Identification of new genetic variants of HLA-DQB1 associated with human longevity and lipid homeostasis—a cross-sectional study in a Chinese population

Abstract

Healthy longevity has been an unremitting pursuit of human, but its genetic and the environment causes are still unclear. As longevity population is a good healthy aging model for understanding how the body begin aging and the process of aging, and plasma lipids metabolism and balance is a very important to life maintain and physiologic functional turnover. It is important to explore how the effect of genetic variants associated long-life individuals on lipids metabolism and balance. Therefore, we developed a comparative study based population which contains 2816 longevity and 2819 control. Through whole-exome sequencing and sanger sequencing genotypes, we identified four new single nucleotide polymorphisms of HLA-DQB1(major histocompatibility complex, class II, DQ beta 1), rs41542812 rs1049107 rs1049100 rs3891176(Prange=0.048-2.811×10−8 for allele frequencies), associated with longevity in Chinese Longevity Cohort. Further, by analysis of the longevity-variants linked to blood lipids, we identified HLA-DQB1 rs1049107, T-carriers (PHDL=0.006, OR: 11.277; PTG=9.095×10−7, OR: 0.025; PLDL/HDL=0.047, OR: 1.901) and HLA-DQB1 rs1049100, T-carriers (PTG=1.799×10-6, OR: 0.028) associated with lipid homeostasis in long lived individuals. Our finding showed that longevity and lipid homeostasis were associated with HLA-DQB1 and suggested that immune gene variants could act on both new function of maintaining the homeostasis and anti-aging in longevity.

Genetics of Human Longevity Within an Eco-Evolutionary Nature-Nurture Framework

“…The literature regarding exome sequencing in human longevity is not so rich, and only few studies used this type of protocol [117][118][119] . The vast majority of data regarding GWAS are based on high-dense microarrays analysis (usually Affymetrix or Illumina) that thanks to imputation process can be compared between different cohorts and populations for millions of SNPs.…”

Viewpoint: A Contributory Role of Shell Ginger (Alpinia zerumbet) for Human Longevity in Okinawa, Japan?

“…There is also a need to expand studies of genomic analysis including HLA in the context of longevity. Respective data published more recently show heterogeneity and inconsistencies among individuals with longevity, providing substantial genetic differences varying from country to country [ 88 , 89 , 90 ]. Indeed, partially contradictory results have been published for Okinawa [ 88 ], China [ 89 ], and the UK [ 90 ].…”

“…Respective data published more recently show heterogeneity and inconsistencies among individuals with longevity, providing substantial genetic differences varying from country to country [ 88 , 89 , 90 ]. Indeed, partially contradictory results have been published for Okinawa [ 88 ], China [ 89 ], and the UK [ 90 ]. For instance, using genome-wide association meta-analysis of 606,059 parents’ survival in Okinawa, two regions associated with longevity ( HLA-DQA1/DRB1 and LPA ) were newly discovered [ 88 ].…”

“…Concomitantly, previous suggestions that APOE , CHRNA3/5 , CDKN2A/B , SH2B3 and FOXO3A influence longevity were validated [ 88 ]. In China using whole-exome sequencing and sanger sequencing genotypes, a comparative population-based study with 2816 elderly people and 2819 controls revealed four new single-nucleotide polymorphisms of HLA-DQB1 (major histocompatibility complex, class II, DQ beta 1): rs41542812, rs1049107, rs1049100, and rs3891176 ( P range = 0.048 − 2.811 × 10 −8 for allele frequencies) associated with longevity in the Chinese Longevity Cohort study [ 89 ]. In the UK, two regions associated with longevity ( HLA-DQA1/DRB1 and LPA ) were discovered, using genome-wide association meta-analysis of the survival of 606,059 parents, and previous suggestions that APOE , CHRNA3/5 , CDKN2A/B , SH2B3, and FOXO3A influence longevity were additionally validated [ 90 ].…”

“…In the UK, two regions associated with longevity ( HLA-DQA1/DRB1 and LPA ) were discovered, using genome-wide association meta-analysis of the survival of 606,059 parents, and previous suggestions that APOE , CHRNA3/5 , CDKN2A/B , SH2B3, and FOXO3A influence longevity were additionally validated [ 90 ]. Most interestingly, all three studies discussed the issue of lipid metabolism [ 88 , 89 , 90 ]. In the UK, high-density lipoprotein (HDL) cholesterol levels were found to be most positively genetically correlated with lifespan [ 90 ].…”