HIV-1 infected Caucasian men have an increased prevalence of lipoatrophy 56
; therefore the European American men on HAART in the MACS represent a high-risk group. We successfully genotyped 536 patients who self identified as “white” and had a Western European, or “N”, mitochondrial macro-haplogroup. Individuals who had L or M macro-haplogroups (found in Africa and East Asia) were excluded from the study, and those within the N haplogroup were further parsed into N haplogroups H, T, IWX, J, T, V, and U. A complete clinical data set for all variables used in the final analyses of lipoatrophy and mitochondrial haplogroup association was available from 410 of these patients.
Clinical characteristics of study participants are shown in . Age at HAART initiation, BMI at the time of lipoatrophy assessment, and cumulative AZT and d4T exposure were all significantly associated with an increased incidence of lipoatrophy, consistent with previous studies33
(). Age was only strongly significant in for atrophy in the legs according to our models, but because of its known importance in previous studies, we included it in all models. We also evaluated whether tenofovir, which has been reported to cause lipodystrophy in a small percentage of patients 57
, or nelfinavir were associated with lipoatrophy, but found no associations between their use and lipoatrophy in the MACS.
Basic characteristics of European American patients in the MACS cohort in this study. Clinical visits for each patient were approximately 6 months apart.
Odds ratios (OR), 95% confidence interval, p-values (p), and population frequency for covariates included in the mtDNA haplogroup models for severity of lipoatrophy in three anatomical sites.
Mitochondrial haplogroup H was strongly associated with significant increases in extremity lipoatrophy (arms: p = 0.007, OR = 1.77, 95% CI = 1.17–2.69; legs: p = 0.03, OR = 1.54, 95% CI = 1.03–2.31) (). We also observed a trend for increased lipoatrophy in the closely related V haplogroup (p = 0.07 OR = 2.59, 95% CI = 0.93–7.26). The phylogenetic tree of the major haplogroups is shown in . In contrast, weak significance suggesting a protective effect against lipoatrophy were observed with haplogroup T (p = 0.05). No significant associations were observed for haplogroup J, which is closely related to T, however, odds ratios were consistently protective.
Odds ratios (OR), 95% confidence interval, p-values (p), and population frequency for major European mtDNA haplogroups with severity of lipoatrophy in three anatomical sites.
Because BMI is a confounding variable during atrophy assessment but is also biologically related to atrophy, we repeated the analysis without BMI as a covariate in the model. Results were generally the same but with slightly weaker associations observed. The association between haplogroup H and increased arm atrophy remained significant (p = 0.021, OR = 1.60, 95% CI = 1.07–2.38), but associations with buttock and leg lipoatrophy became non-significant (p-values of 0.15 and 0.08 respectively). The association between haplogroup T and buttock lipoatrophy diminished to borderline significance (p = 0.07). All other results were non-significant.
Haplogroup H is composed of 6 distinct subhaplogroups (H1-H6) which are separated by SNPs 3010 G>A in 16S rRNA (non-coding), 1438 A > G in the 12S gene (consensus), 6776 C > T in the Cytochrome Oxidase I (synonymous), 4024G > A in ND1 (T240A), 4336 C > T in TQ (tRNA), and 3915 A > G in NDI (synonymous) as shown in . The haplogroups defined by 3010, 4336, and the H* (the remaining unclassified H mtDNA) haplogroup demonstrated significant associations with lipoatrophy in the same direction as the H haplogroup. The other haplogroups occurred infrequently (< 4%) in our sample; therefore any lack of association may simply be a consequence of their low prevalence and lack of power (for genotypes with frequency ~4%, power is only 13% for a OR=1.5 at α=0.05).
Lipoatrophy and lipo-accumulation may arise via different mechanisms because they represent extremes in metabolism and are often independent 22
. In our patients, the presence lipo-accumulation in the back of the neck, known as a dorsocervical fat pad or “buffalo hump”, was correlated with lipoatrophy with a Pearson correlation coefficient of 0.2 (p < 0.0001). We saw a trend for T to be protective against the presence buffalo hump (p = 0.06, OR = 0.30, 95% CI = 0.09–1.04), but no other statistically significant associations were observed.