Soluble CD14 Levels in the Jackson Heart Study: Associations With Cardiovascular Disease Risk and Genetic Variants

Objective: sCD14 (soluble CD14) is a circulating pattern recognition receptor involved in inflammatory signaling. Although it is known that sCD14 levels vary by race, information on the genetic and cardiovascular disease (CVD) risk relationships of sCD14 in Black participants is limited. Approach and Results: We measured sCD14 in plasma at the baseline exam from n=3492 Black participants from the JHS (Jackson Heart Study). We evaluated associations between sCD14 and subclinical CVD measures, incident CVD events, and mortality under 3 levels of covariate adjustment. We used whole-genome sequence data from the Trans-Omics for Personalized Medicine program to identify genetic associations with sCD14. Adjusting for CVD risk factors and C-reactive protein, higher sCD14 was significantly associated with increased risk of mortality (hazard ratio, 1.25 [95% CI, 1.17–1.32]), incident coronary heart disease (hazard ratio, 1.28 [95% CI, 1.11–1.47]), and incident heart failure (hazard ratio, 1.27 [95% CI, 1.15–1.41]), but not stroke (hazard ratio, 0.96 [95% CI, 0.84–1.09]). Some of these relationships differed by age or sex: the association between sCD14 and heart failure was only observed in females; there was an association between sCD14 and stroke only at younger ages (in the lowest tertile of age, <49.4 years). We replicated the association between sCD14 levels with African ancestry-specific allele (rs75652866) on the CD14 region of chromosome 5q31. We additionally identified 2 novel statistically distinct genetic associations with sCD14 represented by index variants rs770147646 and rs57599368, also in the chromosome 5q31 region. Conclusions: sCD14 independently predicts CVD-related outcomes and mortality in Black participants.

The Genetics of Human Schistosomiasis Infection Intensity and Liver Disease: A Review

Schistosomiasis remains the fourth most prevalent parasitic disease affecting over 200 million people worldwide. Control efforts have focussed on the disruption of the life cycle targeting the parasite, vector and human host. Parasite burdens are highly skewed, and the majority of eggs are shed into the environment by a minority of the infected population. Most morbidity results from hepatic fibrosis leading to portal hypertension and is not well-correlated with worm burden. Genetics as well as environmental factors may play a role in these skewed distributions and understanding the genetic risk factors for intensity of infection and morbidity may help improve control measures. In this review, we focus on how genetic factors may influence parasite load, hepatic fibrosis and portal hypertension. We found 28 studies on the genetics of human infection and 20 studies on the genetics of pathology in humans. S. mansoni and S. haematobium infection intensity have been showed to be controlled by a major quantitative trait locus SM1, on chromosome 5q31-q33 containing several genes involved in the Th2 immune response, and three other loci of smaller effect on chromosomes 1, 6, and 7. The most common pathology associated with schistosomiasis is hepatic and portal vein fibroses and the SM2 quantitative trait locus on chromosome six has been linked to intensity of fibrosis. Although there has been an emphasis on Th2 cytokines in candidate gene studies, we found that four of the five QTL regions contain Th17 pathway genes that have been included in schistosomiasis studies: IL17B and IL12B in SM1, IL17A and IL17F in 6p21-q2, IL6R in 1p21-q23 and IL22RA2 in SM2. The Th17 pathway is known to be involved in response to schistosome infection and hepatic fibrosis but variants in this pathway have not been tested for any effect on the regulation of these phenotypes. These should be priorities for future studies.

Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis and, despite the larger estimated heritability for PsA, the majority of genetic susceptibility loci identified to date are shared with psoriasis. Here, we present results from a case–control association study on 1,962 PsA patients and 8,923 controls using the Immunochip genotyping array. We identify eight loci passing genome-wide significance, secondary independent effects at three loci and a distinct PsA-specific variant at the IL23R locus. We report two novel loci and evidence of a novel PsA-specific association at chromosome 5q31. Imputation of classical HLA alleles, amino acids and SNPs across the MHC region highlights three independent associations to class I genes. Finally, we find an enrichment of associated variants to markers of open chromatin in CD8+ memory primary T cells. This study identifies key insights into the genetics of PsA that could begin to explain fundamental differences between psoriasis and PsA.

Host susceptibility to malaria in human and mice: compatible approaches to identify potential resistant genes

There is growing evidence for human genetic factors controlling the outcome of malaria infection, while molecular basis of this genetic control is still poorly understood. Case-control and family-based studies have been carried out to identify genes underlying host susceptibility to malarial infection. Parasitemia and mild malaria have been genetically linked to human chromosomes 5q31-q33 and 6p21.3, and several immune genes located within those regions have been associated with malaria-related phenotypes. Association and linkage studies of resistance to malaria are not easy to carry out in human populations, because of the difficulty in surveying a significant number of families. Murine models have proven to be an excellent genetic tool for studying host response to malaria; their use allowed mapping 14 resistance loci, eight of them controlling parasitic levels and six controlling cerebral malaria. Once quantitative trait loci or genes have been identified, the human ortholog may then be identified. Comparative mapping studies showed that a couple of human and mouse might share similar genetically controlled mechanisms of resistance. In this way, char8, which controls parasitemia, was mapped on chromosome 11; char8 corresponds to human chromosome 5q31-q33 and contains immune genes, such as Il3, Il4, Il5, Il12b, Il13, Irf1, and Csf2. Nevertheless, part of the genetic factors controlling malaria traits might differ in both hosts because of specific host-pathogen interactions. Finally, novel genetic tools including animal models were recently developed and will offer new opportunities for identifying genetic factors underlying host phenotypic response to malaria, which will help in better therapeutic strategies including vaccine and drug development.

Single Nucleotide Polymorphism in the Promoter of the Human Interleukin-13 Gene Is Associated with Asthma in Malaysian Adults

Asthma susceptibility genes are mapped to a region on human chromosome 5q31-q33, which contains a cluster of proinflammatory cytokine genes such as interleukin-13 (IL-13), which is associated with asthma. This study investigated the allele frequencies of two single nucleotide polymorphisms (SNPs) (−1111C>T and 4257C>A) in theIL-13gene between asthmatics and healthy volunteers as well as the relationship between these SNPs and IL-13 production. DNA extracted from buffy coat of asthmatic and control subjects was genotyped using the PCR-RFLP method. Amount of IL-13 produced by mitogen-stimulated peripheral blood leucocytes PBLs (PBLs) was determined by ELISA. The frequencies of the −1111C and 4257G wild-type alleles were 0.52 and 0.55 in asthmatics and were 0.67 and 0.56 in controls. A significant (P<0.05) association was found between genotype and allele frequencies of SNP at position −1111C>T between asthmatic and control groups (OR, 1.810; 95% CI = 1.184 to 2.767;P<0.05). The mitogen-stimulated PBLs from asthmatics produced higher amounts of IL-13 production (P<0.001). The 4257GA heterozygous and 4257AA homozygous mutant alleles were associated with higher IL-13 production in asthmatics (P<0.05). Our results show that the −1111T mutant allele are associated with asthma and the 4257A mutant alleles are associated with elevated IL-13 production.