Lack of association between human longevity and genetic polymorphisms in drug-metabolizing enzymes at the NAT2, GSTM1 and CYP2D6 loci

Received: 4 September 1997/Accepted: 13 December 1997

Abstract In the present study, the possible role of genetic polymorphism of three drug-metabolizing enzymes, debrisoquine/sparteine hydroxylase (CYP2D6), glu- m tathione S-transferase (GSTM1), and N-acetyltransferase (NAT2), as a putative genetic component of human longev- ity, was explored. A total of 817 DNA samples from a cen- tenarian and a control (20–70 years) population was sub- jected to PCR-coupled RFLP methods. Subjects were genotyped for the CYP2D6*3 (A deletion) and 2637 CYP2D6*4 (G A transition) alleles, for four mutations 1934 of NAT2 [namely, NAT2*5A (C T), NAT2*6A (G A), 481 590 NAT2*7A (G A), and NAT2*14A (G A)], and for the 857 191 presence or absence of GSTM1 gene deletion. No signifi- cant difference was found at these three loci between cen- tenarian and control subjects with respect to allelic variant frequencies, genotype distributions or predicted pheno- types deduced from genotype combinations. By comparing the distribution of combined genotypes for the polymor- phisms tested at the CYP2D6, NAT2, and GSTM1 loci, none of the predicted phenotypes concerning debrisoquine hydroxylase extensive-metabolizer or poor-metabolizer phenotypes, slow or fast N-acetylation capacities, and ac- tive or defective glutathione S-transferase, could be corre- lated with human longevity, alone or in combination.

ple who are living to very old age is considerably increas- ing. Attempts at estimating the upper limits to human lon- gevity have failed to reach any definite conclusion (for re- views see Olshansky et al. 1990; Rattan 1995). Neverthe- less, since 1992, the Chronos project at the Fondation Jean Dausset-CEPH collects DNA samples from French cente- narians whose age is systematically confirmed by a birth certificate.

terest in research on the molecular and biochemical basis of aging. This is not only due to the rapidly growing frac- tion of elderly people, but also to the realisation that such persons are prone to age-associated diseases such as car- diovascular and cerebrovascular diseases, senile dementia, renal failure, osteoarthritis and osteoporosis, muscular at- rophy, cataract, non-insulin-dependent diabetes (NIDDM), and cancer (Slagboom and Knook 1996). Centenarians are characterized by their capacity to have reached very old age, yet have escaped these major age-associated diseases, which may result from optimal life-style and environmen- tal conditions as well as from some genetically determined resistance against age-associated diseases and/or the aging process itself (Abbot et al. 1974; Schächter et al. 1993; Johnson 1997). While a genetic component for human lon- gevity has long been postulated, the only defined genetic associations reported so far were found at the HLA (Proust et al. 1982; Takata et al. 1987) and the APOE (Schächter et al. 1994) loci.

Introduction

the susceptibility of an individual to environmentally linked diseases. Most of the specific factors observed so far refer to the metabolism of xenobiotics, which is critical for both toxification and detoxification. This process in- volves products of three gene families: phase I cyto- chromes P-450 and phase II glutathione S-transferases (GSTs) and N-acetyltransferases (NATs) (for nomencla- ture see Mannervik et al. 1992; Vatsis et al. 1995; Daly et al. 1996). The presence of genetic polymorphisms in these genes plays a role, at least in part, in the large variation in expression of xenobiotic-metabolizing enzymes in the general population. Mutations in the wild-type gene do in-

Individuals who have attained the extreme limit of human life in good clinical condition (i.e., centenarians) provide the best example of successful aging. The fraction of peo-

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deed result in the synthesis of enzymes with impaired ac- tivity or no activity at all. Simple genotyping assays have allowed scientists firstly to establish reliable pheno- type/genotype correlations and secondly to estimate the association between these polymorphisms and susceptibil- ity to several diseases. Polymorphisms for human debrisoquine/sparteine hydroxylase (CYP2D6), N- acetyltransferase (NAT2), and glutathione S-transferase M1 (GSTM1) are well documented in this context (for re- views see Daly et al. 1994; Hirvonen 1995).

GSTM1–5 (Pearson et al. 1993). GSTM1 has three alleles: GSTM1*A, GSTM1*B, and GSTM*0. The null allele, GSTM1*0, is a gene deletion, and persons having it in a homozygous state have no protein product or mRNA (Seidegard et al. 1988). The GSTM1 gene is lacking in about 50% of the Caucasian population, placing these in- dividuals at a greater risk for developping lung (Ketterer et al. 1992), bladder (Daly et al. 1993), skin (Heagerty et al. 1994) or colon (Zhong et al. 1993b) cancers. However, some contradictory results also exist, particulary concern- ing the lung cancer risk (Brockmöller et al. 1993). Thus, the involvement of genetically determined variations of GSTM1 in cancer susceptibility remains unclear.

hydroxylase