European Journal of Human Genetics (2005) 13, 1154–1158 & 2005 Nature Publishing Group All rights reserved 1018-4813/05 $30.00

No evidence for an association between extreme longevity and Microsomal Transfer Protein polymorphisms in a longitudinal study of 1651

,1,2 1,2 1,2 2,3 2 Bathum* , Lene Christiansen , Qihua Tan , James Vaupel , Bernard Jeune 2 Kaare Christensen

1Department of Clinical Biochemistry, Odense University Hospital, Odense, Denmark; 2Department of Epidemiology, University of Southern Denmark, Denmark; 3The Max Planck Institute for Demographic Research, Rostock, Germany

studies have reported two SNPs and a haplotype marker within the Microsomal Transfer Protein associated with extreme longevity. Here, we test this finding in a longitudinal study of nonagenarians in an association study. Participants in the Danish 1905 cohort study (1651 participants aged 92–93 were genotyped for the two SNPs (rs2866164 and Q95H) in the Microsomal Transfer Protein gene reported to be associated with longevity. The 1905 Cohort has been followed for 6.5 years, during period 83% of the cohort has died. Furthermore, a group of 575 middle-aged Danish twins (mean

Previous studies have reported two SNPs and a haplotype marker within the Microsomal Transfer gene associated with extreme longevity. Here, we test this finding in a longitudinal study of and in an association study. Participants in the Danish 1905 cohort study (1651 participants aged years) were genotyped for the two SNPs (rs2866164 and Q95H) in the Microsomal Transfer Protein recently reported to be associated with longevity. The 1905 Cohort has been followed for 6.5 years, which period 83% of the cohort has died. Furthermore, a group of 575 middle-aged Danish twins age 53.7 years) were tested as a younger control group. The risk haplotype had no significant survival disadvantage (P-values: 0.56, 0.31 and 0.97 in the total population of nonagenarians, males and respectively) after 6.5 years of follow-up. The distributions of the suggested risk alleles (rs2866164-G Q95) and the resulting haplotypes are very similar and not statistically different between the two age cohorts. The frequency for rs2866164-G is in the middle-aged compared to the nonagenarians 25.4 and 23.6% in males and 23.0 and 26.1% in females. The frequency for the risk haplotype is in the compared to the nonagenarians 22.7 and 19.2% in males and 18.1 and 21.8% in females. In our longitudinal study of survival in the 10th decade of life and an association study in a genetically homogeneous population provided no support for an association between the Microsomal Transfer Protein gene and extreme longevity.

European Journal of Human Genetics (2005) 13, 1154–1158. published online 13 July 2005

Keywords: microsomal transfer protein; ageing; longevity

Introduction

reporting genes influencing human longevity including cytochrome P450 genes, mitochondrial DNA and genes involved in lipoprotein metabolism and coagulation.1 However, only the Apolipoprotein E gene has consistently been associated with age-related changes in frequency.2–4 Recent studies performed a genome-wide linkage scan in long-lived individuals and provided evidence for a locus for longevity at chromosome 4 near microsatellite marker D4S1564.5,6 Fine mapping of the region identified Micro- somal Triglyceride Transfer Protein (MTP) as the gene

Major efforts have been made for identifying genes involved in ageing. An increasing number of studies are

when they were

–

years and the study of Middle-Aged Danish twins (MADT), a random sample of twin pairs born between

and

(

DNA samples).

These studies comprised a home-based

-h multidimen- sional interview and the sampling of DNA by means of a finger prick or a cheek swab. All samples from the

cohort (

% males) were included and

samples (mean age

years, age range

–

years,

% F F males) only one from each twin pair were chosen from MADT.

responsible for the chromosome 4 linkage peak,7 although a confirmatory study in a French population did not confirm this observation.7 The two SNPs found to account for the majority of the variation at the locus were F rs2866164 a SNP in complete linkage disequilibrium with rs1800591 ((cid:2)493G/T), an MTP promoter mutation- F and MTP Q/HF a semiconservative mutation in exon 3 of MTP (glutamine to histidine at aminoacid 95).7 The rs2866164-G allele and the haplotype composed of rs2866164-G/MTP-Q95 were found to be significantly underrepresented in long-lived individuals compared to a group of younger controls.

when they were 92–93 years and the study of Middle-Aged Danish twins (MADT), a random sample of twin pairs born between 1931 and 1952 (4171 DNA samples).12 These studies comprised a home-based 2-h multidimen- sional interview and the sampling of DNA by means of a finger prick or a cheek swab. All samples from the 1905 cohort (28.2% males) were included and 575 samples (mean age 53.7 years, age range 45–67 years, 47.9% F F males) only one from each twin pair were chosen from MADT.

Genotyping

MTP is essential for the assembly of apolipoprotein B-containing lipoproteins by the liver and small intestine8 and lack of the protein leads to abetalipoproteinemia, a rare genetic disorder characterized as an inability to produce chylomicrons and very low-density lipoproteins. MTP is a good candidate for a gene involved in human longevity as its functions and critical position in lipo- protein assembly resembles Apolipoprotein E, the most extensively studied and consistently reproduced gene affecting human longevity.3,4 Lipid-lowering therapy is established as a proven intervention to reduce athero- sclerosis and its complications. MTP is an investigational target for a new generation of lipid-lowering drugs and has reached trials in animal models.9