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The recent completion of the first draft of the human genome sequence and advances in technologies for genomic analysis are generating tremendous opportunities for epidemiologic studies to evaluate the role of genetic variants in human disease. Many methodological issues apply to the investigation of variation in the frequency of allelic variants of human genes, of the possibility that these influence disease risk, and of assessment of the magnitude of the associated risk. Based on a Human Genome Epidemiology workshop, a checklist for reporting and appraising studies of genotype prevalence and studies of gene-disease associations was developed. This focuses on selection of study subjects, analytic validity of genotyping, population stratification, and statistical issues. Use of the checklist should facilitate the integration of evidence from these studies. The relation between the checklist and grading schemes that have been proposed for the evaluation of observational studies is discussed. Although the limitations of grading schemes are recognized, a robust approach is proposed. Other issues in the synthesis of evidence that are particularly relevant to studies of genotype prevalence and gene-disease association are discussed, notably identification of studies, publication bias, criteria for causal inference, and the appropriateness of quantitative synthesis.

Hepatitis D virus (HDV) requires co-infection with hepatitis B virus (HBV). Human immunodeficiency virus (HIV) shares transmission routes with these viruses. Among 4,932 US women infected with or at-risk for HIV during 1994-2015, HBV surface antigen (HBsAg) positivity was more common in women with HIV (2.8% vs. 1.2%; p = 0.001); HDV was more common among participants enrolled during 2013-2015 (p = 0.0004) and those with resolved rather than active hepatitis C (1.9% vs. 0.5%; p = 0.02). Among HBsAg-positive women (n = 117), HDV antibody prevalence was 22% and did not vary by HIV status; HDV infection was associated with the presence of advanced fibrosis/cirrhosis at enrollment (adjusted odds ratio, 5.70; 95% confidence interval, 1.46-22.29). Our results demonstrate the importance of HDV testing in HBV-infected US women.

Background: Hepatocellular carcinoma (HCC) incidence was rising in the United States. Previously, using data collected by the Surveillance, Epidemiology, and End Results (SEER) Program through 2017, we found that overall incidence had begun to decline, although not in Black and American Indian/Alaska Native (AI/AN) populations. Utilizing expanded SEER data encompassing ~50% of the population, we examined secular trends and demographic differences in HCC incidence through 2019. Methods: We included cases of HCC diagnosed in adults aged ≥20 years residing in SEER‐22 registry areas. We examined case counts, incidence rates (per 100,000 person‐years), annual percent changes (APCs), and calendar years when APCs changed significantly. Results: HCC incidence increased from 5.56 in 2000 to 8.89 in 2009 (APC, 5.17%), then rose more slowly during 2009–2015 (APC, 2.28%). After peaking at 10.03 in 2015, incidence fell to 9.20 in 2019 (APC, −2.26%). In Asian/Pacific Islanders (A/PI), the decline began in 2007 and accelerated in 2015 (APCs: 2007–2015, −1.84%; 2015–2019, −5.80%). In 2014, incidence began to fall in the White (APC: 2014–2019, −1.11%) and Hispanic populations (APC: 2014–2019, −1.72%). In 2016, rates began to fall in Black individuals (APC: 2016–2019, −6.05%). In the AI/AN population, incidence was highest in 2017, although the subsequent decline was not statistically significant. In 2019, population‐specific rates were: White, 6.94; Black, 10.74; A/PI, 12.11; AI/AN, 14.56; Hispanic, 15.48. Conclusion: HCC incidence is now decreasing in most US racial/ethnic populations, including among Black individuals. The onset of decline differed among racial/ethnic groups and wide disparities in HCC rates remain. [ABSTRACT FROM AUTHOR]

Chronic infection with the hepatitis C virus (HCV) is a major cause of cirrhosis and hepatocellular carcinoma. In 2009, genome-wide association studies (GWAS) strongly linked genetic variants in the interferon lambda (IFN-λ) chromosomal region to HCV clearance. In 2013, discovery of the IFNL4 gene provided a functional explanation for those GWAS findings. The IFNL4-ΔG/TT (rs368234815) variant controls generation of the IFN-λ4 protein. Paradoxically, the IFNL4-TT allele, which abrogates IFN-λ4, associates with higher rates of spontaneous HCV clearance and better response to treatments for HCV infection. The finding that a "knock-out" allele for IFN-λ4 enhances HCV clearance challenges the paradigm of IFNs as antiviral cytokines. Genetic variants in the IFN-λ region have also been associated with hepatic inflammation and fibrosis from various etiologies, however, alleles that are linked with improved HCV clearance associates with worse inflammation and fibrosis. These studies demonstrate that GWAS of infectious diseases may yield important and unexpected biological insights. [ABSTRACT FROM AUTHOR]

