulfonylureas, discover and validate selective biomarkers for the transporters and discover other genes that associate with response to sulfonylureas. To achieve our goals, we will use two large clinical resources: MetGen PLUS, a large multi-ethnic international consortium, established during this granting period and SUGAR-MGH, a rich deeply phenotyped consortium of healthy volunteers, which can be used to probe clinical pharmacokinetic and pharmacodynamic mechanisms. Three specific aims are proposed. In aim 1, we will employ a genome-wide approach in MetGen PLUS to identify common genetic variants in SLCO1B1/1B3 and other genes that impact response to sulfonylureas. In aim 2, we will identify the causal variants in the SLCO1B1/1B3 locus associated with drug response, using a multi-tiered approach, beginning with targeted resequencing of the SLCO1B3/1B1 locus and extending through detailed functional genomic studies in cells and in samples obtained from healthy volunteers in SUGAR-MGH. Finally, in aim 3, we will discover and validate metabolomic biomarkers of SLCO1B3 that can be used as tools to predict OATP1B3 activity including OATP1B3-mediated drug-drug interactions for a wide range of prescription drugs that are substrates, inhibitors or inducers of the transporter. Our proposed methods range from genomewide association and NextGen sequencing studies and analyses in large cohorts of patients to high throughput functional genomic and metabolomic studies in cellular assays to clinical pharmacokinetic studies in healthy volunteers. We postulate that this comprehensive genomic, metabolomic and functional approach including deep clinical phenotyping will serve as a blueprint for systematic evaluations of other drugs, paving the way for precision therapeutics.

PROJECT SUMMARY Despite widespread publicity of the obesity epidemic in the US and other developed countries, its prevalence remains unabated. With almost 20% of children and adolescents and 40% of adults in the US with obesity, we face a public health crisis. Blacks, Hispanics, and people with low socioeconomic status are disproportionately affected. Multi-level and multi-pronged approaches are needed to stem this epidemic. One recommended approach is population-based strategies that make it easier for people to make more healthful choices. One such strategy is imposing taxes to reduce consumption of sugar-sweetened beverages (SSB). Not only are SSB the largest contributor of added sugar in the US diet and have been tied to obesity and its comorbidities, but national survey data suggest that ½ of adults and 2/3 of youth consume at least one SSB on a given day. If taxes can reduce SSB consumption, it follows that obesity prevalence will fall, along with obesity-related diseases. In Berkeley, CA (the first city to levy a SSB tax [in 2015]) SSB sales declined 9.6% and SSB consumption declined 19.8% in the first year after tax implementation. There are indications that effects were greater in low-income neighborhoods. We propose to evaluate the natural experiment of SSB taxes on weight change in youth and adults and to explore possible effects on glycated hemoglobin (HbA1c) levels and diabetes incidence among a cohort of adults with prediabetes. Oakland, Albany, and San Francisco have also levied an excise tax on SSB ? cities in which a large number of residents are patients (approximately 230,000 adults and 50,000 youth) of Kaiser Permanente Northern California (KPNC). Using our electronic medical records (EMR), we will examine body mass index (BMI; kg/m2) trajectories, HbA1c levels, and incidence of diabetes prior and after initiation of SSB taxes, using two different analyses (synthetic controls and differences in differences) to optimize the rigor of our results. KP patients living in Northern California and Southern California cities comparable to cities with a SSB tax will be used as controls. We hypothesize that cities with a SSB tax will experience favorable changes in BMI, HbA1c, and diabetes incidence compared with comparison cities. Our specific aims are to 1) Examine differences in BMI trajectories and prevalence of overweight and obesity before and after implementation of a SSB tax among youth and adults separately in California cities with and without a SSB tax. 2) Assess how youth and adult characteristics, such as age, race/ethnicity, BMI category, and neighborhood socioeconomic status, may modify the impact of SSB taxes on BMI and prevalence of overweight and obesity. 3) Explore differences in mean HbA1c levels and diabetes incidence among an age/sex/race/BMI and neighborhood socioeconomic status matched cohort of adults with prediabetes who live and do not live in SSB tax cities. This information is needed to guide health advocates and policy makers with respect to the role of SSB taxes in obesity prevention.

PROJECT SUMMARY This U19 application, referred to as SWAN-Aging, is designed to determine the extent to which midlife health, and specifically the menopause transition (MT), affects successful aging in women. This proposal capitalizes on the rich resources of the Study of Women's Health Across the Nation (SWAN), a longitudinal cohort study initiated in 1994 to characterize the physiological and psychosocial changes that occur during the MT. A total of 3302 Black, Chinese, Japanese, Hispanic and White women were enrolled at seven sites, with 74% of still- living women completing up to 16 visits spanning the pre-menopause to post-menopause. SWAN has described the natural history of the MT -- its timing, patterns of hormonal changes, and symptoms ? and their relation to midlife health indicators. In SWAN-Aging, we will extend follow-up of the SWAN cohort into early old age (66-75 years) and will prospectively link comprehensive longitudinal characterization of both the MT and midlife health indicators to functioning and health across multiple domains in early old age, a pivotal time of transition into old age when adverse changes in health and functioning begin to accumulate. The global specific aims of this U19 application are to: 1) determine the impact of MT characteristics and trajectories of midlife health indicators on the preservation of cognitive, physical, genitourinary, sexual, and psychosocial function and sleep in early old age; 2) determine the impact of MT characteristics and trajectories of midlife health indicators on risk of adverse health outcomes, including falls, osteoporosis and fractures, poor cardiometabolic function, cardiovascular events and early mortality; 3) determine if racial/ethnic disparities in health and functioning in early old age are attributable to midlife racial/ethnic differences in MT characteristics and midlife health indicators; and 4) translate the SWAN and SWAN-Aging findings for women and their health care providers. These aims will be achieved through three integrated scientific Projects that are organized around key health domains (functioning, cardiometabolic health and musculoskeletal health) and linked by a common focus on MT characteristics and midlife changes in health indicators as key exposures. The three Projects will be supported by three Cores which will a) provide the necessary organizational infrastructure to conduct this study and to disseminate results to the research and medical communities; b) conduct accurate, high volume assays, adopting new methods as needed to provide state-of-the-art laboratory data, and c) oversee the design and conduct of the core clinic visit, data collection and data management, and the creation of the analytic datasets. SWAN-Aging will include one clinic visit and a National Death Index search to ensure complete mortality ascertainment for the cohort. SWAN-Aging is uniquely positioned to fill important scientific gaps in understanding of the impact of the MT and midlife indicators on women's health and functioning in early old age and to facilitate the application of new knowledge to clinical practice. This study will provide valuable insights into modifiable factors relevant to the design of future prevention and treatment programs.