Toward clinical genomics in everyday medicine: perspectives and recommendations.

Precision or personalized medicine through clinical genome and exome sequencing has been described by some as a revolution that could transform healthcare delivery, yet it is currently used in only a small fraction of patients, principally for the diagnosis of suspected Mendelian conditions and for targeting cancer treatments. Given the burden of illness in our society, it is of interest to ask how clinical genome and exome sequencing can be constructively integrated more broadly into the routine practice of medicine for the betterment of public health. In November 2014, 46 experts from academia, industry, policy and patient advocacy gathered in a conference sponsored by Illumina, Inc.

Clinical application of pharmacogenetics: focusing on practical issues.

Recent large-scale genetic-based studies have transformed the field of pharmacogenetics to identify, characterize and leverage genetic information to inform patient care. Genetic testing can be used to alter drug selection, optimize drug dosing and prevent unnecessary adverse events. As precision medicine becomes the mainstay in the clinic, it becomes critical for clinicians to utilize pharmacogenetics to guide patient care.

Genomic medicine: a decade of successes, challenges, and opportunities.

Genomic medicine--an aspirational term 10 years ago--is gaining momentum across the entire clinical continuum from risk assessment in healthy individuals to genome-guided treatment in patients with complex diseases. We review the latest achievements in genome research and their impact on medicine, primarily in the past decade. In most cases, genomic medicine tools remain in the realm of research, but some tools are crossing over into clinical application, where they have the potential to markedly alter the clinical care of patients.

Pleiotropy and allelic heterogeneity in the TOMM40-APOE genomic region related to clinical and metabolic features of hepatitis C infection.

Hepatitis C virus (HCV) modulates host lipid metabolism as part of its lifecycle and is dependent upon VLDL for co-assembly and secretion. HCV dyslipidemia is associated with steatosis, insulin resistance, IL28B genotype and disease progression. Apolipoprotein E (ApoE) is an important lipid transport protein, a key constituent of VLDL, and is involved in immunomodulation.

Characterization of the poly-T variant in the TOMM40 gene in diverse populations.

We previously discovered that a polymorphic, deoxythymidine-homopolymer (poly-T, rs10524523) in intron 6 of the TOMM40 gene is associated with age-of-onset of Alzheimer's disease and with cognitive performance in elderly. Three allele groups were defined for rs10524523, hereafter '523', based on the number of 'T'-residues: 'Short' (S, T≤19), 'Long' (L, 20≤T≤29) and 'Very Long' (VL, T≥30). Homopolymers, particularly long homopolymers like '523', are difficult to genotype because 'slippage' occurs during PCR-amplification.

Characterization of serum proteins associated with IL28B genotype among patients with chronic hepatitis C.

Introduction: Polymorphisms near the IL28B gene (e.g. rs12979860) encoding interferon λ3 have recently been associated with both spontaneous clearance and treatment response to pegIFN/RBV in chronic hepatitis C (CHC) patients.

Beneficial IL28B genotype associated with lower frequency of hepatic steatosis in patients with chronic hepatitis C.

Background & Aims: IL28B polymorphisms have been associated with both treatment induced and spontaneous clearance of hepatitis C virus (HCV). We previously found that LDL cholesterol levels were higher in chronic hepatitis C (CHC) patients with the CC genotype at the rs12979860 polymorphism, located proximal to the IL28 gene. Here we analyzed the association of steatosis with IL28B genotype in treatment naïve patients with CHC.

High predictive accuracy of an unbiased proteomic profile for sustained virologic response in chronic hepatitis C patients.

Unlabelled: Chronic hepatitis C (CHC) infection is a leading cause of endstage liver disease. Current standard-of-care (SOC) interferon-based therapy results in sustained virological response (SVR) in only one-half of patients, and is associated with significant side effects. Accurate host predictors of virologic response are needed to individualize treatment regimens.

Gene by sex interaction for measures of obesity in the framingham heart study.

Obesity is an increasingly prevalent and severe health concern with a substantial heritable component and marked sex differences. We sought to determine if the effect of genetic variants also differed by sex by performing a genome-wide association study modeling the effect of genotype-by-sex interaction on obesity phenotypes. Genotype data from individuals in the Framingham Heart Study Offspring cohort were analyzed across five exams.

The Alzheimer's associated 5' region of the SORL1 gene cis regulates SORL1 transcripts expression.

SORL1 has been identified as a major contributor to late onset Alzheimer's disease (LOAD). We test whether genetic variability in the 5' of SORL1 gene modulates the risk to develop LOAD via regulation of SORL1-messenger ribonucleic acid (mRNA) expression and splicing. Two brain structures, differentially vulnerable to LOAD pathology, were examined in 144 brain samples from 92 neurologically normal individuals.

The effect of SNCA 3' region on the levels of SNCA-112 splicing variant.

Genetic variability at the 3' region of SNCA locus has been repeatedly associated with susceptibility to sporadic Parkinson's disease (PD). Accumulated evidence emphasizes the importance of SNCA dosage and expression levels in PD pathogenesis. However, the mechanism through which the 3' region of SNCA gene modulates the risk to develop sporadic PD remained elusive.

Genome-wide association study of Lp-PLA(2) activity and mass in the Framingham Heart Study.