Background: In the United States, incidence and mortality rates of hepatocellular carcinoma (HCC) are increasing in older individuals. Chronic infection with hepatitis C virus (HCV) and hepatitis B virus (HBV) are important causes of HCC; however, the contribution of viral hepatitis to recent trends in HCC incidence among older Americans is unclear.Methods: Data from the Surveillance, Epidemiology, and End Results-Medicare linkage (SEER-Medicare) for the years 2001 through 2013 were used to identify HCC cases among individuals aged ≥66 years and Medicare files were used to assess the HCV and HBV status of these HCC cases. Age-standardized incidence rates of HCV-attributable, HBV-attributable, and HCV/HBV-unrelated HCC were estimated overall and by age group, sex, and race/ethnicity. The authors also calculated annual percent changes (APCs) in HCC incidence.Results: Between 2001 and 2013, a total of 15,300 HCC cases occurred in this population. Overall HCC rates increased 43% from 16.3 to 23.3 per 100,000 population (APC, 3.40% per year), whereas HCV-attributable HCC rates nearly doubled from 4.2 to 8.2 per 100,000 population (APC, 5.62% per year). HCC rates increased more slowly for HBV-attributable HCC (1.3 to 1.8 per 100,000 population; APC, 3.17% per year) and HCV/HBV-unrelated HCC (11.3 to 14.1 per 100,000 population; APC, 2.35% per year). The percentage of HCC cases with evidence of HCV infection increased from 25.7% in 2001 through 2004 to 32.3% in 2011 through 2013, whereas the percentage with HBV remained stable at 8%. In 2013, higher rates for both HCV-attributable and HBV-attributable HCC were noted among individuals aged 66 to 75 years, men, and individuals of Asian ancestry.Conclusions: Among Americans aged ≥66 years, HCC rates increased rapidly between 2001 and 2013. Although HCV-attributable cases contributed substantially to this increase, rates of HBV-attributable and HCV/HBV-unrelated HCC also rose during this period. [ABSTRACT FROM AUTHOR]

Summary: Hepatocellular carcinoma (HCC) incidence is high in The Gambia, and hepatitis B virus (HBV) infection is the main cause. People coinfected with HBV and hepatitis D virus (HDV) have an even greater risk of HCC and cirrhosis. Using a new HDV quantitative microarray antibody capture (Q‐MAC) assay, we evaluated the association between HDV infection and HCC or cirrhosis among participants in The Gambia Liver Cancer Study. In this case‐control study, cases had HCC (n = 312) or cirrhosis (n = 119). Controls (n = 470) had no clinical evidence of liver disease and normal serum alpha‐foetoprotein. Participants were previously tested for hepatitis B surface antigen (HBsAg); we tested HBsAg+ specimens by HDV Q‐MAC, western blot and RNA assays. We evaluated separate cut‐offs of the Q‐MAC assay for predicting anti‐HDV and RNA positivity. Q‐MAC correctly identified 29/29 subjects who were western blot‐positive (sensitivity = 100%, specificity = 99.4%) and 16/17 who were RNA‐positive (sensitivity = 94.1%, specificity = 100%). Compared to controls, cases more often had HBV monoinfection (HBsAg+/HDV RNA−; 54.1% vs 17.0%; odds ratio [OR] = 6.28; P < 0.001) or HBV‐HDV coinfection (HBsAg+/HDV RNA+; 3.9% vs 0%; P < 0.001). Risk estimates (for HCC or cirrhosis) based on HDV antibody status and adjusted for covariates (demographics, alcohol, smoking, body mass index, anti‐HCV and aflatoxin B1 exposure) yielded consistent results for both HBV monoinfection (adjusted OR = 8.29; 95% confidence interval = 5.74‐11.98) and HBV‐HDV coinfection (adjusted OR = 30.66; 95% confidence interval = 6.97‐134.95). In this Gambian population, HDV Q‐MAC had high sensitivity and specificity for both anti‐HDV and HDV RNA. HDV infection contributed to the high risk of HCC in The Gambia. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections can lead to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Over the past decade, studies of individuals infected with these viruses have established genetic associations with the probability of developing a chronic infection, risk of disease progression, and likelihood of treatment response. We review genetic and genomic methods that have been used to study risk of HBV and HCV infection and patient outcomes. For example, genome-wide association studies have linked a region containing the interferon lambda genes to spontaneous and treatment-induced clearance of HCV. We review the genetic variants associated with HCV and HBV infection, and how these variants affect specific expression or activities of their products. Further studies of these variants could provide insights into risk factors for and mechanisms of chronic infection and disease progression, as well as new strategies for treatment. [ABSTRACT FROM AUTHOR]

