SNP rs6543176 is associated with extreme human longevity but increased risk for cancer

Abstract

Using whole-genome sequencing (WGS) might offer insights into rare genetic variants associated with healthy aging and extreme longevity (EL), potentially pointing to useful therapeutic targets. In this study, we conducted a genome-wide association study using WGS data from the Long Life Family Study and identified a novel longevity-associated variant rs6543176 in the SLC9A2 gene. This SNP also showed a significant association with reduced hypertension risk and an increased, though not statistically significant, cancer risk. The association with cancer risk was replicated in the UK Biobank and FinnGen. Metabolomic analyses linked the rs6543176 longevity allele to higher serine levels, potentially associated with delayed mortality. Our findings warrant further investigation of SLC9A2's role in both longevity and cancer susceptibility, and they highlight the need for careful evaluation in developing anti-aging therapies based on EL-associated alleles.

Keywords: Cancer; Extreme Longevity; rs6543176.

Fig. 1

A Survival free of self-reported hypertension in carriers of the rare longevity allele (red) and non-carriers (blue). The p-value here is from the unadjusted log-rank test, so it is slightly different from the p-value of the adjusted model in Supplementary Table 1. B Summary statistics from the associations between cancer phenotypes and the longevity SNP rs6543176 (rare allele A is the coded allele here) in the UKBB and FinnGen studies that reach a nominal significance level of p-value < 0.05. These data come from https://pheweb.org/UKB-SAIGE/variant/2-103281960-A-G (UKBB) and https://r9.finngen.fi/variant/2:102665501-A-G (FinnGen). C Boxplot of serine levels in carriers of the rare extreme longevity-associated allele (AG) (left) and the common allele (GG) (right). D Distribution of serine in ~ 2500 LLFS participants with different ages. E Survival analysis (time to death) using Cox proportional hazards regression with serine as an independent predictor. The model was adjusted by age at enrollment, sex, education, whether participants were enrolled in Denmark or in the USA, medications for type 2 diabetes, dyslipidemia, heart disease, and hypertension, PC1-PC4, and full genetic relationship matrix. High/older (H/O): above-the-mean metabolite in individuals born < 1935. High/younger (H/Y): above-the-mean metabolite in individuals born ≥ 1935. Low/older (L/O): below-the-mean mean metabolite in individuals born < 1935. Low/Younger (L/Y): below-the-mean mean metabolite in individuals born ≥ 1935. FU_time: years after enrollment in the LLFS

Fig. 2

Pedigree with a distinct pattern of co-segregation of the carriers of the rare longevity allele on chromosome 2 and cancer. The left part of each node/subject is having (filled in)/not having a genetic variant. The right part of each node/subject is having (shaded)/not having cancer. When available, the age of the last contact is reported under each node/subject. The ages were truncated for subjects who are 89 + years old