Province Lab

Michael Province, Ph.D.

Michael Province, Ph.D.

Professor of Genetics and Biostatistics Director Division of Statistical Genomics

Long Life Family Study (LLFS)

Long Life Family Study (LLFS)

Province and the Long Life Family Study (LLFS)

The Long Life Family Study (LLFS) is an international collaborative study, sponsored by the National Institute on Aging, which was started in late 2004. Recruitment and data collection for Phase I of the LLFS was completed in summer of 2009. LLFS is now entering Phase II which, in addition to ongoing participant follow-up, will begin phenotypic and genetic analysis, including sequencing under found linkage peaks. This is a very exciting time for LLFS!

CHAPS

CHARGE Adiposity Project (CHAPS)

Goals: to pursue scientific questions regarding the genetic and environmental factors associated with adiposity traits

Description:  Obesity continues to grow as a modern-day epidemic and is a strong risk factor for numerous other metabolic derangements and morbidities.  The CHARGE* Adiposity Project (CHAPS), therefore, aims to extend the statistical benefits of cohort aggregation (e.g. through meta-analysis of ~40,000 people) to adiposity traits such as body mass index (BMI, kg/m2), waist circumference (WC), waist-hip ratio (WHR), longitudinal weight change in adulthood, obesity (BMI>30 kg/m2) and extreme obesity (BMI>40 kg/m2).  Moreover, with uniquely sufficient power to detect variants influencing as little as ~1% of trait variance CHAPS can address 4 major aims beyond primary gene discovery:  CHAPS proposes to contrast the genetic architecture for adiposity traits between Caucasians and African-Americans using novel methods; to investigate a series of gene x environment interaction hypotheses, including sex, age, diet, physical activity, and smoking; to identify adiposity loci with pleiotropic effects on lipid and glucose metabolism traits in order to deconstruct the correlations among these risk factors; and to identify and test potentially sex- or race-dependent pathways with high impact on adiposity traits. This work will stimulate the discovery of variants and pathways comprising the genetic basis of obesity risk and suggest potential therapeutic targets.

*The international Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

http://www.chargeconsortium.com/_/rsrc/1473975083335/config/customLogo.gif?revision=3

 

The primary goal of the proposed research is to leverage existing GWAS and Exome Chip data in 27 large multi-ethnic cohorts to discover additional genetic loci for cardiovascular traits by modeling gene-lifestyle interactions, using pleiotropy analysis of correlated traits, and pathway analysis. The investigation will be carried out in over 150,000 samples of European Americans, African Americans, Hispanic Americans, and Asians. Approximately equal sample sizes will be used for replication.

GOLDN

GOLDN is an approved study funded by the National Institutes of Health through the University of Minnesota and in collaboration with the University of Utah, Washington University, Tufts University, University of Texas – Housten, University of Michigan, and Fairview-University Medical Center. GOLDN is part of the PROGENI Network, a group of family intervention studies focusing on gene-environment interactions.

Hypertriglyceridemia is emerging as an important predictor of atherosclerosis, and recent evidence suggests related phenotypes of triglycerides (TGs), such as TG remnant particles and small LDL particles, are particularly atherogenic. There is considerable variation in the response of TGs and related phenotypes to the environment. The aim of the proposed study is to characterize the genetic basis of the variable response of TGs to two environmental contexts, one that raises TGs (dietary fat), and one that lowers TGs (fenofibrate treatment).

We will recruit 1,200 family members from 3-generational pedigrees of the ongoing NHLBI Family Heart Study (FHS) in two genetically homogeneous centers (Minneapolis and Salt Lake City). We will collect measurements before and after a dietary fat challenge to assess postprandial TGs and related atherogenic phenotypes (VLDL TGs, chylomicron TGs, TG remnant particles, HDL and LDL particle sizes, total cholesterol, LDL-C, and HDL-C). In addition, every subject will participate in a three week unblinded clinical trial of treatment (micronized fenofibrate, 160 mg).