More than 150 million people worldwide are chronically infected with hepatitis C virus (HCV) and face higher risk of cirrhosis and hepatocellular carcinoma. Highly effective HCV treatments have recently been developed; however, they are costly and therefore poorly suited for application in resource-limited settings where HCV burden is high. Pegylated-interferon alpha (PEG-IFNα) and ribavirin (RBV) therapy is far less costly, but also less effective. Vitamin D supplementation has been proposed as an inexpensive adjuvant to treatment, however, prior epidemiological evidence on its effectiveness is inconsistent, with little data available among African Americans who naturally have lower vitamin D concentrations. We thus evaluated associations between baseline vitamin D status, measured by circulating 25-hydroxyvitamin D (25(OH)D), which is considered to be the best marker of vitamin D status in humans, and subsequent response to PEG-IFNα/RBV therapy in two large clinical trials that together included 1292 patients infected with HCV genotype 1. We used race-stratified logistic regression models to evaluate multivariable-adjusted associations of 25(OH)D with early virologic response (EVR; 2-log10 HCV RNA decline at week 12) and sustained virologic response (SVR). Among African Americans, we saw no associations. Among European Americans, we saw no association with low vitamin D (≤20 ng/mL) versus sufficient concentrations (20-<30 ng/mL). However, patients with 25(OH)D ≥30 ng/mL were actually less likely to attain EVR (OR = 0.64, 95% CI = 0.43–0.94) than those with sufficient concentrations, with a similar but non-significant association observed for SVR (OR = 0.49, 95% CI = 0.20–1.17). Conclusion: Higher vitamin D status was not beneficially associated with responses to therapy; if anything, patients with higher vitamin D concentrations were less likely to attain SVR. Our data do not support a role for vitamin D supplementation as an adjuvant therapy for HCV. [ABSTRACT FROM AUTHOR]

Background: CC-chemokine receptor 5 (CCR5) is a co-receptor for human immunodeficiency virus type 1 (HIV-1) infection. Homozygosity for a 32–base pair (bp) deletion (Δ32) in the CCR5 gene confers resistance to HIV-1. Previous studies found an increased prevalence of hypertension among CCR5-Δ32 homozygotes and among carriers of a polymorphism (CCR2-64I) found on the gene that codes a closely related chemokine receptor. The present study was carried out to verify these associations. Methods: Subjects in this cross-sectional study were selected from the Global Repository at Genomics Collaborative, which includes patients and healthy control subjects enrolled at multiple clinical sites in the United States and other nations. The current study includes 2842 subjects with hypertension and 2893 nonhypertensive control subjects from white populations in the United States and Poland. Case and control subjects were frequency matched by age, gender, and birthplace. All subjects were genotyped for CCR5-Δ32 and CCR2-64I polymorphisms by established Taqman assays. Results: The CCR5-Δ32 genotype was not found to be associated with hypertension (CCR5-Δ32 heterozygosity: odds ratio [OR] 0.99, 95% confidence interval [CI] 0.87 to 1.14; CCR5-Δ32 homozygosity: OR 1.07, 95% CI 0.68 to 1.67) among these subjects. There was also no association between CCR2-64I genotype and hypertension (CCR2-64I heterozygosity: OR 0.96, 95% CI 0.83 to 1.10; CCR2-64I homozygosity: OR 1.18, 95% CI 0.73 to 1.92). These results changed little after adjustment for potential confounding variables. Conclusion: The results of the present study, which is much larger than previously published studies, provide no evidence that either CCR5-Δ32 or CCR2-64I is associated with hypertension. [Copyright &y& Elsevier]

Morbidity and mortality from hepatocellular carcinoma (HCC), which is primarily caused by hepatitis B virus or hepatitis C virus. can be prevented. Public health interventions have eliminated transfusion transmission of these viruses and, in endemic countries with effective hepatitis B virus vaccination programs, have greatly reduced incident hepatitis B virus infections land HCC) in children. Antiviral treatment can eliminate detectable hepatitis C virus in 50%-80% of chronically infected patients. presumably reducing their risk of cancer. HCC survival rates remain universally poor, but early detection and treatment in developed countries has improved survival in selected patients. Despite these advances. worldwide HCC rates remain high, and additional preventive efforts are needed. The most important opportunity is wider distribution of hepatitis B virus vaccine in endemic areas. Development of an HCV vaccine. improved aritiviral therapies. and better methods for HCC detection would also help decrease morbidity and mortality from HCC. HCC prevention efforts provide a paradigm for preventive oncology in cancers of viral etiology. [ABSTRACT FROM AUTHOR]

The article presents a commentary on a study which conducted a meta-analysis of individual participants' data (MIPD) with time-to-event analyses in the field of genetic epidemiology. The study has found that the MIPD offers many advantages over a meta-analysis of the published literature, including inclusion of extended databases from published studies, inclusion of data from unpublished studies and better time-to-event analyses. A disadvantage of an MIPD is the inability for published data to be made available for synthesis.

The task of identifying genetic determinants for complex, multigenetic diseases is hampered by small studies, publication and reporting biases, and lack of common standards worldwide. The authors propose the creation of a network of networks that include groups of investigators collecting data for human genome epidemiology research. Twenty-three networks of investigators addressing specific diseases or research topics and representing several hundreds of teams have already joined this initiative. For each field, the authors are currently creating a core registry of teams already participating in the respective network. A wider international registry will include all other teams also working in the same field. Independent investigators are invited to join the registries and existing networks and to join forces in creating additional ones as needed. The network of networks aims to register these networks, teams, and investigators; be a resource for information about or connections to the many networks; offer methodological support; promote sound design and standardization of analytical practices; generate inclusive overviews of fields at large; facilitate rapid confirmation of findings; and avoid duplication of effort. [ABSTRACT FROM AUTHOR]