Variation at the Klotho gene locus does not affect cognitive function in up to 335,074 British Caucasians in the UK Biobank

Abstract

25The proportion of older adults in Western populations is increasing and there is, 26 therefore, a need to define factors affecting maintenance of physical and 27 cognitive health in old age. Variations in the Klotho (KL) gene, and specifically 28 the KL-VS haplotype, have been identified by several authors as potentially 29 influencing cognitive function and decline. We have attempted to verify the 30 reported associations between KL variants, including the KL-VS haplotype, and 31 cognitive function in up to 335,074 British Caucasian participants aged 40-79 32 years from the UK Biobank. We do not find evidence that KL-VS affects 33 cognitive function or its decline with increasing age. We examined a further 244 34 KL variants and found that rs117650866 was associated with Prospective 35Memory, but could not replicate this in follow-up samples. In conclusion, there is 36 insufficient evidence in the UK Biobank to support the concept that KL variants 37 affect cognitive function or its rate of decline. 38 39 42proportion of older adults. There is, thus, a need to define the factors affecting 43 maintenance of physical and cognitive health in old age. Cognition can be 44 defined as any process that is required for an individual to be aware of their 45 situation and to use that information to respond to it (1). As individuals get older, 46 memory, learning and processing speed decline (2); often leading to reduced 47 independence and increased reliance on families and social care. As life 48 expectancy increases, it becomes ever more necessary to explore some of the 49 factors that might explain variation in cognitive function and cognitive decline in 50 adults. 51 52 Several authors have highlighted variants in the Klotho (KL) gene as associated 53 with ageing. KL is located on chromosome 13 in humans, and encodes a single-54 pass transmembrane protein that acts as an FGF23 co-receptor (3-5). It was 55 first identified in mice by Kuro-o et al. (6) who showed that decreased kl 56 expression resulted in a condition resembling premature ageing. In humans, KL 57 variants have been reported to be associated with longevity, cardiovascular risk 58 factors and cancer (7-10).59 60 In addition, multiple studies have been carried out exploring the relationship 61 between KL variants and cognitive function and decline, mostly focusing on the 62 KL-VS haplotype, which refers to a pair of functional variants that result in 63 F352V (rs9536314) and C370S (rs9527025) substitutions. Previous evidence 64 has been varied: some authors have suggested that among adults aged 70 65 years or more, people homozygous for V (valine) at position 352 have poorer 66 cognitive function (11,12), but also suggests that V352 heterozygotes have 67 better cognitive function than those who are homozygous for (F) phenylalanine 68 at position 352 (11,13). On the other hand, Mengel-From et al. (14) showed 69 that, in Danish populations aged between 92-100 years, V352 heterozygotes 70 had poorer cognition and Almeida et al. (15) showed that among m...

The impact of increasing levels of blood C-reactive protein on the inflammatory loci SPI1 and CD33 in Alzheimer’s disease

“…Finally, UKBB had a relatively lower AD incidence rate than many other cohorts reported. We reasoned that in UKBB, the population evaluated had a shorter follow-up time and that more AD incident cases would be observed when the study continued to evolve [72]. Nevertheless, our study using three different cohorts suggests a role for the clinical biomarker CRP used under infection or inflammation conditions in monitoring risk in those with specific genetic factors for AD development as well as a role in precision medicine-based drug development.…”