Many family members were genotyped by the Mammalian Genotyping Service (MGS; Marshfield WI) as part of NHLBI FHS; the remaining will be typed using the same marker set. We will conduct genome-wide linkage analyses using state-of-the-art methods to localize novel genetic loci contributing to TG response in the context of fat loading and fenofibrate treatment. We will type 15 single nucleotide polymorphisms (SNPs) in ten candidate genes known to contribute to the response of TGs to dietary fat and fenofibrate, and create haplotypes for association studies. We will use combinatorial partitioning methods and neural networks to test association of the individual SNPs and haplotypes with response to the two environmental interventions. The identification of genetic loci that predict TG response in the presence of two disparate contexts, fat loading and fibrate therapy, may provide insights into genetic pathways (a) predisposing to hypertriglyceridemia, ultimately leading to avenues for primary prevention, and (b) predicting response to TG lowering, leading to new drug targets for hypertriglyceridemia.

Family Heart Study (FAMHS)

Mike Province and the Family Heart Study (FamHS)

Goals:  To determine the genetic and non-genetic determinants of coronary heart disease.

Description: The NHLBI Family Heart Study (FamHS) is a multicenter, population-based study of genetic and non-genetic determinants of coronary heart disease (CHD), atherosclerosis, and cardiovascular risk factors. Phase I was conducted from 1992 to 1995. First, 2,000 randomly selected participants and 2,000 participants with family histories of CHD were identified among 14,592 middle-aged participants.  The parent epidemiologic studies were in four geographically dispersed field centers.  Medical histories from these individuals, their parents, and their siblings were used to calculate family risk scores that compared the number of reported and validated CHD events with the number expected based on the size, sex, and age of family members. Next, a total of 541 randomly sampled families (2673 individuals), and 610 families (3037 individuals) with the highest risk scores, had clinic examinations.  The study recruited parents, siblings, spouse, and children (age >=25) of the probands in the above families. The clinic examination included electrocardiograms, carotid artery ultrasound scans, spirometry, body size measurements, blood pressure, lipids, lipoproteins, hemostatic factors, insulin, glucose, and routine chemistries.   In addition, data on lifestyle, diet, exercise, and psychosocial indicators were collected.  Participants also provided their medications for documentation and categorization.

Phase II of FamHS constituted the FamHS SCAN Study (Family Heart Study – Subclinical Coronary Atherosclerosis Network).  The 3,000 subjects from the largest FamHS pedigrees were invited back for a second clinic exam about eight years later.  In this exam, the major heart disease risk factors were re-assessed (including metabolic, behavioral, and environmental data) along with additional measures of subclinical atherosclerosis (coronary and aortic artery calcium volume) and inflammatory response.  2,756 individuals participated (including some new family members not previously examined).  In addition, a fifth field center was added where 633 African American individuals, previously examined and comparably genotyped by the HyperGEN network of the Family Blood Pressure Program, were enrolled to address the study questions in this minority population.

The FamHS has identified major linkage peaks for genomic regions predisposing to heart disease pathway phenotypes, which has resulted in three R01s to positionally clone QTLs for heart disease risk factors.

Key References:

Higgins, et al, 1996: http://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=8651220&ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

 

Mike Province and the Dark Matter Study

Recent large scale GWAS, including ours in the NHLBI Family Heart Study (FamHS), have identified and validated many loci for heart disease phenotypes at GW levels of significance. Yet the importance of these loci remains uncertain as nearly all appear to explain minimal amounts of the variance for the traits studied. A number of large scale exome sequencing projects are now being conducted on case-control cohorts to address whether rare coding variants may be behind this “missing heritability”. But so far, signals have been difficult to distinguish from noise, partly due to a large number of evolutionarily recent variants found in human populations (e.g. Coventry et al., 2010). For such nearly private, lineage-specific mutations, unrelated case-control studies result in a large number of singleton variants with low individual power, and which collectively pose a challenge to burden testing. The recently developed “exome-chip” addresses part of this problem by focusing on the “not so rare” exonic variants (seen in multiple unrelated subjects), but neglects the evolutionarily recent lineage-specific exonic variants which the Fisher-Wright model predicts would have the greatest penetrance effects. More importantly, the exclusive focus on exonic variation in both case-control sequencing and exome chip studies ignores regulatory variants, which may be most important to many of the quantitative endophenotypes of cardiovascular disease (e.g. serum lipids, cytokines, obesity, CAC).