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an emerging risk factor and therapeutic target for cardiovascular disease. The activity and mass of this enzyme are heritable traits, but major genetic determinants have not been explored in a systematic, genome-wide fashion. We carried out a genome-wide association study of Lp-PLA(2) activity and mass in 6,668 Caucasian subjects from the population-based Framingham Heart Study.

Interferon-lambda genotype and low serum low-density lipoprotein cholesterol levels in patients with chronic hepatitis C infection.

Unlabelled: Recently, genetic polymorphisms occurring in the interferon (IFN)-lambda gene region were associated with response to IFN-based treatment of hepatitis C infection. Both infection with the hepatitis C virus and IFN therapy are associated with decreased serum cholesterol and high cholesterol has been associated with increased likelihood to respond to IFN. We sought to determine if the IFN-lambda gene variant was also associated with serum lipid levels in chronic hepatitis C patients.

Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin.

Background & Aims: Patients with chronic hepatitis C virus (HCV) infections are treated with pegylated interferon and ribavirin (PEG-IFN/RBV), which is effective in less than 50% of those infected with HCV genotype 1. Genome-wide association studies have linked response to PEG-IFN/RBV with common single nucleotide polymorphisms in the vicinity of interferon (IFN)-lambda genes on chromosome 19. We investigated the association between the polymorphism rs12979860 and treatment response in a diverse cohort of chronic HCV patients.

Impact of gene variants on sex-specific regulation of human Scavenger receptor class B type 1 (SR-BI) expression in liver and association with lipid levels in a population-based study.

Background: Several studies have noted that genetic variants of SCARB1, a lipoprotein receptor involved in reverse cholesterol transport, are associated with serum lipid levels in a sex-dependent fashion. However, the mechanism underlying this gene by sex interaction has not been explored.

Methods: We utilized both epidemiological and molecular methods to study how estrogen and gene variants interact to influence SCARB1 expression and lipid levels.

Racial differences in the interaction between family history and risk factors associated with diabetes in the National Health and Nutritional Examination Survey, 1999-2004.

Purpose: We sought to determine whether the association between family history, a surrogate for genetic predisposition, and diabetes was modified by any known diabetes risk factors and if these relationships were constant across different ethnic groups.

Methods: We examined 10,899 adults from the National Health and Nutrition Examination Survey (1999 -2004) to identify interactions between family history and clinical, demographic, and lifestyle variables for the outcome of diabetes using logistic regression analysis in racial/ethnic subgroups.

Results: There was significant heterogeneity by race/ethnicity in the interaction between covariates and family history in relation to diabetes.

Polymorphisms of the scavenger receptor class B member 1 are associated with insulin resistance with evidence of gene by sex interaction.

Background: Genetic variation in diabetes-associated genes cumulatively explain little of the overall heritability of this trait. We sought to determine whether polymorphisms of the scavenger receptor class B, member I (SCARB1), an estrogen-regulated chromosome 12q24 positional candidate diabetes gene, were associated with type 2 diabetes or insulin resistance in a sex-specific fashion.

Methods: We evaluated 34 haplotype-tagged single-nucleotide polymorphisms (SNPs) of SCARB1 for their association with type 2 diabetes and measures of insulin resistance in two populations: a clinic-based sample of 444 Mexican-American women from Proyecto SALSA and a community-based sample of 830 white women from the Rancho Bernardo Study.

Transforming the practice of medicine using genomics.

Recent studies have demonstrated the use of genomic data, particularly gene expression signatures, as clinical prognostic factors in complex diseases. Such studies herald the future for genomic medicine and the opportunity for personalized prognosis in a variety of clinical contexts that utilize genomescale molecular information. Several key areas represent logical and critical next steps in the use of complex genomic profiling data towards the goal of personalized medicine.

Family History of Diabetes, Acculturation, and the Metabolic Syndrome among Mexican Americans: Proyecto SALSA.

Background: The purpose of this study was to examine effect modifiers of the relationship between family history of diabetes, a proxy for genetic predisposition, and the metabolic syndrome.

Methods: Subjects were a cross-sectional sample of 205 Mexican-Americans patients of the San Ysidro Health Center in San Diego County. Self-reported parental history of diabetes was examined as a risk factor for individual metabolic syndrome traits (hyperglycemia, hypertension, abdominal obesity, hypertriglyceridemia and low HDL-cholesterol) and a composite phenotype, defined both by standard modified National Cholesterol Education Program- Adult Treatment Panel III (NCEP-ATPIII) criteria and using principal components analysis, in age and sex-adjusted multiple logistic and linear regression models.

Taking cardiovascular genetic association studies to the next level.

Genetic information is beginning to have a direct impact on patient care and it is important that cardiologists appreciate the value and approaches to associating genetic variation and health outcomes. Genetic associations should be based on compelling genetic and biological hypotheses and should be statistically sound so as to reduce the possibility of "false discovery" in the setting of testing multiple hypotheses. Study designs should clearly define cases and controls and measurement of phenotypes.

Gene by sex interaction in the etiology of coronary heart disease and the preceding metabolic syndrome.

Background: Despite decades of research, the genetic basis of coronary heart disease and its metabolic risk factors is poorly understood. Few studies consider that sex may modify the effect of gene variants on disease. Investigation of gene by sex interaction may help to elucidate underlying genetic susceptibilities and explain the sexual dimorphism of these complex traits.