Homozygous loss-of-function variants in European cosmopolitan and isolate populations.

Homozygous loss of function (HLOF) variants provide a valuable window on gene function in humans, as well as an inventory of the human genes that are not essential for survival and reproduction. All humans carry at least a few HLOF variants, but the exact number of inactivated genes that can be tolerated is currently unknown­as are the phenotypic effects of losing function for most human genes. Here, we make use of 1432 whole exome sequences from five European populations to expand the catalogue of known human HLOF mutations; after stringent filtering of variants in our dataset, we identify a total of 173 HLOF mutations, 76 (44%) of which have not been observed previously. We find that population isolates are particularly well suited to surveys of novel HLOF genes because individuals in such populations carry extensive runs of homozygosity, which we show are enriched for novel, rare HLOF variants. Further, we make use of extensive phenotypic data to show that most HLOFs, ascertained in population-based samples, appear to have little detectable effect on the phenotype. On the contrary, we document several genes directly implicated in disease that seem to tolerate HLOF variants. Overall HLOF genes are enriched for olfactory receptor function and are expressed in testes more often than expected, consistent with reduced purifying selection and incipient pseudogenisation.

Host genetics and susceptibility to congenital and childhood cytomegalovirus infection: a systematic review.

AIM: To summarize available evidence on the role of host genetics in the susceptibility to congenital and childhood cytomegalovirus (CMV) infections by conducting a systematic review of published studies. METHODS: We searched online databases (PubMed, Web of Science, Scopus and HuGe Navigator) for relevant studies with well-defined inclusion and exclusion criteria and assessed the risk of bias using novel Confounding-Selection-Information bias score (CSI). RESULTS: 5105 studies were initially identified, but only 5 met all the inclusion criteria and were analyzed in detail. Polymorphisms of the toll-like receptors (TLRs) and mannose-binding lectin (MBL) genes were shown to have an impact on the CMV infection in infants. Polymorphisms of the TLR2 (rs3804100, rs1898830), TLR4 (rs4986791), and TLR9 (rs352140) were shown to have a role in congenital CMV infection. Low MBL levels were associated with CMV infection in Chinese individuals, a finding that was not replicated in Caucasians. The overall credibility of evidence was weak. CONCLUSIONS: Based on currently available very limited amount of evidence, it is uncertain whether congenital and childhood CMV infections are under host genetic control. Additional primary studies are needed with more specific research hypotheses that will enable gradual understanding of specific mechanisms of the CMV pathogenesis. More genetic studies in the future will facilitate better understanding of host susceptibility and likely enable novel preventative and curative measures.

The Association between Salt Taste Perception, Mediterranean Diet and Metabolic Syndrome: A Cross-Sectional Study.

Metabolic syndrome (MetS) is a widespread disorder and an important public health challenge. The purpose of this study was to identify the association between salt taste perception, Mediterranean diet and MetS. This cross-sectional study included 2798 subjects from the general population of Dalmatia, Croatia. MetS was determined using the Joint Interim Statement definition, and Mediterranean diet compliance was estimated using Mediterranean Diet Serving Score. Salt taste perception was assessed by threshold and suprathreshold testing (intensity and hedonic perception). Logistic regression was used in the analysis, adjusting for important confounding factors. As many as 44% of subjects had MetS, with elevated waist circumference as the most common component (77%). Higher salt taste sensitivity (lower threshold) was associated with several positive outcomes: lower odds of MetS (OR = 0.69; 95% CI 0.52-0.92), lower odds for elevated waist circumference (0.47; 0.27-0.82), elevated fasting glucose or diabetes (0.65; 0.45-0.94), and reduced HDL cholesterol (0.59; 0.42-0.84), compared to the higher threshold group. Subjects with lower salt taste threshold were more likely to consume more fruit, and less likely to adhere to olive oil and white meat guidelines, but without a difference in the overall Mediterranean diet compliance. Salt taste intensity perception was not associated with any of the investigated outcomes, while salty solution liking was associated with MetS (OR = 1.85, CI 95% 1.02-3.35). This study identified an association between salt taste perception and MetS and gave a new insight into taste perception, nutrition, and possible health outcomes.

The role of host genetic factors in respiratory tract infectious diseases: systematic review, meta-analyses and field synopsis.

Host genetic factors have frequently been implicated in respiratory infectious diseases, often with inconsistent results in replication studies. We identified 386 studies from the total of 24,823 studies identified in a systematic search of four bibliographic databases. We performed meta-analyses of studies on tuberculosis, influenza, respiratory syncytial virus, SARS-Coronavirus and pneumonia. One single-nucleotide polymorphism from IL4 gene was significant for pooled respiratory infections (rs2070874; 1.66 [1.29-2.14]). We also detected an association of TLR2 gene with tuberculosis (rs5743708; 3.19 [2.03-5.02]). Subset analyses identified CCL2 as an additional risk factor for tuberculosis (rs1024611; OR = 0.79 [0.72-0.88]). The IL4-TLR2-CCL2 axis could be a highly interesting target for translation towards clinical use. However, this conclusion is based on low credibility of evidence - almost 95% of all identified studies had strong risk of bias or confounding. Future studies must build upon larger-scale collaborations, but also strictly adhere to the highest evidence-based principles in study design, in order to reduce research waste and provide clinically translatable evidence.