To address these research gaps, we propose using the large, well characterized family study, FamHS, as a platform for Whole Exome Sequencing (WES), plus Targeted Regulatory Sequencing (TRS) for variants associated with cardiovascular disease, atherosclerosis and associated endophenotypes. The FamHS represents the ideal resource for the proposed studies, having a unique combination of features which no other NHLBI cohort possesses. Results from GAW 17 show (Wilson and Ziegler, 2011), and our own simulations confirm, that family studies have greater power to detect near-private, lineage-specific rare variants than studies of unrelated subjects, allowing us greater ability to detect novel associated exonic variants than the current case-control WES and exome chip studies. Further, our FamHS pedigrees continue to show provocatively strong, independently replicated linkage evidence for a variety of cardiovascular traits, unexplained by GWAS SNPs, suggesting that these particular regions may contain rare coding and/or regulatory variants. We propose a two-stage, WES+TRS experiment on all N=5,763 European-Americans (EAs) (in 1,253 families) from the extensively phenotyped FamHS cohort. In Stage 1, we will obtain WES information for 3,389 FamHS EAs comprising the largest 491 pedigrees (mean family size=6.9), to scan for novel rare coding/regulatory variants for CHD, atherosclerosis, and their risk factor phenotypes, such as obesity, hypertension, dyslipidemia, diabetes, insulin resistance, and inflammation. In Stage 2, we will validate these regions by sequencing all implicated loci in the remaining independent FamHS subjects (N=2,374 EAs in 660 families). We will also validate these findings in the N=622 (F=221 families) African-Americans in FamHS by conducting parallel WES+TRS.

Family Heart Study SCAN

Mike Province and the Family Heart Study (FamHS)

Goals:  To determine the genetic and non-genetic determinants of coronary heart disease.

Description: The NHLBI Family Heart Study (FamHS) is a multicenter, population-based study of genetic and non-genetic determinants of coronary heart disease (CHD), atherosclerosis, and cardiovascular risk factors. Phase I was conducted from 1992 to 1995. First, 2,000 randomly selected participants and 2,000 participants with family histories of CHD were identified among 14,592 middle-aged participants.  The parent epidemiologic studies were in four geographically dispersed field centers.  Medical histories from these individuals, their parents, and their siblings were used to calculate family risk scores that compared the number of reported and validated CHD events with the number expected based on the size, sex, and age of family members. Next, a total of 541 randomly sampled families (2673 individuals), and 610 families (3037 individuals) with the highest risk scores, had clinic examinations.  The study recruited parents, siblings, spouse, and children (age >=25) of the probands in the above families. The clinic examination included electrocardiograms, carotid artery ultrasound scans, spirometry, body size measurements, blood pressure, lipids, lipoproteins, hemostatic factors, insulin, glucose, and routine chemistries.   In addition, data on lifestyle, diet, exercise, and psychosocial indicators were collected.  Participants also provided their medications for documentation and categorization.

Phase II of FamHS constituted the FamHS SCAN Study (Family Heart Study – Subclinical Coronary Atherosclerosis Network).  The 3,000 subjects from the largest FamHS pedigrees were invited back for a second clinic exam about eight years later.  In this exam, the major heart disease risk factors were re-assessed (including metabolic, behavioral, and environmental data) along with additional measures of subclinical atherosclerosis (coronary and aortic artery calcium volume) and inflammatory response.  2,756 individuals participated (including some new family members not previously examined).  In addition, a fifth field center was added where 633 African American individuals, previously examined and comparably genotyped by the HyperGEN network of the Family Blood Pressure Program, were enrolled to address the study questions in this minority population.

The FamHS has identified major linkage peaks for genomic regions predisposing to heart disease pathway phenotypes, which has resulted in three R01s to positionally clone QTLs for heart disease risk factors.

Key References:

Higgins, et al, 1996: http://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=8651220&ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum