255119rs881980a °5aa=Q244ES166N1128T098EQ95H-164-388-468-416  -5638g           6TISSzzs4es86TSss.0262!aeNOSTS g§é    

no evidence for an association between MTTP gene hap- lotype, carrier status, and longevity. The original observa- tion has also been challenged by Bathum and colleagues in a study of 1651 92- to 93-year-old persons (13). They studied the effect of two of the original SNPs used by Geesaman and colleagues (5) but failed to find a difference in gene frequency compared with a smaller (n ¼ 575) and younger (average age 53 years) control cohort. The present study reports no difference in haplotype frequencies for the MTTP gene between younger and older populations; this finding is consistent with the findings of the German case– control study. Nebel and colleagues pointed out that there may have been some evidence of bias in the North American younger control group, which is likely to have caused the positive identification of the MTTP gene in that study. We agree with the reasoning that the SNP allele frequency of the most crucial of the polymorphisms in the study of Geesaman and colleagues appears to be unbalanced. The MTTP-5038C/G (MTTP_rs2866164), MTTP-493G/T (MTTP_rs1800591), MTP-164C/T (MTTP_rs1800804), and MTTP I128T (MTP_rs3816873) are all in complete LD, are located on the same haplotype within the populations studied so far, and can therefore be compared with previously published studies. There is a surprisingly close range in distribution for the less common variant (0.25–0.29) within Caucasian populations: healthy 50-year-old Swedish men (0.25) (14), Irish diabetic persons (0.25) (15), Norwegian persons with familial hypercholesterolemia (0.26) (16), moderately hypercholesterolemic Scottish men (0.26) and Scottish men with cardiovascular disease (0.26) (7), and Framingham men (0.29) and women (0.26) (17). This is in contrast to the results in the control population reported by Geesaman and colleagues which show a frequency of 0.34 (5).

Figure 1. Linkage disequilibrium between the single nucleotides (SNPs) in the microsomal triglyceride transfer protein (MTTP) gene typed to estimate the haplotype frequencies in the old population and the control population. [Linkage disequilibrium statistics and graphical output were created by the program JLIN: A Java based Linkage Disequilibrium Plotter (http://www.genepi.com.au/ projects/jlin/).]

using the chosen SNPs against those within the HapMapII database, it is concluded that, of the 14 SNPs genotyped in the younger population, 7 were identifiable within HapMapII (MTTP-1428, MTTP-164, MTTP D98E, MTTP I128T, MTTP S166N, MTTP H297Q, and MTTP_rs881980). Of these seven SNPs, there were two pairs in complete LD

The SNPs used in this study were identified primarily from previous publications in which MTTP haplotypes have been studied, not from data within the HapMapII Project. Comparing the haplotype coverage across the MTTP region

Table 2. Haplotypes Across the MTTP Gene and Haplotype Frequencies in Older People and Controls

(cid:1)5038 (cid:1)1428 (cid:1)410 (cid:1)400 (cid:1)388 (cid:1)164 Q95H D98E I128T S166N Q244E H297Q rs881980 rs2255119 Alleles Alleles Haplotype C/G G/A G/A T/A G/A C/T (C/G) (C/G) (C/T) (G/A) (C/G) (C/G) (C/A) (C/T) (Count) Fq (Count) Fq 1 C G G T G C C C C G C C C C 803 0.517 1512 0.519 3 C G G T G C C C C G C G A C 212 0.136 345 0.118 2 G A G A G T C C T G C C C T 167 0.107 285 0.098 7 G A G A A T G C T G C G C C 87 0.056 184 0.063 4 G A G A A T C C T G C G C C 78 0.050 179 0.061 5.1 C A G A A C C G C A C G C C 63 0.041 136 0.047 5.2 C A A A A C C C C G C G C C 56 0.036 130 0.045 6 G A G A A T C C T G G G C C 48 0.031 120 0.041 SNP minor allele fq Control 0.24 0.33 0.04 0.33 0.06 n/a 0.06 0.04 0.25 0.04 0.04 0.36 0.14 0.11 Old people n/a 0.36 0.04 0.36 0.06 n/a 0.07 0.05 0.27 n/a 0.04 0.38 0.12 0.10

Notes: Most of the genotype loci have rs numbers, which are as follows: (cid:1)5038C/G (rs2866164), (cid:1)1428G/A (rs3811800), (cid:1)410G/A (rs6532821), D98E (rs2306986), I128T (rs3816873), S166N (rs37926683), and H297Q (rs2306985). Counts are derived from the PHASE program and thus represent posterior probabilities rather than observed counts. MTTP¼Microsomal triglyceride transfer protein; SNP¼single-nucleotide polymorphism; n/a¼not analyzed (analysis was not done because it was known that the SNP was in complete linkage disequilibrium with another SNP that was typed).

MTTP¼Microsomal triglyceride transfer protein; SNP¼single-nucleotide polymorphism; n/a¼not analyzed (analysis was not done because it was known that the SNP was in complete linkage disequilibrium with another SNP that was typed).

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