Person:

Tabrizi, Shervin

Rapidly evolving viruses and other pathogens can have an immense impact on human evolution as natural selection acts to increase the prevalence of genetic variants providing resistance to disease. With the emergence of large datasets of human genetic variation, we can search for signatures of natural selection in the human genome driven by such disease-causing microorganisms. Based on this approach, we have previously hypothesized that Lassa virus (LASV) may have been a driver of natural selection in West African populations where Lassa haemorrhagic fever is endemic. In this study, we provide further evidence for this notion. By applying tests for selection to genome-wide data from the International Haplotype Map Consortium and the 1000 Genomes Consortium, we demonstrate evidence for positive selection in LARGE and interleukin 21 (IL21), two genes implicated in LASV infectivity and immunity. We further localized the signals of selection, using the recently developed composite of multiple signals method, to introns and putative regulatory regions of those genes. Our results suggest that natural selection may have targeted variants giving rise to alternative splicing or differential gene expression of LARGE and IL21. Overall, our study supports the hypothesis that selective pressures imposed by LASV may have led to the emergence of particular alleles conferring resistance to Lassa fever, and opens up new avenues of research pursuit.

Background: Lassa fever is a viral haemorrhagic disease endemic to west Africa. No large-scale studies exist from Nigeria, where the Lassa virus (LASV) is most diverse. LASV diversity, coupled with host genetic and environmental factors, might cause di erences in disease pathophysiology. Small-scale studies in Nigeria suggest that acute kidney injury is an important clinical feature and might be a determinant of survival. We aimed to establish the demographic, clinical, and laboratory factors associated with mortality in Nigerian patients with Lassa fever, and hypothesised that LASV was the direct cause of intrinsic renal damage for a subset of the patients with Lassa fever. Methods: We did a retrospective, observational cohort study of consecutive patients in Nigeria with Lassa fever, who tested positive for LASV with RT-PCR, and were treated in Irrua Specialist Teaching Hospital. We did univariate and multivariate statistical analyses, including logistic regression, of all demographic, clinical, and laboratory variables available at presentation to identify the factors associated with patient mortality. Findings: Of 291 patients treated in Irrua Specialist Teaching Hospital between Jan 3, 2011, and Dec 11, 2015, 284 (98%) had known outcomes (died or survived) and seven (2%) were discharged against medical advice. Overall case-fatality rate was 24% (68 of 284 patients), with a 1·4 times increase in mortality risk for each 10 years of age (p=0·00017), reaching 39% (22 of 57) for patients older than 50 years. Of 284 patients, 81 (28%) had acute kidney injury and 104 (37%) had CNS manifestations and thus both were considered important complications of acute Lassa fever in Nigeria. Acute kidney injury was strongly associated with poor outcome (case-fatality rate of 60% [49 of 81 patients]; odds ratio [OR] 15, p<0·00001). Compared with patients without acute kidney injury, those with acute kidney injury had higher incidence of proteinuria (32 [82%] of 39 patients) and haematuria (29 [76%] of 38) and higher mean serum potassium (4·63 [SD 1·04] mmol/L) and lower blood urea nitrogen to creatinine ratio (8·6 for patients without clinical history of uid loss), suggesting intrinsic renal damage. Normalisation of creatinine concentration was associated with recovery. Elevated serum creatinine (OR 1·3; p=0·046), aspartate aminotransferase (OR 1·5; p=0·075), and potassium (OR 3·6; p=0·0024) were independent predictors of death. Interpretation: Our study presents detailed clinical and laboratory data for Nigerian patients with Lassa fever and provides strong evidence for intrinsic renal dysfunction in acute Lassa fever. Early recognition and treatment of acute kidney injury might signicantly reduce mortality.