Table 2 shows HLA-DRB1 allele frequencies among controls and long-lived groups. When two or more nonagenarians of the same sex were genotyped in a family, all genotypes were taken into account and weighed so that in every case two alleles per family were counted.

Table 3 shows homozygosity in control and longevous groups. Homozygotes are given for two control groups for which individual genotypes were available. Adult populations are in Hardy-Weinberg equilibrium. The slight departure from Hardy-Weinberg equilibrium in centenarians does not reach statistical significance. However, the rate of homozygosity is significantly higher in centenarians than in controls (P < 0.01 for this one comparison).

HLA-DR homozygotes were more frequent in centenarians than in controls (16.3% versus 11.1%, P < 0.01) both in males (18.2%) and females (15.8%), as shown in Table 3. The proportion of homozygotes in centenarians was also slightly, but not significantly, higher than the proportion expected from allele frequencies under Hardy-Weinberg equilibrium. Both observations suggested a survival advantage of homozygotes in individual centenarians. The proportion of homozygotes was not higher in the SIB groups (11.3% and 11.7% in men and women SIB, respectively), nor was it higher in the SIB-centenarians (10.7%).

In order to estimate the statistical significance of the allelic associations, taking into account putative interactions between gender and specific alleles in the effect on survival, we applied a model of logistic regression. Computations were done for each allele, comparing controls with either VIE or SIB groups. Allele frequencies were assumed to be identical in male or female adult controls.

Table 4 shows sex-genotype interaction and odds ratios for associated alleles. Results are presented for the seven most common alleles, including the only three comparisons out of 13 that reached statistical significance, namely for alleles DR7, DR11 and DR13.

One year after obtaining the above data, our collection of centenarians had grown and we decided to evaluate the previously identified associations in a new cohort. Therefore, 208 more centenarians were genotyped, 185 women and 23 men. The allelic distributions were again significantly different between controls and this second cohort of centenarians (P < 0.05, c2 = 22 for df = 12), whereas the distributions were similar in the two cohorts of centenarians. The male-specific increase in DR7 was observed (23.9%) and almost reached significance, despite the small number of male centenarians. The increase in DR13 was too (17.8%, P < 0.05 for the allele-specific comparison controls and this new cohort). Since the previously distribution pattern in centenarians was conserved, we entitled to merge the two cohorts into one population - 533 centenarians, 89 men, and 444 women. Table 5 shows the overall allele frequencies. The logistic regression applied to these data provides a better estimate of ORs for the interaction with sex was now detected as for DR7, with an OR of 1.72 (95% CI: 1.19-2.5, P = 0.004) for male centenarians. DR13 displayed no sex but(0.81-6, P = 0.5). DR4 was not assessed. The odds ratios (OR) and their corresponding confidence intervals (CI) were calculated for DR4 (0.98, 0.78-1.26, P = 0.93), DR7 (1.52, 0.92-2.5, P = 0.1), DR11 (0.56, 0.27-1.18, P = 0.13), DR13 (1.0, 0.61-1.7, P = 0.99), and DR15 (1.14, 0.59-2.2, P = 0.7). For DR4, the assessment was not carried out due to reasons unspecified in the text.
Table 5 shows the HLA-DRB1 allele frequencies and homozygotes in controls and pooled centenarians of both sexes. Homozygotes were found to be significantly more frequent in centenarians of both genders than in controls and exceeded the proportion expected under the assumption of Hardy Weinberg equilibrium.
The study aimed to assess the contributions of individual alleles to longevity and their putative interaction with sex in this contribution using a log-linear model that compared either centenarians or nonagenarian siblings with adult controls for each allele. The allele-specific effects reached statistical significance for three alleles: DR7, DR11, and DR13.
DR7 emerged as a risk factor for CMV infection, chronic HBV infection, chronic B-cell lymphocytosis in French women, celiac disease in three independent populations from Spain, France and Ireland, Crohn's disease in a population from Germany and long-QT syndrome characterized by syncope and fatal ventricular arrhythmias; while it has proven protective against gold salt toxicity in rheumatoid arthritis treatment and disease progression in psoriatic arthritis.
In conclusion, the study presents evidence of a direct role of HLA-DR alleles in differential susceptibility to a vast array of pathologies. The penetrance of HLA-DR genotypes in disease phenotypes is commonly found to depend on sex. The authors suggest that the existence of a homozygous advantage at the HLA-DR locus, at least very late in life, warrants further investigation.versus 15.6%) DR11 increased in females (12% versus 22%) DR11 not significantly different in males (14.3% versus 15.6%)

In males, the class III region gradually disappears with age. We are not aware of any published data that mentions increased heterozygosity at the HLA-DR locus in association with aging. On the contrary, Takata et al. noted an increase of HLA-DR homozygotes in their centenarians (15). They remarked that a bias for homozygosity may stem from imperfect matching between centenarians and controls, the former coming from a more rural background and less admixed population. However, we note that the rate of homozygosity was not increased in the nonagenarian SIB group, for which the same argument would apply.